Category Archives: Gene therapy

Patil S. R. et al.

364

ery. Several gene therapy protocols for AIDS have been approved.

Elimination of virus from an infected person is an unlikely eventu-

ality, therefore the aims must be to maintain the virus in its latent period

as long as possible and to protect uninfected cells from viral infection

and perhaps to enhance the immune response against virus. These meth-

odologies are particularly amenable to a gene therapy approach and it

seems likely that in future the combination therapy including both phar-

nmacological agents and gene therapy agents, will be used in concert to

minimize this spread of the HIV with in an infected individual and thus

prolong their disease free life.A gene therapy based vaccine is also a

serious possibility.

8) Cancer26)

Several approaches to cancer therapy are being explored

1) Immune responses to tumors are being enhanced

2) Genes are being inserted into tumor cells to evoke cell suicide

3) Finally methods are being developed to modify tumor suppressor

or anti-oncogenes.

The primary target for stimulating an immune response to a tumor is

major histocompatability complex(MHC) class1-restricted tumor specif-

ic cytotoxic (CD8) T cell.

Two criteria must be met

1) The CD8 T cell receptors must be occupied by an MHC class 1

peptide complex

2) A helper T cell must be activated to secrete cytokines, which acts

on CD 8 T cell.

This second signal could be bypassed by inducing CD 8 cell to pro-

duce their own cytokines.

Cell suicide involves insertion of Herpes simples virus thymidine

kinase (HSV-TK) gene. Tumar suppressor genes are being inserted into

human tumors. One protocol involves inserting a normal p53 gene inot

non-small cell lung carcinomas that are p53 defective.

In another, antisense DNA is injected to try to suppress the activity

of activated oncogenes, in this case k-ras in lung carcinoma.

9) Gene Therapy and Viral Vaccination27)

Live viral vaccines have had a major impact on the incedence of

acute viral infections world-wide. Virus infections recognize as future

vaccine targets will require a modified approach based on the detailed

understanding of the immunobiology of specific infections combined

with the application of the new technologies designed to generate spe-

cific and appropriate protective immunity. A similar vector technology

directed at in vivo gene delivery is currently being exploited both gene

therapy and vaccination. The induction of an immune response to an

expressed transgene represents potential hazards for a gene therapy pro-

tocol but is the object of a vaccine strategy. In Vivo gene delivery using

replication-competent or replication-deficient viral vector systems and

by direct transfer of naked DNA can generate an effective humoral, sec-

retary and cell mediated immune response to expressed transgenes.

10) Also Gene therapy is a serious consideration in many

diseases caused by Virus, Bacteria and other microorgan-

isms.

FUTURE OF GENE THERAPY

To cure genetic diseases, scientists must first determine which gene

or set of genes causes each disease. The Human Genome Project and

other international efforts have recently completed the initial work of

sequencing and mapping virtually all of the 30,000 genes in the human

cell. This research will provide new strategies to diagnose, treat, cure,

and possibly prevent human diseases17).

Although this information will help scientists determine the genetic

basis of many diseases, it will be a long time before diseases actually

can be treated through gene therapy. "The Human Genome Project is

just a start," Nicholson says. "It's going to locate genes for us, but it's

not going to tell us what these genes do. That will be the next step. Once

we have that information, we'll be able to take advantage of that knowl-

edge to provide treatment and/or cures28)."

Gene therapy's potential to revolutionize medicine in the future is

exciting, and its expectations for curing and preventing childhood dis-

eases are encouraging. One day it may be possible to treat an unborn

child in utero for a genetic disease even before it comes in to this

world29).

Scientists are hoping, the mapping of the human genome will lead

the way toward cures for many diseases and that the successes of cur-

rent clinical trials will create new opportunities and challenges. For

now, however, it's a wait-and-see situation, calling for cautious opti-

mism.

REFERENCES

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inducing transformation of pneumococcal types. Induction of transformation by a

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1944;79:137-158.

2) Pearson H (May 2006). "Genetics: what is a gene?". Nature. 441 (7092): 398-401.

3) Gericke, Niklas Markus; Hagberg, Mariana (5 December 2006). "Definition of histori-

cal models of gene function and their relation to students' understanding of genetics".

Science & Education. 16 (7-8): 849-881.

4) Kaufmann KB, B ing H, Galy A, Schambach A, Grez M. Gene therapy on the move.

EMBO Mol Med. 2013 Nov; 5(11): 1642-1661.

5) Wang D, Gao G. State-of-the-art human gene therapy: part ii. gene therapy strategies

and applications. Discov Med. 2014 Sep; 18(98): 151-161.

6) Moss JA. Gene therapy review. Radiol Technol. 2014 Nov-Dec;86(2):155-80; quiz 181-

4.

7) Mali S. Delivery systems for gene therapy. Indian J Hum Genet. 2013 Jan-Mar; 19(1):

3-8.

8) Gardlk R, Plffy R, Hodosy J, Lukcs J, Turna J, Celec P. Vectors and delivery systems

in gene therapy. Med Sci Monit. 2005;11:RA110-21.

9) Robbins PD, Ghivizzani SC. Viral vectors for gene therapy.Pharmacol Ther. 1998

Oct;80(1):35-47.

10 ) Nayerossadat N, Maedeh T, Ali PA. Viral and nonviral delivery systems for gene deliv-

ery. Adv Biomed Res. 2012; 1: 27.

11) Miller N, Vile R. Targeted vectors for gene therapy. FASEB J. 1995 Feb;9(2):190-9.

Read this article:
(PDF) Gene therapy: A comprehensive review

Update: On Aug. 20, Audentes announced that a third patient in the AT132 clinical trial has died.

Gene therapy has emerged rapidly in recent years because the field overcame safety concerns most notably, the tragic death of teenager Jesse Gelsinger in a clinical trial in 1999 that cooled initial optimism and slowed research.

Newer methods to deliver genetic medicine have been proven out in clinical testing and two therapies are now approved in the U.S., both for rare inherited diseases. Others, for diseases like hemophilia and Duchenne muscular dystrophy, could soon follow.

So far, this current wave of therapies have generally appeared safe. Encouraged, developers have tested higher and higher doses of gene therapies, aiming to expand their potential effectiveness. Higher doses are particularly important for neuromuscular diseases, since the treatment must travel through the bloodstream to reach the right tissue.

Two years ago, gene therapy pioneer Jim Wilson who led the Gelsinger trial at the University of Pennsylvania two decades ago expressed concern about the strategy, fearing that pushing doses too high might lead to safety problems. Wilson and UPenn colleagues published a paper in the journal Human Gene Therapy noting liver and nerve damage in animal experiments with a certain type of gene therapy, and called for researchers to do more monitoring.

While other gene therapy studies have been stopped in recent years, the deaths observed in Audentes' trial are particularly worrisome.

Audentes' therapy has shown promise in early tests, enough for Astellas to pay $3 billion for the company in December. The pivotal study of AT132 began in 2017 and Audentes aimed to submit an application with the Food and Drug Administration this year.

According to a letter Audentes sent to patient groups, however, that will no longer happen.

On May 6, Audentes told the groups that a patient treated with a high dose of AT132 had died from sepsis. Two others also given the high dose had then experienced serious side effects.

Six weeks later, on June 23, Audentes CEO Natalie Holles and chief medical officer Edward Conner sent a second letter explaining that one of those two had also died. That patient experienced progressive liver dysfunction, which didn't respond to standard treatment. His condition worsened and he ultimately died from a bacterial infection and sepsis.

"There have been some incredible outcome measures with some of the children but the science needs to continue to evolve," said Alison Rockett Frase, president of the Joshua Frase Foundation, one of the patient groups Audentes wrote. "Our community is devastated by the loss of these two children," she added in an interview.

On Aug. 20,Audentes reported that a third patient, also treated with a high dose of the gene therapy,had died from gastrointestinal bleeding.

Audentes is still collecting information, monitoring all of the study's other patients and is in touch with regulators. A total of 17 patients have been treated with the high dose of AT132 300 trillion vector genomes per kilogram of body weight.

"We are taking all necessary steps to understand these events and incorporate what we learn into our development plan going forward," Holles and Conner wrote in their letter. "We are currently assessing the impact on potential regulatory filing timelines, however we will not be filing in mid-2020 as previously communicated."

They added, however, that none of these issues have been seen in the six patients treated with a lower dose, and all of those patients are "years out from treatment." Four of those patients had a history of liver or biliary system problems.

All three of the patients who died also had evidence of pre-existing liver problems and showed signs of liver dysfunction within a month of treatment with AT132, Audentes said.All three patients with liver problems were of older age and heavier weight.

None of those treated with a high dose currently have the type of liver dysfunction seen in the patients who died, Audentes said.

Audentes uses a type of adeno-associated virus, called AAV8, to deliver its gene therapy. Other companies, including Ultragenyx, RegenxBio and Biogen are developing gene therapies that also rely on AAV8.

The high dose Audentes uses is among the largest being tested in gene therapy.

Ned Pagliarulo contributed reporting.

The rest is here:
Third patient dies in halted study of Audentes gene therapy

I had been debating whether to write about something other than COVID-19 this week, given how thoroughly the pandemic has come to dominate the blog (at least my contributions), to the point where it seems that I write about little else. On the other hand, theres a topic thats been bugging me, a niggling annoying bit of antivaccine disinformation that I keep seeing as it pops up hither, thither, and yon in antivaccine social media and on antivax websites and blogs, to the point where I finally feel as though I have to break down and address it. Such is life.

What Im referring to is the claim that Ive been seeing that the existing COVID-19 vaccines developed by Moderna and by Pfizer/BioNTech and currently being distributed under an emergency use authorization (EUA) by the FDA are not, in fact, really vaccines at all. Why? Because they are not traditional vaccines based on killed organism, proteins, or weakened versions of pathogenic viruses, but mRNA-based vaccines. This claim tends to take on one of two flavors. The first is that mRNA vaccines are not vaccines but rather medical devices. This one is the easiest one to dispose of which is why I will deal with it first. The second is that mRNA vaccines are not vaccines at all, but rather gene therapy, which sounds more plausible if you dont know molecular biology but is also very much incorrect. According to antivaxxers, the consequences of mRNA vaccines being gene therapy are horrible complications, specifically that they will prematurely kill large amounts of the population and disable exponentially more.

I first came across the claim that mRNA-based COVID-19 vaccines are not really vaccines at all from a very familiar antivaccine propaganda blog that Ive followed as part of my effort to stay on top of all the latest antivaccine talking points since its very inception, Age of Autism. It comes courtesy of an antivaccine quack named Dr. Ken Stoller and was posted a couple of weeks ago to the AoA website under the title, Pfizer, Moderna et al Covid Products are Medical Devices Not Vaccines.

