Category Archives: Genetic medicine

Call it The Case of the Dueling Genes. A woman at high risk for early-onset Alzheimers disease because of an inherited genetic mutation unexpectedly stayed dementia-free for decades, and investigators believe a different genetic mutation may have protected herproviding potential clues for an Alzheimers treatment.

The womans family carries a genetic mutation