Who is Ken Stoller? Although I couldnt find any instance of our having written about him here, I knew who he was and did find other mentions of him. Lets just say that hes been antivaccine for a long time, with the first time I remember ever having encountered him being in 2006. Sadly, he is a pediatrician (and regular readers know how much contempt I have for antivaccine pediatricians like Dr. Bob Sears and Dr. Paul Thomas). He even has his own Whale.to entry! (If you dont know what that means, lets just say that only the mostout therecranks get the honor of their own Whale.to entry.) Dr. Stoller also got a mention when he was investigated by the San Francisco attorneys office for issuing medical exemptions based on conditions not scientifically supported as valid reasons for a medical exemption to school vaccine mandates, because, well, in the age of SB 277, the California law passed in 2015 to eliminate personal belief exemptions and other nonmedical exemptions to school vaccine mandates, antivax grifters gonna grift. Basically, although Dr. Stoller didnt reach the heights of antivaccine exemption grift that, say, Dr. Tara Zandvliet did (she wrote one-third of all the medical exemptions in the entire San Diego Unified School District!), but he did write a lot of dubious exemptions. Apparently his legal case is still going on, as his lawyer Rick Jaffe (who, I note, was Stanislaw Burzynskis lawyer) is still soliciting funds for his legal defense, while the antivaccine doctors group Physicians for Informed Consent has been supporting him.

Basically, Dr. Stoller is into all manner of autism quackery and pseudoscience, be it vaccines as a cause of autism, hyperbaric oxygen to treat autism (Dr. Stoller loves hyperbaric oxygen treatments, or HBOT), chelation therapy, and many others. And conspiracy theories. Naturally, he believes that They are keeping you from learning about the evidence that vaccines cause autism and that his quackery works to reverse it.

Unfortunately (or maybe fortunately), Dr. Stollers claims regarding COVID-19 mRNA vaccines are rather ridiculous even on the surface:

You are not antivax if you are against the COVID-19 injections

You are not anti-vax because the COIVD injections are not vaccines.

Yes, they are being called vaccines, but this is to bypass the regulatory requirements for a medical device.

This vaccine is actually a medical device that has never been used in humans before and rushed to market without any appreciation for what it will do either in the short term or long term.

This injection is also being called a vaccine to gain more acceptance, because most people assume that all vaccines are safe and effective. Thats what the CDC tells us. So if it is a vaccine, it must be safe and effective for ending the pandemic.

Im sorry, but Dr. Stollers claim is just plain silly. You dont get to redefine terms to suit your narrative, try as you might. Ill explain why hes so off-base in a minute. First, I need to let him let out sufficient rope to hang himselfor at least to hang his argument, although I cant help but note that he makes the claim that the short term adverse event rate is 80%. I dont know where he got that number for the overall adverse event rate, but Modernas reported data, for example, would seem tocontradictthat number.

Actually, its very clear where Dr. Stoller got that number. He looked at reports of local reaction and pain at the injection site andwell, duh!over 80% of people reported pain or swelling at the injection site. True, thats an adverse event, but its an adverse event that nearly all vaccines produce. Minor pain and swelling at the injection site are to be expected and are considered minor adverse events. In fact, the rate of significant or non-minor adverse events has been very low for both vaccines. None of that stops Stoller from asking disingenuously, But if the short-term adverse event rate is 80 percent, what is in store for the long term? Oh, I dont know. Maybe that all those sore shoulders will get better over several days.

Lets dive into the core (if you can call it that) of Stollers claim, which, as many antivaxxers cant resist, he cant help but preface by comparing COVID-19 vaccination to the Tuskegee syphilis experiment, but only a billion-fold worse:

While this is an over simplification, a vaccine, as defined by the CDC & FDA, is procedure that introduces into the body a foreign protein or weakened virus or bacteria and activates the immune system to make antibodies to same. In theory, to be effective, those antibodies actually have to perform in a useful manner.

If it works as advertised, a vaccine gets in your body and programs itself to attack the infection should it cross your path. It has to stimulate both immunity and disrupt transmission by definition, but the COVID-19 injection does not encourage your body to program your immune system. Instead, it is the program.

This mRNA injection bypasses that step and takes over the programming of our cells to make proteins it wants to make, which presumably will stop, prevent or modulate the infection in question in this case the COVID-19 virus.

This is, of course, utter nonsense. Yes, in general vaccines can use either protein (or protein fragments) from a pathogenic organism, be it a virus, bacteria, or other organism that provoke an immune response that can protect against the whole organism when the body encounters it. Such proteins or protein fragments that can provoke a specific immune response are known as antigens. (The acellular pertussis vaccine is a good example of this form of vaccine.) One other major form of traditional vaccines against viruses (a live-attenuated vaccine) uses a weakened form of the pathogenic virus that can infect your cells but cannot cause the disease that the full-strength natural (or wild type) form of the virus can. The measles vaccine is a good example of this latter form.

Heres how the CDC actually does define a vaccine, a definition that is easily found on the CDC website under Immunization: The Basics:

Vaccine: A product that stimulates a persons immune system to produce immunity to a specific disease, protecting the person from that disease. Vaccines are usually administered through needle injections, but can also be administered by mouth or sprayed into the nose.

Vaccination: The act of introducing a vaccine into the body to produce immunity to a specific disease.

Immunization: A process by which a person becomes protected against a disease through vaccination. This term is often used interchangeably with vaccination or inoculation.

And heres the FDAs definition of a vaccine:

Vaccines work by mimicking the infectious bacteria or viruses that cause disease. Vaccination stimulates the bodys immune system to build up defenses against the infectious bacteria or virus (organism) without causing the disease. The parts of the infectious organism that the immune system recognizes are foreign to the body and are called antigens. Vaccination exposes the body to these antigens.

Some vaccines contain weakened versions of a bacteria or virus, other vaccines contain only part of the bacteria or virus. Some vaccines contain only the genetic material for a specific protein and direct the body to produce a small amount of that protein. The bodys immune system reacts defensively once it detects this protein.

After vaccination, the immune system is prepared to respond quickly and forcefully when the body encounters the real disease-causing organism.

See what I mean? The definition of vaccine, be it the FDAs or the CDCs definition, does not require that the compound injected be a protein or a weakened virus. The definition is far more general than that, and under the definition above the Moderna and Pfizer/BioNTech mRNA vaccines are without a doubt, well, vaccines, as they do exactly what the CDC definition of vaccine states: They are products that stimulate a persons immune system to produce immunity to a specific disease, protecting the person from that disease. The fact that they do it using a method other than simply injecting protein isolated from the pathogenic microorganism or injecting or giving by mouth a weakened form of the pathogenic microorganism is completely irrelevant. That the Moderna and Pfizer/BioNTech vaccines use mRNA wrapped in lipid nanoparticles to introduce mRNA coding for a the SARS-CoV-2 spike protein in order to induce a persons own cells to make that protein and thereby stimulate the immune system to react against it does not make it any less of a vaccine than an old-fashioned vaccine like the whole-cell pertussis vaccine, which basically used killed whole bacteria.

To be honest, I feel kind of silly even having to explain this here on SBM, but I keep seeing this talking point, whether it comes from Dr. Stoller or is a variant of the same talking point showing up elsewhere in the antivaccine griftosophere. Worse, Dr. Stoller seems very confused. In brief, he cant seem to make up his mind whether the current mRNA COVID-19 vaccines are a medical device or a gene therapy (or even just a treatment, rather than a vaccine). Ill use his confusion as an introduction to the next section and an explanation of why the gene therapy trope is just that, a trope, as I pivot to an article by ber-quack natural health entrepreneur Dr. Joe Mercola entitled How COVID-19 Vaccines May Destroy the Lives of Millions. Before I do, though, I cant help but suggest that COVID-19 vaccines will destroy those lives by preventing people from catching a potentially deadly disease thats currently spreading like wildfire through a mostly immunologically-nave population.

I also cant help but address Dr. Stollers conclusion:

In truth this is a medical device, and it should undergo the safety evaluations any medical device needs to undergo.

Seriously, this is most definitely not what Dr. Stoller wants, and its clear that he has no clue about medical device regulation. Dr. Stoller is either unaware or lying about the longstanding problem that the approval process for medical devices is much more lax than it is for drugs, vaccines, and biologics. Indeed, this is such an issue that problems with the laxness in the standards for medical device approval have made the news rather frequently over the last few years. (Books have been written about this problem.) Thats because medical devices are regulated under a different law than drugs, vaccines, or biologics:

Devices are subject to weaker standards than drugs because theyre regulated under a different law. The Medical Device Amendments of 1976 was intended to encourage innovation while allowing for a range of review standards based on risk, according to legal expert Richard A. Merrill. An array of corporate lobbying has since prompted Congress to ease regulations and make it easier for devices to get the FDAs OK (heres one 2015 example).

Seriously, as conspiracy theories go, Dr. Stollers is even dumber than usual, particularly given how he seems to conflate gene therapy with biologics with medical devices.

Before I deal with Mercola, let me first conclude my discussion of Dr. Stollers rather clueless confusion. First, Dr. Stoller makes a simple, Well, duh! observation but frames it in such a manner as to make it seem terrifying if you dont know molecular biology:

This mRNA injection bypasses that step and takes over the programming of our cells to make proteins it wants to make, which presumably will stop, prevent or modulate the infection in question in this case the COVID-19 virus.

Yes, that is how mRNA vaccines worksort of. mRNA vaccines do introduce a specific mRNA coding for the desired protein antigen into the recipients muscle cells; that much is true. The mRNA then serves as a template for the cells ribosomes to make that protein; that much is also true. Ill also add here that there are other ways of achieving this same result, inducing the vaccine recipients own cells to make antigen. Putting the cDNA (the DNA with the gene for a protein) coding for the desired protein antigen in an adenovirus vector that cant replicate is another method. (Indeed, thats how the COVID-19 vaccine candidates from Johnson & Johnson and AstraZeneca work.)

Note, though, how Dr. Stoller, in his effort to portray mRNA vaccines as therapy (specifically a gene therapy), obfuscates by saying that the recombinant proteins made by the vaccines presumably will stop, prevent or modulate the infection in question. First, theres no presumably about it; the mRNA vaccines work. Second, the goal is to prevent severe disease from the infection by provoking an immune response and providing immune memory, so that the immune system, when encountering SARS-CoV-2 again, will be able to rapidly ramp up a response to shut the virus down before it can cause disease. Thats how all vaccines designed to prevent viral diseases work! Theres nothing special about the COVID-19 vaccines in that aspect, Dr. Stollers risibly feverish effort to suggest otherwise notwithstanding. Note further how he tries to redefine prevention as treatment:

In actuality, all the COVID-19 injection does is provide a treatment to supposedly modulate the severity of the COVID-19 illness should you get it and become symptomatic.

In other words, it is a treatment a genetic treatment that has never been used in humans before.

And if it is only a treatment that neither prevents infection nor transmission, in truth, it is no better than any of the other treatments floating around like Ivermection/Zinc/Vit D/HCQ/Vit C/ HBOT/ozone, etc.

Note the false equivalence. It is true that vaccines can be treatments. The rabies vaccine is a good example, as are various experimental vaccines against a variety of cancers. However, such vaccines are also preventatives. The rabies vaccine, when given before exposure to rabies, is prevention; when given after, it can be treatment designed to ramp up the immune system before the virus can take hold. Dr. Stoller is either ignorant of that distinction or cynically misrepresenting it because he knows that his antivax and COVID-19-denying followers dont understand or know about it. (Take your pick.) More amusing to me is how he compares it to a variety of quack or unproven treatments for COVID-19, in order to downplay it. Wait, what? Dont COVID-19 quacks think that all (or at least several) of the treatments disparaged by Dr. Stoller are very effective against COVID-19? Its also odd that he didnt mention dexamethasone, which is one treatment for COVID-19 that has been validated in randomized clinical trials, unlike the rest that he mentioned.

Or maybe not:

We do know that there are other treatments and if this were just called a treatment people would ask how it stacks up to the other available treatments.

I would argue it is not even a biologic because it is so clearly gene manipulation direct gene manipulation something that has never ever taken place before in the history of mankind.

The problem with Dr. Stollers claim is that the mRNA vaccines are indeed vaccines by any reasonable definition. But what about biologics? According to the FDA, biologics include a wide range of products such as vaccines, blood and blood components, allergenics, somatic cells, gene therapy, tissues, and recombinant therapeutic proteins. Under that definition, sure, the mRNA vaccines are considered biologics, but so what? That doesnt make them any less vaccines, as biologics can be vaccines; in fact, vaccines are, by definition, a form of biologic because they either contain biologic material (killed virus or bacteria, weakened virus, etc.) or, in the case of mRNA vaccines, recombinant nucleic acids designed to make protein. Dr. Stoller is again either ignorant or showing contempt for his reader. As for gene manipulation? Do I really have to get into that again? I guess I do, but Ill wait until I deal with one last aspect of Stollers little rant, namely how Dr. Stoller sees conspiracies everywhere:

Obviously the COVID-19 injection is the treatment the so-called experts want you to have because not only are they so invested in it for economic and political reasons, but because it allows them to exercise even more control over the population, which is what this has been all about anyway.

Im surprised he didnt mention microchips in the vaccine, 5G, and Bill Gates, but whatever. I commend him for his restraint.

Unfortunately, a much louder voice is amplifying the same conspiracy theory, namely Joe Mercola. To do that, he cites Judy Mikovits. Does anyone remember Judy Mikovits? She was all the rage in COVID-19 conspiracy circles in May (which in the course of the COVID-19 pandemic seems like ancient history now) with her plandemic conspiracy theory that claimed that the pandemic was planned. Thats not a great look, but Mikovits does have a PhD and used to be a scientist; so that makes it easy for Mercola to portray her as an expert when in fact she is a pseudoexpert:

The COVID-19 vaccine really isnt a vaccine in the medical definition of a vaccine. It does not improve your immune response to the infection, nor does not limit you from getting the infection. Its really an experimental gene therapy that could prematurely kill large amounts of the population and disable exponentially more.

Im just beside myself with anger over this synthetic gene therapy, this chemical poison, and what theyre doing worldwide, Mikovits says. Were already seeing deaths from this shot. Its illegal. It shouldnt be done. It should be stopped right now. It should have never been allowed to happen, yet we see it being forced on the most vulnerable populations.

Indeed, news and social media reports suggest recipients are starting to drop like flies. Many die of unknown causes within days, sometimes hours of getting the first or second shot.

I wont go into the bit about dropping like flies other than to point you to my previous discussions of how, when tens of millions of people are vaccinated in a short period of time, the law of large numbers dictates that there will deaths and bad things that happen to some of them unrelated to the vaccine by random chance alone and that the only way to tell if such events might be related to the vaccine include epidemiology to determine if there is an increase of such adverse reactions above the expected baseline and careful scientific investigation. Antivaxxers, of course, automatically assume that any death within a month of vaccination against COVID-19 must have been caused by the vaccine.

Mercola adds to the misinformation spread by Stoller by mischaracterizing the mRNA vaccines. First, he goes out of his way to portray them as artificial and unnatural:

The messenger RNA (mRNA) used in many COVID-19 vaccines are not natural. Theyre synthetic. Since naturally produced mRNA rapidly degrades, it must be complexed with lipids or polymers to prevent this from happening. COVID-19 vaccines use PEGylated lipid nanoparticles, and PEG is known to cause anaphylaxis. Lipid nanoparticles may also cause other problems.

And:

However, if they call their drugs vaccines, they can bypass the safety studies. All of a sudden, they expect us to believe that all of these safety issues have been resolved? Another problem is related to how long the mRNA remains stable in your system. Its encased in nanolipid to prevent it from degrading too rapidly, but what happens if the mRNA degrades too slowly, or not at all?

The idea behind mRNA vaccines is that by tricking your body into creating the SARS-CoV-2 spike protein, your immune system will produce antibodies in response. But what happens when you turn your body into a viral protein factory, thus keeping antibody production activated on a continual basis with no ability to shut down?

And:

So, just how long will the synthetic RNA in COVID-19 vaccines be maintained within your body, causing your cells to produce this aberrant protein? Mikovits believes it will escape degradation for months, years, maybe even for life in some cases.

No, no, no, no, no!

Lets start with the same talking point used by Stoller and parroted by Mercola, the claim that Moderna and Pfizer called their products vaccines in order to bypass safety studies? This is, quite simply, a lie. (Im assuming that Mercola is not so ignorant or stupid not to know that what he is saying is incorrect, but I suppose I do have to concede the possibility that Im giving him too much credit. Basically, hes either ignorant or a liar. Judge for yourself and take your pick.) It is, of course, true that neither vaccine has obtained full FDA approval yet, having been allowed by the FDA to be distributed under an EUA because of the emergency of the pandemic, but it is not true that either vaccine bypassed safety studies. I mean, seriously: There were over 70,000 subjects in the phase 3 studies of the two vaccines that led to their approval under an EUA, producing scads and scads of safety data. Post-EUA pharmacovigilance monitoring of these vaccines is unprecedented in its intensity.

But what about the synthetic mRNA? Yes, the mRNA in both vaccines is indeed chemically modified. The reasons are simple, as I discussed before in my usual ridiculous level of detail. First, RNA is unstable, as Mercola mentioned. In regular aqueous solution (in this case, water with some buffer and salt) RNA rapidly degrades at room temperature (or even in the refrigerator) and can degrade too quickly even at -20C. The second, and more important, reason is that mRNA has a short half-life in cells, normally on the order of hours or even minutes. (I used to measure mRNA half-life for the gene I cloned back in the 1990s, and it was regulated by stimuli that dramatically shortened or lengthened its half-life in the cell from four hours to around an hour hour.) Basically, the modification of the RNA in both vaccines is designed to make them more stable, but not infinitely stable, which is what Mikovits and Mercola are claiming. No biological molecule, modified or not, lasts forever, which is what the RNA would have to do to turn your body into a viral protein factory, thus keeping antibody production activated on a continual basis with no ability to shut down. Seriously, does Mercola know anything about molecular biology? Indeed, from Moderna, for example:

The delivered mRNA does not enter the cell nucleus or interact with the genome, is nonreplicating, and is expressed transiently. The estimated half-life for mRNA after injection is approximately 8 to 10 hours, before degradation by native RNases in the body, but the duration of effect also depends on the half-life of the expressed protein, which persists in the body for several days. mRNA vaccines have been used to induce immune responses against infectious pathogens such as cytomegalovirus (CMV), human metapneumovirus (hMPV) and parainfluenza virus type 3 (PIV3), Zika, and influenza virus.

Basically, with a half-life of ten hours, the mRNA will be completely gone within a few days and the protein completely gone after, at most, a few weeks. The Pfizer mRNA vaccine is similar. Again, does Mercola understand anything about basic molecular biology? Apparently not, or hes lying.

Meanwhile, Mikovits adds to the deceptive fear mongering claiming that the mRNA vaccines are permanent genetic alteration:

So, taking a synthetic messenger RNA and making it thermostable making it not break down [is problematic]. We have lots of enzymes (RNAses and DNAses) that degrade free RNA and DNA because, again, those are danger signals to your immune system. They literally drive inflammatory diseases.

Now youve got PEG, PEGylated and polyethylene glycol, and a lipid nanoparticle that will allow it to enter every cell of the body and change the regulation of our own genes with this synthetic RNA, part of which actually is the message for the gene syncytin

Syncytin is the endogenous gammaretrovirus envelope thats encoded in the human genome We know that if syncytin is expressed aberrantly in the body, for instance in the brain, which these lipid nanoparticles will go into, then youve got multiple sclerosis.

The expression of that gene alone enrages microglia, literally inflames and dysregulates the communication between the brain microglia, which are critical for clearing toxins and pathogens in the brain and the communication with astrocytes.

And:

Making matters worse, the synthetic mRNA also has an HIV envelope expressed in it, which can cause immune dysregulation. This is a nightmare, Mikovits says. Im angry, as this should never be allowed.

As we discussed in previous interviews, SARS-CoV-2 has been engineered in the lab with gain-of-function research that included introducing the HIV envelope into the spike protein.

Note that truly ignorant claim again about syncytin. I dealt with that one once before when I discussed why, contrary to antivaccine fear mongering, COVID-19 mRNA vaccines will not render women infertile. The Cliffs Notes version is that the mRNA for the SARS-CoV-2 spike protein used in these vaccines does not make a protein with amino acid sequences sufficiently similar to sequences in syncytin to provoke a crossreacting immune response to syncytin that could render women infertile or do any of the things claimed by Mikovits. Moreover, the claim that sequences from the gene encoding the HIV-1 envelope protein are in the COVID-19 spike protein is an antivax distortion. Basically, the amino acid sequences in the spike protein that antivaxxers call HIV-1 envelope sequences are in fact amino acid sequences so short that they are commonly found in many proteins, as I discussed a while back. mRNA vaccines making spike protein are not going to lead to immune dysregulation due HIV-1 envelope because it doesnt express HIV-1 envelope. One wonders how Mikovits ever managed to do science back in the day before she became a conspiracy theorist and crank.

Then, of course, because antivaxxers will always go for the toxins gambit, Mercola and Mikovits are so very, very concerned about the polyethylene glycol (PEG) in the lipid nanoparticles that envelope the mRNA used in the vaccines:

Another common side effect from the vaccine were seeing is allergic reactions, including anaphylactic shock. A likely culprit in this is PEG, which an estimated 70% of Americans are allergic to. These instantaneous effects are almost certainly the PEG and that lipid nano particle, the toxic particle thats being injected, Mikovits says.

In the longer term, she suspects well see a significant uptick in migraines, tics, Parkinsons disease, microvascular disorders, different cancers, including prostate cancer, severe pain syndromes like fibromyalgia and rheumatoid arthritis, bladder problems, kidney disease, psychosis, neurodegenerative diseases such as Lou Gehrigs disease (ALS) and sleep disorders, including narcolepsy. In young children, autism-like symptoms are likely to develop as well, she thinks.

Yes, although PEG hasnt been used in an approved vaccine before, it has for a long time been used in a number of products, including toothpastes, shampoos, and some drugs with a good safety record. Indeed, the claim above that 70% of Americans are allergic to PEG is utter BS on its surface because if that were true allergists would be swamped with a tsunami of patients with allergic reactions to a wide variety of common household products. It is true that PEG has come under suspicion as a possible cause of the small number of anaphylactic reactions observed after COVID-19 vaccination, as a recent report in Science notes:

Severe allergy-like reactions in at least eight people who received the COVID-19 vaccine produced by Pfizer and BioNTech over the past 2 weeks may be due to a compound in the packaging of the messenger RNA (mRNA) that forms the vaccines main ingredient, scientists say. A similar mRNA vaccine developed by Moderna, which was authorized for emergency use in the United States on Friday, also contains the compound, polyethylene glycol (PEG).

PEG has never been used before in an approved vaccine, but it is found in many drugs that have occasionally triggered anaphylaxisa potentially life-threatening reaction that can cause rashes, a plummeting blood pressure, shortness of breath, and a fast heartbeat. Some allergists and immunologists believe a small number of people previously exposed to PEG may have high levels of antibodies against PEG, putting them at risk of an anaphylactic reaction to the vaccine.

Others are skeptical of the link. Still, the U.S. National Institute of Allergy and Infectious Diseases (NIAID) was concerned enough to convene several meetings last week to discuss the allergic reactions with representatives of Pfizer and Moderna, independent scientists and physicians, and the Food and Drug Administration (FDA).

NIAID is also setting up a study in collaboration with FDA to analyze the response to the vaccine in people who have high levels of anti-PEG antibodies or have experienced severe allergic responses to drugs or vaccines before.

A report published ten days ago by the CDC notes:

During December 21, 2020January 10, 2021, monitoring by the Vaccine Adverse Event Reporting System detected 10 cases of anaphylaxis after administration of a reported 4,041,396 first doses of Moderna COVID-19 vaccine (2.5 cases per million doses administered). In nine cases, onset occurred within 15 minutes of vaccination. No anaphylaxis-related deaths were reported.

And two weeks before that the CDC reported:

During December 1423, 2020, monitoring by the Vaccine Adverse Event Reporting System detected 21 cases of anaphylaxis after administration of a reported 1,893,360 first doses of the Pfizer-BioNTech COVID-19 vaccine (11.1 cases per million doses); 71% of these occurred within 15 minutes of vaccination.

In other words, these reactions are rare, managed relatively easily, and not outside the range of what is normally observed after other, older vaccines. Moreover, the risk of anaphylaxis from the vaccine, which hasnt killed anyone, is certainly far, far smaller than the risk of death from COVID-19, which has already killed over 450,000 people or 130/100,000 people in the US in just one year and hospitalized millions, or 417/100,000 people since the beginning of the pandemic.

As for the central claim of Mercola and Mikovits that these vaccines are permanent genetic alterations that may last for life, I will refer you back to what I wrote long ago about that claim showing why the Moderna and Pfizer/BioNTech vaccines will not permanently alter your DNA. Again, anyone whos ever taken Molecular Biology 101 will understand why this is the case, but apparently Joe Mercola and Judy Mikovits either did not or are lying. Again, read their words and take your pick.

Nor are these vaccines gene therapy. According to the FDA:

Gene therapy is a technique that modifies a persons genes to treat or cure disease. Gene therapies can work by several mechanisms:

Gene therapy products are being studied to treat diseases including cancer, genetic diseases, and infectious diseases.

And the types of gene therapy:

Oh, dear. mRNA is not any of those. The not-so-dynamic duo might make a better case that the J&J or AstraZeneca vaccines are gene therapy, but so what? Those vaccines will not permanently alter the DNA of the recipients cells either.

The bottom line is that grifting antivaxxers like Ken Stoller, Joe Mercola, and Judy Mikovits are using claims about COVID-19 vaccines that are grossly incorrect or obviously deceptive to spread fear and doubt about COVID-19 vaccines in the middle of a pandemic by combining new disinformation about COVID-19 vaccines with very old antivaccine tropes (i.e., false claims that vaccines will permanently alter your DNA, cause autoimmune disease, render women infertile, or in other ways be more dangerous than the disease) in order to frighten people. In doing so, they have blood on their hands because for every 100 people whom they frighten out of vaccinating and who as a result contract COVID-19, its likely that there will be one death.

Unsurprisingly, the onslaught still continues today, except that in this case Vaxxter, the house organ of Barbara Loe Fishers hoary antivaccine organization with an Orwellian namethe National Vaccine Information Center (NVIC)published an article entitled Moderna, Pfizer Test mRNA Experimental Biologics on Children, because calling the Pfizer and Moderna vaccines experimental biologics and raising the specter of experimentation on children are so much scarier than referring to it as testing COVID-19 vaccines in children.

Original post:
The latest antivax false claim: mRNA vaccines against ...

Medicine is becoming more personalized. Cell therapies, such as CAR-T, are perhaps the most dramatic example of personalized medicine. Blood is drawn from a lymphoma patient, their immune cells are separated out and shipped off to a central manufacturer site. A pharmaceutical company genetically modifies each batch of immune cells. These genetically engineered immune cells are then shipped back to the patient and infused back into their body. Thousands of patients have now been treated with these CAR-T cell therapies.

Could this CAR-T process be more efficient if we decentralized the manufacturing process?

What if regional hospitals and academic centers genetically engineered the patients immune cells on site, without shipping to a central manufacturer? This could shave many weeks off the processing time. For 3rd line cancer patients, time is critical. Many 3rd line lymphoma patients pass away while waiting for their cells to return from a centralized manufacturer. Each week eliminated in cell manufacturing time would save lives.

This 2020 article in Cancer Therapy and Prevention analyzes the potential costs savings of decentralized cell therapy.

Ill be exploring various applications of decentralization in cell and genetic medicine in future articles. If this concept is interesting to you, then please reach out and share your thoughts.

~Kevin

Continue reading here:
List of Gene Therapy Clinical Trials - Rising Tide Biology

Definition

Gene therapy is a type of treatment designed to modify the expression of an individuals genes or to correct abnormal genes to treat a disease.

R. Michael Blaese, W. French Anderson and Kenneth Culver at a press conference announcing the start of the first gene therapy trial for treating children with severe combined immunodeficiency, 13 September 1990. Source: National Cancer Institute

Gene therapy gained a lot of commercial interest in the 1980s. In part this was because many assumed such treatment would move swiftly and easily from proof of concept into clinical trials. Such hopes, however, were dashed following the death of the first patient in a gene therapy trial in 1999. It would take another decade before optimism about the therapy resurfaced. From 2008 onwards dozens of new start-ups began to be created around gene therapy. These were founded on the back of sponsorship from pharmaceutical companies and the stock market. Just how much weight began to be attached to gene therapy can be seen by the stock markets valuation of Juno Therapeutics. In 2014, just one year after Juno was set up, the company was valued at US$4 billion. When the first gene therapy was approved in the United States there were 854 companies developing such therapies. According to the Alliance for Regenerative Medicine there were 1085 companies in that space by the end of 2020 and more than 400 gene therapy trials under way.

Scientists first demonstrated the feasibility of incorporating new genetic functions in mammalian cells in the late 1960s. Several methods were used. One involved injecting genes with a micropipette directly into a living mammalian cell. Another exposed cells to a precipitate of DNA containing the desired genes. A virus could also be used as a vehicle, or vector, to deliver the genes into cells.

One of the first people to report the direct incorporation of functional DNA into a mammalian cell was Lorraine Kraus at the University of Tennessee. In 1961 she managed to genetically alter the haemoglobin of cells from bone marrow taken from a patient with sickle-cell anaemia. She did this by incubating the patients cells in tissue culture with DNA extracted from a donor with normal haemoglobin. Seven years later, Theodore Friedmann, Jay Seegmiller and John Subak-Sharpe at the National Institutes of Health (NIH), Bethesda, successfully corrected genetic defects associated with Lesch-Nyhan syndrome, a debilitating neurological disease. They did this by adding foreign DNA to cultured cells collected from patients suffering from the disease.

The first humans to receive gene therapy took place in 1970. It was administered to two very young West German sisters suffering from hyperargininemia, an extremely rare genetic disorder that prevents the production of arginase. This is an enzyme that helps prevent the build up of arginine in bodily fluids. Any accumulation can cause brain damage, epilepsy and other neurological and muscular problems. Each sister received an injection of a rabbit virus (Shope papilloma) known to induce the production of arginase. The injection was given as a last desperate measure to rescue the children. The treatment was carried out by Stanfield Rogers, an American physician, together with H. G. Terheggen, a German paediatrician. They took the risk based on observations Rogers had previously made with some laboratory technicians at Oak Ridge National Laboratory who became infected with the rabbit virus when working with it. None of the technicians experienced ill-effects from the virus but had abnormally low levels of arginine in their blood. This was apparent even in a technician whose last exposure to the virus had been 20 years before. Rogers connected the technicians abnormal arginine levels with a gene in the rabbit virus which was known to encourage the production of arginase in rabbits. By giving the rabbit virus to the girls, Rogers hoped to transfer genetic instructions to their cells to produce arginase. After the two sisters were treated a third sister was born afflicted with hyperargininemia. She was also injected with the virus. Disappointingly none of the sisters responded to the treatment.

A new pathway for gene therapy opened up with the development of genetic engineering in the early 1970s. The technique provided two key tools. Firstly, a means to clone specific disease genes. Secondly, an efficient method for gene transfer. The potential of the technology for gene therapy was first highlighted by the US scientists Theodore Friedmann and Richard Roblin. In 1972 they published an article in Science suggesting genetically modified tumour viruses might be used to transfer the necessary genetic information to treat genetic disorders in patients.

The technique was first tried out in the case of beta-thalassemia. Linked to an inherited defect in a gene for beta-globin, this blood disorder usually causes premature death. The beta-globin gene was first cloned by scientists at Cold Spring Harbor Laboratory and Harvard University in 1976. It was the first disease gene ever cloned. Three years later, a team led by Martin Cline at the University of California, Los Angeles, reported the successful introduction of the gene into the bone marrow of irradiated mice. Following this, Cline and his team unsuccessfully tried to treat two beta-thalassemia patients, one in Italy and another in Israel by inserting the gene into bone marrow extracted from them and then reinfusing the cells. Cline was immediately reprimanded for failing to secure the necessary permission from his home institutions Institutional Review Board to carry out the work and having insufficient animal data to demonstrate the effectiveness of his procedure. The incident cost Cline his university chair and most of his funding from the NIH. It also ignited a furious public debate about the social and ethical implications of gene therapy. This led to the tightening up of regulations for the future testing of gene therapy in humans, which were to be overseen by the NIHs Recombinant DNA Advisory Committee (RAC).

Gene therapy entered a new era in the 1980s following the discovery of retroviruses which proved a much more efficient tool for gene transfer. The first suitable retroviral vector for gene therapy was developed by Richard Mulligan, a researcher at Massachusetts Institute of Technology and former doctoral student of Paul Berg, a key pioneer in genetic engineering at Stanford University. By 1983 Mulligan had managed to genetically modify a mouse leukemia retrovirus with his colleagues so that it could deliver any desired DNA without reproducing in humans. The new vector also contained a selective marker, a piece of DNA from Escherichia coli bacteria, which made it possible to identify how many genes a cell picked up during gene transfer.

One of the first people to use Mulligans new vector was French Anderson, a geneticist at the NIHs National Heart, Lung and Blood Institute. By 1989 he had secured permission from the RAC to begin the first approved clinical trial with gene therapy. This was to be done with the help of Michael Blease, a paediatrician and immunologist. The teams aim was to test gene therapy in children with severe combined immunodeficiency, an inherited immune disorder caused by a defective adenosine deaminase (ADA) gene. Most children born with the disorder did not live long and only survived by being confined in sterile plastic enclosures, giving rise to the term bubble disease. Those with the condition had only two treatment options. The first was to have a bone marrow transplant, but this was hampered by the need to find a matching donor and the risks of an immune reaction. The second was to have frequent injections of PEG-ADA, a synthetic enzyme. Children who had such treatment usually showed a marked improvement after the first injection but this was usually of short duration and subsequent doses were largely ineffective.

Prior to treating the children the team partnered with Steven Rosenberg at the National Cancer Institute (NCI) conducted a test of their proposed procedure in a 52 year old man dying from malignant melanoma in May 1989. This was designed to assess three things: assess the safety of Mulligans retroviral vector, determine how much of the marked gene it could transfer and how long the gene lasted. The experiment involved a number of stages. In the first instance, the scientists needed to cultivate tumour infiltrating lymphocytes (TIL cells), a type of tumour-killing cell. This involved incubating white blood cells removed from the mans tumour with interleukin-2, a molecule found to activate T in the destruction of cancer cells in the 1960s. A DNA marker was then inserted into the TIL cells before they were reinfused into the patient. The same procedure was repeated in seven more patients at the NCI with terminal malignant melanoma. Encouragingly all of the patients absorbed the marker genes with no ill-effects and a third of them responded positively to the treatment. One experienced a near-complete remission. The study marked a major turning point. Firstly, it established the feasibility and safety of gene therapy. Secondly, it opened the door to the development of gene therapy for cancer.

Andersons team started trying out the gene therapy in children with ADA-SCID in early 1990. The first patient to receive the therapy was Ashanti DeSilva, a four year old girl. Her treatment lasted twelve days. It necessitating extracting Ashantis blood cells, inserting a new working copy of the ADA gene into them and then reinfusing the cells into her. Overall, the procedure was similar to a bone marrow transplant. The goal was to replenish Ashantis blood cells with ones that could produce ADA. Gene therapy had the advantage that the cells originated from Ashanti so there was no risk of rejection. To everyones delight Ashanti improved so much she no longer needed to be kept in isolation and was able to start school. She remains alive to this day.

Numerous gene therapy trials were launched in the 1990s in the light of the success with Ashanti. A significant shift took place during this decade. Critically the field moved away from just looking to treat rare diseases caused by a single gene, as had been the case with Ashanti. By 2000 gene therapy had been tried out in nearly 3,000 patients in almost 400 trials. Most of the trials targeted cancer, but cardiovascular disease, AIDS, cystic fibrosis and Gaucher disease were also investigated.

Some of the early enthusiasm for gene therapy witnessed at the beginning of the decade, however, had begun to disappear by the end of the 1990s. This was because researchers struggled to get the therapy to work because of the inefficiency of the retroviral vectors they had to hand. Negative attitudes to gene therapy increased following the first death in a trial. In September 1999, Jesse Gelsinger, an 18 year old American died while taking part as a volunteer in a dosing escalation trial. Led by James M Wilson, the trial was designed to treat newborn infants with a fatal inherited a metabolic disorder, known as ornithine transcarbamylase deficiency, which leads to the buildup of excessive ammonia in the body. Gelsinger had himself been born with the condition, but had managed to keep it in check by restricting his diet and taking special medications. He was allocated to the last group in the trial who received the highest dose. Four days after treatment Gelsinger died from major organ failure because of his violent immune reaction to the vector used in the treatment. The vector was derived from adenovirus, a group of viruses first isolated from the tonsils and adenoid tissue of children in the early 1950s. One of the reasons such a virus was used was because such viruses were well characterised and had a small genome so were easy to manipulate. Moreover, most people carry adenoviruses without experiencing any significant clinical symptoms. Investigations into Gelsingers death revealed insufficient care had been taken during the trial and poor clarity in terms of its safety guidelines.

While the tragedy led to the enforcement of more stringent regulations for gene therapy trials, Gelsinger was not the last to suffer the consequences of an adenoviral vector. Three years later, in 2002, a number of British and French children were discovered to have developed T cell leukaemia three years after receiving gene therapy for a form of SCID linked to a defect on the X chromosome. Their cancer turned out to have been caused by an adenoviral vector that integrated into a part of their genome that activated a gene for leukaemia. This too the scientists by total surprise because most adenoviruses are unable to integrate into the host genome.

Despite the difficulties, gene therapy began to turn a corner the following decade, aided by the arrival of safer and more effective vectors. Positive results began to be reported for a number of gene therapy trials. Most were small-scale academic studies. In 2007 Jean Bennett, an ophthalmologist at the University of Pennsylvania, demonstrated in a small trial that gene therapy could provide a promising treatment for inherited retinal disease. Subsequent trials in more patients carried out in 2015 backed this up. In addition to eye disease, gene therapy was found to help haemophilic patients, a number of whom no longer needed to take blood clotting factor drugs. Good news also emerged in 2015 from trials of gene therapy for rare single-mutation blood diseases like thalassemia and sickle-cell anaemia, with some patients able to stay healthy without blood transfusions. A year later, two small trials showed gene therapy could help in the treatment of patients with cerebral adrenoleukodystrophy, an inherited disorder that affects the central nervous system, and with spinal muscular atrophy, a neuromuscular disease that is one of the leading causes of genetic death in infants.

The first gene therapy was licensed in China in 2003. Designed for the treatment of neck and head cancer, this treatment did not make it across to other countries. The first gene therapy was approved in Europe nine years later. It was developed by UniQure, a Dutch company for treating lipoprotein lipase deficiency, a rare metabolic disease that causes acute and recurrent abdominal pain and inflammation of the pancreas. The drug, however, failed to be a commercial success because too few patients needed the drug. This led to UniQure withdrawing marketing authorisation for the drug by 2017.

In 2016 Europe licensed a second gene therapy, developed by GlaxoSmithKline for children suffering from ADA-SCID. A year later Novartis secured approval for the first gene therapy in the United States. Designed to treat acute lymphoblastic leukaemia, the therapy had grown out of the preliminary work Anderson and Rosenberg had originally undertaken to establish the safety of gene therapy for treating children with ADA-SCID in 1989.

Gene therapy takes different forms. It can involve the insertion of a copy of a new gene, modifying or inactivating a gene, or correcting a gene mutation. This is done with the help of a vector derived from a genetically modified virus. Several different viral vectors are now used for this purpose.

Adenoviral vectors are some of the most common ones. These vectors work best in nondividing cells such as found in the brain or retina. Lentiviral vectors are also popular. These are derived from lentiviruses, a group of retroviruses. Two of the most commonly used, which emerged in the late 1990s, are the human immunodeficiency virus and the herpes simplex virus. Such vectors have the advantage that they can carry large quantities of genes and work in non-dividing cells. Nonetheless, they, present some safety issues because it is difficult to predict where they will integrate into the host genome. For this reason, lentiviral vectors are generally deployed in the genetic alteration of cells extracted from patients. Lentiviral vectors are particularly helpful in the introduction of genes into the genome of cells that are generally difficult to modify. Lentiviral vectors made from the herpes simplex virus are currently being used in gene therapies being explored for pain and brain diseases.

New horizons have opened up for gene therapy with the recent development of CRISPR-Cas9, a much more precise technique for altering genes. At the end of 2016 a group of Chinese scientists, led by the oncologist Lu You at Sichuan University, launched a safety trial to see if it was possible to treat cancer patients by using CRISPR-Cas to disable a particular gene in their cells that codes for the PD1 protein which often impedes a cells immune response to cancer. A few months later, in 2017, a similar trial was initiated by an American team headed by Carl June at the University of Pennsylvania.

While gene therapy has made remarkable progress in the last few years, its development still raises significant questions in terms of safety. One of the major differences between gene therapy and conventional small molecule drugs or other biological products, like protein therapeutics, is that once gene therapy has been administered it is difficult to stop treatment. It is also too early to know how long the effects of a gene therapy last. Moreover, too few patients have been given gene therapy for any length of time to know whether it poses any safety risks long term.

Another major stumbling block is that so far the price of gene therapy has been incredibly high. Gene therapies are currently some of the most expensive treatments on the market. In part this reflects the fact that most of them are custom-made for individual patients.

This piece was written by Lara Marks in January 2018. It draws on the work of Courtney Addison and her chapter Gene therapy: An evolving story, in Lara V Marks, ed, Engineering Health: How biotechnology changed medicine, (Royal Society of Chemistry, October 2017).

Paul Zamecnik was born in Cleveland, Ohio, USA

Roland Levinsky was born in Bloemfontein, South Africa

First successful direct incorporation of functional DNA into a human cell

First evidence published suggesting a virus could provide delivery tool for transferring functional genes

American scientists demonstrate that adding foreign genes to cultured cells from patients with Lesch-Nethan syndrome can correct genetic defects that cause the neurological disease

Three West German very young sisters fail to respond to first ever administered gene therapy

First time gene therapy proposed as treatment for genetic disorders

First human disease gene, beta-globin, cloned

Beta-thalassemia gene successfully inserted into bone marrow of irradiated mice

Gene therapy unsuccessfully tried out in two patients with beta-thalaessemia sparks controversy

First experiment launched to test feasibility of gene targeting in the human genome

Creation of first retroviral vector suitable for gene therapy

Experiment published demonstrating possibility of inserting a corrective DNA in the right place in genome of mammalian cells

NIH published its first draft guidelines for proposing experiments in human somatic cell gene theray

Technique published for the accurate insertion of a corrective DNA in the human genome

First human test demonstrated safety of retroviral vector for gene therapy and potential of laboratory produced tumor killing cells for cancer immunotherapy

First use of genetically engineered T cells to redirect T cells to recognise and attack tumour cells

Concept of enhancing T cells using chimeric antigen receptors published for first time

Gene therapy concept proven in first human trials

Treatment with gene modified tumour-infiltrating lymphocytes shown to be promising immunotherapy for patients with advance melanoma

Four year old Ashanti DeSilva becomes first patient successfully treated with gene therapy for severe combined immunodeficiency caused by defective ADA gene

Stem cells used as vectors to deliver the genes needed to correct the genetic disorder SCID

Chimeric receptor genes added to T lymphocytes shown to enhance power of adoptive cellular therapy against tumours

FDA published its regulations governing gene therapy

Death of the first patient in a gene therapy trial prompted major setback for the field

Multi-centre trials with gene therapy using stem cells to treat children with SCID

Two French boys suffering from SCID reported to be cured using gene therapy

Polyoma virus shown to be potential tool for delivering gene therapy

Suspension of French and US gene therapy trials for treating SCID children

First human trial of gene therapy using modified lentivirus as a vector

China approved the world's first commercial gene therapy

Zinc finger method reported capable of modifying some genes in the human genome, laying the foundation for its use as tool to correct genes for monogenic disorders

Genetically engineered lymphocytes shown to be promising cancer treatment

Adoptive cellular therapy using chimeric antigen receptor T cells shown to be safe in small group of patients with ovarian cancer

Small trial published demonstrating possibility of using gene therapy for inherited retinal disease

Zinc finger method explored as means to develop treatment for glioblastoma (brain tumour)

Zinc finger method used to make HIV-resistant CD4 cells to develop immunotherapy for HIV

Almost blind child with rare inherited eye disease gains normal vision following gene therapy

Gene therapy halts progression of degenerative disease adrenoleukodystrophy in two boys

Stem-cell transplant reported to be promising treatment for curing HIV

Gene therapy for treatment of lipoprotein lipase deficiency fails to win European approval

Gene therapy successful in treating beta-thalassaemia

Studies show CD19-specific CAR-modified T cells to be promising treatment in patients with B cell malignancies

Research published suggesting gene therapy could help preserve neural circuits and protect against vision loss in patients with multiple sclerosis

Gene therapy reduces symptoms in six patients with haemophilia B

Patient suffering from acute myeloid leukaemia is cured of HIV-1 after receiving bone marrow stem cells transplanted from donor with mutated CCR5 gene. This awakens interest in developing HIV treatment that renders a patient's cells resistant to HIV-1

Gene repair kit used successfully to treat blood-clotting disorder haemophilia in mice

European Union asks European Medicines Agency to reconsider approval of alipogene tiparvovec

First gene therapy approved for treatment of patients with familial lipoprotein lipase deficiency

Basic studies conducted with TALENs to see if can correct mutant genes associated with Epidermolysis Bullosa, a rare inherited skin disorder

Fiven children with ADA-SCID successfully treated with gene therapy

Eyesight reported to improve in six patients suffering from choroideremia after receiving gene therapy

Promising results announced from trial conducted with HIV patients

Phase I trial using Zinc finger nuclease modified CD4 cells to treat 12 HIV patients shows the approch is safe.

Mice trials show CD4 T-cells genetically modified with Zinc fingers could be effective HIV-1 gene therapy

US FDA cleared Investigative Drug Application for clinical trial of gene therapy for haemophila B. The therapy was the first in vivo genome editing application to enter the clinic

Phase 1 clinical trial launched with RNAi treatment for Huntingdon's disease

First oncology gene therapy approved in US and Europe

First successful use of gene therapy to treat baby dying from leukaemia

Preliminary results presented for phase 2 trial using Zinc finger nuclease modified CD4 and CD8 cells to treat HIV patients

Gene editiing tool, CRISPR, successfully used to improve muscle function in mouse model of Duchenne muscular dystrophy

2016: NIH gives green light for first clinical trial using gene editing tool CRISPR/Cas 9 to treat patients

Gene therapy shown to restore hearing in deaf mice

Gene therapy reported to successfully reverse sickle cell disease in first patient

First gene therapy approved in Europe for lipoprotein lipase deficiency (Glybera) withdrawn from market

US FDA Oncologic Drugs Advisory Committee recommended the approval of the first adoptive cell therapy (CAR-T cell therapy) for B cell acute leukaemia

USA FDA approved CAR-T therapy for certain pediatric and young adult patients with a form of acute lymphoblastic leukemia

Gene therapy shown in clinical trials to halt progression of adrenoleukodystrophy, a fatal brain disease inherited by boys

First patient received therapy involving gene editing inside the body

Gene therapy shown to be safe and efficacious treatment for haemophilia A in British trials

US FDA approved gene therapy approved to treat rare genetic retinal disease

Researchers identify pre-existing antibodies targeting CAS9 proteins raising possibility of immune responses undermining utility of CRISPR-Cas9 for gene therapy

Gene therapy shown to be promising treatment in clinical trials for beta thalassemia

First CRISPR-Cas9 clinical trial launched

Gene therapy approved in Europe for treatment of patients with vision loss linked to genetic mutation

Original post:
Gene therapy | Summary - WhatisBiotechnology.org

In medical research, gene therapy is an advanced procedure that uses genes to help eliminate or cure diseases. In this strategy, the aim is to create a potential society where doctors will cure complex diseases by injecting genes into the cells of a patient instead of using surgery, medications, or other health improvement treatments.

Today, there are many distinct approaches to gene therapy being studied. One procedure entails a defective gene being replaced with a healthy copy of it. There is the chance of deactivating a mutant gene so that its improper functionality stops. To help them fight a disease, doctors could also put new genetic material into the body of a patient.

The pros and cons of gene therapy indicate that, for certain inherited disorders, tumors, and viral infections, this promising treatment choice is potentially useful. It is also a strategy that comes with a more critical collection of hazards than conventional methods. In order to decide whether it is safe and efficient for everyday use when targeting diseases that have no other cures, experts are still researching the method.

There are multiple births that suffer abnormalities and genetic disorders, even with rigorous tests in place for parents. One of every 33 babies suffers a birth defect of some sort in the United States. Thats 3% or so of all births.

The leading cause of child death in the US, responsible for 1 in 5 deaths, is birth defects. Any of these mutations may be reversed with gene therapy to decrease these deaths.

There are small prospects of remission when replacing a dysfunctional gene with a functional gene in a condition such as cystic fibrosis, and this is typically a one-off procedure that will see you free of symptoms for life.

In addition, gene therapy is not only a treatment for the person suffering from a given disease, but it covers the generation as a whole. They cannot pass the damaged genes to their descendants when you remove a gene that predisposes us to breast cancer, but the new functional gene.

About 10 percent of the general population is afflicted by rare diseases. More than 30 million persons are affected in the United States. There are over 7,000 different diseases that occur and flawed genetics are responsible for approximately 80 percent of those diseases.

Healthy cells may substitute the damaged cells with gene therapy to provide the infected person with a legitimate cure.

It is possible to extend the lifespan of animals as gene therapies are applied to veterinary science. To avoid loss, we could treat genetic disorders in animals. This will stabilize our animal protein food chain as added to livestock.

It could be extended to plants so that, without extra DNA and genes added to them, they would naturally survive disease. The chances to support life, in whatever shape it may take, are nearly infinite.

Gene therapy approaches could provide the ability to start their own biological families for people suffering from infertility. Successful fertility changes have occurred in mice using a modified gene therapy procedure called CRISPR. This creates the potential to one day have a similar impact in humans.

In the United States, approximately 3% of births contain a disease that is theoretically treatable by the application of gene therapy techniques. Many of the children born in this demographic, die shortly after birth due to the debilitating consequences of their disease.

With this option, which affects approximately 20 percent of families per year, birth defects are also potentially preventable. Instead of paying for hospice services or being pressured to say goodbye right away, physicians and scientists give parents more hope for a better future because of the accessibility of this technology.

Since gene therapies are technologically oriented, their average expense may decrease as new techniques and advances reach the medical industry. Initial therapies can be costly, but there may be no future for treatment in the coming generations. As more research happens in this sector, prices will drop.

We have experienced this with penicillin once. The price was $20 per 100,000 units when it was first launched. Thats the equivalent price of $70,000 per treatment, with a standard dosage being 4 million units. The price of penicillin today is just pennies per dose in many cases.

There are some options for gene therapy that are available right now, but they come at a high cost. If you are using Luxturna to treat both eyes as a means to treat blindness, more than $1 million may be the final bill. Even the affordable solutions begin at $200,000 per care in this area.

That is why many patients wait for clinical trials to start, and then qualify for a spot in one to get the assistance they need. Because of the uncertainty, most health care insurance plans would not bear the expense of these treatments.

Nature can readily respond to changes that occur, as we have seen with the increasing resistance to antibiotics. Gene therapy may be beneficial today, but in the future, further alterations to genetic profiles may trigger unexpected diseases.

There is no certainty that gene therapys future prospects could live up to its current potential for particular diseases to be treated. Without understanding it, we could be developing new diseases for future generations by altering genes.

The most common method for gene therapy to be delivered to patients is via retrovirus delivery systems. The concern with this option is that before it has the opportunity to function, the enzyme used to facilitate the transmission of genetic data can be destroyed by the immune system.

Problems with cell division or replication that limit the treatment s efficacy may occur. If there is a visible change in the cell, the body can attack itself without the presence of an immunosuppressant. The success stories for gene therapy will always be hit or miss until we can remove and substitute genetic data with greater certainty.

The immune system of the body can see the different viruses that we use as invaders to replace unwanted genes that must be extinguished before they cause damage. It is not uncommon for a patient to develop health complications such as inflammation, dizziness, and headaches when white blood cells invade the newly added genetic material.

In extreme reactions, it is possible for the immune response to attack the organs of the body and cause them to malfunction. Thats why an immunosuppressant is used with medication plans, but this medicine can make someone more vulnerable to illnesses and disease.

The science of eugenics becomes plausible when mankind has the knowledge to manipulate a genetic profile. It will build a future in which children have their genetic profiles altered in vitro such that a particular outcome is obtained.

This will introduce numerous standards of humanity, establishing a distinct class of people who has been perfected. It would also dramatically introduce the income inequalities that occur in certain cultures so only anyone who could afford it would have access to this facility.

For a valid cause, gene therapies have been stuck in trials for a generation. It has been proven that all of the gene therapies that actually exist are mostly ineffective.

For a brief amount of time, diseases that are treated by gene therapy improve, but soon return to the state they were before treatment started. Even for the successful ones, continuous procedures or tissue donations, such as bone marrow, may be needed.

It can encourage gene doping. Although gene doping is not actually understood to exist, it is a mechanism that may equalize sports or educational opportunity if fair access to technology is provided.

If an individual succeeds because of therapy when they may not have the same levels of success without gene therapy, it is a matter of ethical consideration, particularly when contemplating athletic competition.

Excerpt from:
14 Pros and Cons of Gene Therapy

Innoforce Pharmaceuticals has opened a new advanced cell and gene therapy development facility in Hangzhou, China. Analytical development (AD) and process development (PD) represents a critical step towards providing services for potential clients in their cell and gene therapy product development to support clinical trials and further commercialization. Innoforce's development facility further strengthens the company's capability in analytical development, process characterization, validation, and staff training for a broad range of cell and gene products.The facility is set up as an AD-PD development laboratory to provide analytical method development and qualification, quality control preparations, process development, and building platform technology approach in preparation for the launch of Innoforce's GMP manufacturing facility in 2022."The capability of analytical and process development largely dictates the success of any cell and gene therapy development. It is understood by all players in the industry that this is a critical aspect of cell and gene therapy product development, said Yuling Li, CEO, Innoforce. Innoforce's development facility aims to address the crucial need for quality and expertise in the process and analytical development areas.The new facility significantly accelerates Innoforce's ability to develop and deliver cost-effective, robust, scalable, analytical capability and processing technologies to drive client's programs' efficient and rapid progression to GMP manufacturing. Innoforce will provide end-to-end manufacturing services, including GMP commercial manufacturing of plasmid DNA, viral vector, and cell therapy products by the middle of 2022. Innoforce's new Development Facility is located at the ChuanHua Science and Technology Building, Xiaoshan Innovation Zone.

Excerpt from:
Innoforce Expands Cell And Gene Therapy Capabilities - Contract Pharma

A recent announcement from Voyager Therapeutics outlined a shift in the companys strategy towards an exciting new technology for gene therapy delivery. Unfortunately this also means that in the short term, they have dropped previous plans to test an HD gene therapy in people with HD. While this news is disappointing, the decision to embrace a novel approach now could potentially lead to a safer, more accurate, and less invasive HD therapeutic in the longer term.

This news provides an opportunity for the HDBuzz team to talk more about the current landscape and share the latest news from the gene therapy pipeline.

Before we get into the HD gene therapy pipeline, lets review some basic genetics. With the advent of RNA-based COVID vaccines, weve all been hearing a lot about RNA. But how does RNA differ from DNA, and what does it mean if we alter either of these?

You can think of DNA like a blueprint its the master plan at the genetic level for every cell in your body. To ensure that master plan stays in pristine condition, cells make copies of DNA to work from when they make proteins. That copy of the DNA is RNA. Because RNA is just a copy, it can be well-used without much care if it gets a bit tattered. If it does, the cell can just make another RNA copy from the DNA blueprint, and voila! The cell has a fresh RNA copy that can be used to produce more protein.

Scientists have leveraged this knowledge to come up with clever ways to get cells to produce more or less of the proteins theyre interested in.

In the case of Huntingtons disease, were interested in reducing production of the huntingtin protein that damages cells referred to as huntingtin-lowering. That could be done in 2 ways:

1) Destroy the RNA copies as they are produced, but leave the DNA blueprint intact. This is the strategy behind antisense oligonucleotides (ASOs), like those that were being tested in trials by Roche and Wave.

2) Modify the message of the DNA blueprint, so it either cant be copied into RNA or contains new instructions to help destroy the RNA. This approach is what we refer to when we say gene therapy it changes what is made from the blueprint without altering it.

While both of the strategies above ultimately lower huntingtin protein production, they are different for several reasons. The primary difference is that destroying only the RNA copy requires repeated doses. Because the cell still has the original DNA blueprint for the huntingtin protein, it will continue to make more RNA copies. So unless the copy is constantly destroyed, the huntingtin protein will still be produced. While the repeated doses may seem like a nuisance, this type of approach means that the effect of any drug that targets only the RNA will eventually wear off an added safety benefit.

Gene therapy approaches for huntingtin-lowering, like those being pursued by uniQure and Voyager, target huntingtin with a one-time delivery of genetic instructions to cells of the brain. These instructions then tell the cells to continuously produce RNA molecules that can interfere with the making of huntingtin, leading to lower protein levels. This is a one-and-done type of approach no repeated doses necessary. But something to consider is that this approach also means that if there are other effects because of huntingtin-lowering, theres no going back.

Its important to note that even though DNA is being added in these gene therapy approaches, a persons DNA is not being edited. This means that while the gene therapy will have benefits in the person being treated, it wont be passed to future generations. That would require a gene editing strategy like CRISPR.

Current gene therapy strategies for brain diseases like HD would require brain surgery since these DNA-altering drugs cant get past the barrier of the brain. This major limitation is something Voyager wanted to get around.

On August 9th, 2021, Voyager Therapeutics issued a press release about their finances, recent leadership transitions, and importantly, a major shift in their scientific pipeline. The announcement had a lot of corporate and investor information, but the science content centered around an improved gene therapy delivery system and a proprietary discovery platform, which in combination could allow Voyager to develop less invasive methods of delivering gene therapies for rare diseases like HD.

Like previous genetic therapies developed by Voyager (and other companies, like uniQure), delivery involves packaging genetic drugs inside a harmless virus called an AAV. In the field of HD gene therapy, AAVs are used to deliver genetic instructions that cause cells to divert one tiny wing of their machinery towards producing a genetic antidote to the expanded HD gene.

Voyager has developed a proprietary new AAV packaging and has collected evidence from monkeys that these AAVs can be delivered with greater safety, potency, and accuracy. They have also invested in a new discovery system for identifying and improving upon AAVs for additional diseases and drug targets.

Whereas AAV delivery of HD therapies has so far required a brain surgery, drugs developed using Voyagers new platform can be designed for delivery through an injection into the blood, so there is potential for less invasive delivery to the brain.

The press release shared that Voyager will shift its focus to the new technologies and away from older existing ones. The upside is the next-generation technology; the downside is that this means that Voyager will no longerbe pursuing the therapy that they had previously developed for HD. This drug, VY-HTT01, was meant to be the focus of a planned clinical safety trial called VYTAL, which would have begun later this year. No participants had yet been recruited it was still in early planning stages.

Although the loss of a gene therapy that was approaching the clinic is a significant short-term setback, Voyagers shift in focus now to accommodate a new scientific development provides a new and potentially better therapeutic avenue for HD.

Luckily, there are other companies working on gene therapy approaches, who have also provided recent public updates on their ongoing or upcoming trials for Huntingtons disease. Weve provided brief summaries for each of these below; stay tuned for additional updates as these efforts advance.

The first company out of the HD gene therapy gate was uniQure, who are developing a viral therapy known as AMT-130, which has the goal of delivering instructions to brain cells for the making of a special kind of RNA that will find and destroy the RNA for the huntingtin gene. In this way, gene therapy can be used to permanently induce huntingtin-lowering. After many years of careful work in animals, uniQure launched their safety study, and as of this summer they have excitingly been able to complete surgeries for 12 of the planned 26 patients. A strictly regulated schedule has allowed the team to carefully monitor any safety worries, and none have emerged so far.

Additional companies in the preclinical stages of development of virus-based huntingtin-lowering gene therapies include Spark, Sanofi, and AskBio.

Another gene therapy approach to huntingtin-lowering relies on a novel tool known as a Zinc Finger. Weve been writing about this approach at HDBuzz since 2012, and more recently (2019) about a large scale study of the tools in HD mice. Recently, the Japanese drug company Takeda has taken over the HD program from Sangamo Therapeutics, who initially developed the drugs. A key benefit of the Zinc Finger approach for huntingtin-lowering is that it allows selective silencing of just the mutant huntingtin gene, while sparing the normal copy that nearly every HD patient has.

We mentioned the multiple-delivery strategy which was used by Roche and Wave in the trials that concluded unsuccessfully this spring. Despite these setbacks, ASOs and other RNA-based strategies are still being actively developed as HD therapies.

Wave Life Sciences has redesigned the chemistry of their ASO drugs, which could lead to better potency and the ability to use lower doses in people with HD. They have announced plans to launch a safety trial of a new ASO by the end of 2021. The drug is called WVE-003, and it targets the expanded form of huntingtin.

Novartis and PTC Therapeutics are developing drugs called splice modulators that also target huntingtin RNA, but can be delivered by mouth. We covered Novartiss drug, branaplam, in a recent article; a trial in HD patients is planned to begin by the end of 2021.

NeuBase Therapeutics is developing an ASO drug called NT0100 which also aims to target only the expanded form of huntingtin.

At the end of July, a company called Vico Therapeutics received a special rare disease therapeutics status, known as Orphan Drug Designation, to develop their ASO for HD, known as VO659.

Companies like Atalanta and Alnylam/Regeneron are developing ways to lower huntingtin through RNA interference (RNAi) which, similar to ASOs, target copies of RNA and would require multiple deliveries.

There are more strategies in the works, some of which also rely on gene therapy or destroying copies of RNA, like targeting the expansion of CAG repeats, which is being explored by companies like Triplet Therapeutics and LoQus23 Therapeutics.

There are also many approaches to HD drug development that diverge from genetics but focus on addressing other aspects of HD biology, like preserving or boosting connections between neurons, or treating aggression, memory issues, or movement problems. Those already being tested in human we explored in a recent clinical trials roundup. Other companies have pre-clinical programs aimed at strategies like cleaning up existing huntingtin protein that litters brain cells, suppressing inflammation in the HD brain, and more newcomers to HD research are quite frequent (and very welcome)!

Gene therapy for brain diseases is amongst the most cutting edge approaches to trying to fight HD. As with any new field, there are bound to be many ups and downs on the way to a treatment. The recent update from Voyager is a good example of this while its disappointing that theyll not be running their planned trial later this year, its very exciting that theyve developed these new technologies and want to apply them to help HD families. The extensive efforts from other companies in the gene therapy space and beyond suggest that a lot of really exciting strategies are being applied to the problem of HD.

Read more:
Unpacking recent gene therapy press - HDBuzz

A rare disease is, by its very nature, rare. The CDC defines a rare disease as a condition that affects fewer than 200,000 people in the United States, or no more than one out of every 2,000 people in Europe.1 And yet, rare diseaseswhich frequently have a genetic componentaffect many: there may be as many 7,000 different types of rare diseases, impacting 25 to 30 million people in the United States, according to the National Center for Advancing Translational Sciences.2 Often, rare diseases lack treatments, leaving patients with little hope.

An ambitious new project, called Accelerating Research and Development for Advanced Therapies (ARDAT), is working to change that. This five-year endeavor through the Innovative Medicines Initiative (IMI), "the world's biggest private-public partnership in the life sciences," is seeking to better understand ways of treating rare diseases through something called advanced therapy medicinal products (ATMPs), such as cell and gene therapies.

Led by Pfizer and University of Sheffield, ARDAT is a consortium made up of more than 30 academic, nonprofit, and private organizations from Europe and the United States that is collaborating to work with regulators and share research and data. The goal is ultimately to improve our understanding of ATMPs, which may helpbring more effective medicines to patients with rare diseases. Gene therapy is one of the new transformative frontiers of medicine, says Greg LaRosa, who is the projects lead at Pfizer, where he serves as Vice President, Head of Scientific Research in the Rare Disease Research Unit.

By collaborating with so many other experienced partners, James Eshelby, Vice President of Global Public-Private Partnerships with Pfizer, hopes researchers will be able to gain a deeper understanding, faster, about this new class of drugs that are advancing toward the marketplace. The project being conducted as a public-private partnership is much more robust than it would be if we were all making separate efforts, he says. Theres a shared hope that findings from ARDAT will also lead to a deeper understanding of ATMPS that may translate into advanced therapies for other diseases.

When a person has a genetic disease, doctors have insights into what the defect is. We know what the cellular activity the gene and the protein product from that gene is responsible for performing, and often we really understand why the people have this disease, says LaRosa. Gene therapy allows them to essentially replace that mutated gene with the correct gene.

I think one thing that's fabulous about gene therapy is it's not just treating the symptom, it's attempting to treat the cause, says Eshelby. Its trying to get the body to do what it should have been doing in the first place.

One example of gene therapy that Pfizer has been studying, in collaboration with ARDAT partner Spark Therapeutics, targets a rare bleeding disorder called Hemophilia B. When a person has Hemophilia B, their body doesnt make enough Factor IX, which is a protein that helps with clotting. Because of that genetic mutation, their blood doesnt clot as quickly as it normally would, which puts them at a greater risk of bleeding excessively, from minor injuries, or even spontaneously.

In an ongoing Phase 3 clinical trial, scientists are placing the Factor IX gene into an AAV viral vector, which is used to deliver the gene to cells of the patient. The viruses are modified so they cannot replicate or cause disease. After receiving the potential therapy intravenously, the body should begin making Factor IX, helping the blood to clot.

With the currently available treatments for Hemophilia B, every few days patients need to receive intravenous medication that aids clotting. Whereas if a gene therapy treatment is successful and approved for this purpose, a single treatment could have long-lasting effects. It just really frees the patients up to live a more normal life, says LaRosa. It gives them something that could dramatically change the path they're on with their disease.

Because most advanced therapy medicinal products such as gene therapy are still being developed, theres much to learn about how and why these advanced medicines work, how long the effects will last and how to overcome barriers to developing medicines with the aim of obtaining regulatory approvals and getting them to patients as rapidly as they need them. Through ARDAT, which launched in late 2020, partners in the consortium are sharing data to collectively gain a deeper understanding of ATMPs. Data sets within single institutions are not as big as that which would be compiled under the ARDAT collaboration, says Eshelby. By sharing individual data sets, you have a better potential to get to data set sizes where you can undertake a more comprehensive analysis.

In addition, Eshelby says sharing knowledge has the potential to benefit other areas, including product development, research, communication and awareness campaigns and more. The partners have expertise in areas such as gene therapy, immunology, chemistry, engineering, biotechnology, drug safety, viral vector creation, and regulatory and clinical trials. They include organizations from 10 countriesas well asprominent universities, research institutes,and biotech firms,includingBayer, Sanofi, University of Oxford,and more.

Together, the partners of ARDAT seek to better understand ATMPs and build upon that knowledge, without having to reinvent the wheel at each individual organization. By working with regulatory agencies as well, LaRosa says theyre hoping to streamline the development path of these therapeutics to make them available faster and give people suffering from rare diseases an offering of hope. For some, that might mean they no longer have to receive intravenous treatments multiple times a week; for others, it could mean continuing to move about without the use of a wheelchair. For many, it could mean a better quality of life.

With many of these rare diseases, there's no treatment yet available, says LaRosa. So the goal of this collaboration is to try to fill those knowledge gaps in cell and gene therapyso we can get these potentially curative products into the clinic, and then to the patients that need them.

References:

1. National Institutes of Health. Public Health and Rare Diseases: Oxymoron No More https://rarediseases.info.nih.gov/diseases/pages/31/faqs-about-rare-diseases

2. National Center for Advancing Translational Sciences, FAQs About Rare Diseases https://rarediseases.info.nih.gov/diseases/pages/31/faqs-about-rare-diseases

About ARDAT

The ARDAT project is a precompetitive 25.5M,5 yearconsortium that brings together the leading expertise of 34 academic, nonprofit, and private organizations, with the shared goal of helping to standardize and accelerate development of Advanced Therapy Medicinal Products (ATMPs) and potentially helping to bring these transformative treatments to patients sooner. For more information on ARDAT, visitwww.ardat.org

TheIMIis Europe's largest public-private initiative aiming to speed up the development of better and safer medicines for patients. IMI supports collaborative research projects and builds networks of patients, industrial and academic experts in order to boost pharmaceutical innovation in Europe. IMI is a joint undertaking between the European Union and the European Federation of Pharmaceutical Industries and Associations (EFPIA). For further details please visit:http://imi.europa.eu/

This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No [945473]. This Joint Undertaking receives support from the European Unions Horizon 2020 research and innovationprogrammeand EFPIA.

This communication reflects the views of the authors and neither the IMI nor the European Union, EFPIA or any other partners are liable for any use that may be made of the information contained herein.

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Through Public-Private Partnership, Scientists are Working to Better Understand Gene Therapy and How it Could Help Patients With Rare Diseases |...

Aclinical trial testing a novel gene therapy for a rare neurological disease has been put on hold after one of the participants in a Phase 3 trial developed a bone marrow disorder that can lead to cancer. The pause, announced Monday by the trials sponsor, bluebird bio, and mandated by the US Food and Drug Administration (FDA), was taken out of an abundance of caution, the companys president of rare genetic diseases, Andrew Obenshain, said in a recent quarterly call.

The therapy targets cerebral adrenoleukodystrophy, which is caused by a mutation in the gene for an enzyme called adrenoleukodystrophy protein (ALDP) that breaks down fats. The mutation causes fat to build up in the brain, where it breaks down the insulating myelin that allows neurons to communicate with one another. Because the gene is on the X chromosome, women typically have a least one good copy, so the disease primarily strikes men. Left untreated, it causes damage to hearing, vision, cognition, and coordination. It is often fatal.

Bluebirds gene therapy uses an engineered lentivirus to correct the mutation associated with the disease. Lentiviruses belong to the same family as HIVretrovirusesand have been widely used in gene therapies and other medical applications for many years. While other virus-based platforms using retroviruses had previously been linked to cancer among patients, it is only recently that a lentivirus has been implicated in such an outcome: in February of this year, bluebird bio paused another trial, one for a blood disorder, after two patients developed leukemia-like cancer, Sciencereports, although it was later determined that the virus was likely not the cause, and the trial resumed.

Most in the field were hoping that we would not see such an event with lentiviral vectors, Harry Malech, a gene therapy researcher at the National Institutes of Health, tells Science, adding, I dont think anybodys been . . . saying this couldnt happen.

The cerebral adrenoleukodystrophy therapy involves taking samples of a patients bone marrow and treating the stem cells therein with the modified virus that contains a corrected copy of the gene that encodes ALDP. After a round of chemotherapy to reduce the persons bone marrow cells, the treated cells are infused back into the patient. Thereafter, the patients stem cells produce healthy blood cells with a functional copy of the gene for ALDP. The therapy entered the market in Europe last month following a previous safety and efficacy trial that included 32 patients. A second trial, the one that has now been paused, was set to finish in 2024.

Speaking on the call, bluebird bios Chief Scientific Officer Philip Gregory said that one patient in the second trial developed myelodysplastic syndrome (MDS), a blood disorder that sometimes leads to leukemia, and another two had abnormal bone marrow cells that could progress to MDS. When scientists examined their cells, they found lentiviral DNA inserted at a site in the genome that has previously been linked to MDS in retrovirus-based therapies, suggesting that the virus may have caused the changes.

Specifically, Gregory said the issue is likely caused by the virus promoter, the DNA sequence that turns on the therapeutic copy of the gene. To ensure the gene produces enough ALDP in the brain to be an effective treatment, the researchers needed a strong promoter, but as a consequence, the promoter had off-target effects, turning on other genes in the area around the mutation, including cancer genes, Gregory speculated.

Donald Kohn, a gene therapy researcher at the University of California, Los Angeles, who helped design the viral vector, tells Sciencethat in the time since bluebird bio first began developing the therapy, researchers have identified other promoters that might be able to do the job with a lower risk of causing cancer. He adds that this particular incident shouldnt preclude scientists from pursuing other lentivirus treatments, as the issue seems to come down to design, and Kohn doesnt know of any other lentivirus therapies that use the same type of promoter.

Panam Malik, a hematologist at Cincinnati Childrens Hospital who was not involved in the work, similarly tells Science that virus-based platforms should be highlighted for the good they have done. This is a severe adverse event, she says, but adds, we should never lose sight of the fact that so many patients . . . have been helped. Despite this rare incident, the findings could help scientists and researchers design safer and better vectors for the future.

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Participants Diagnosis Halts Gene Therapy Clinical Trial - The Scientist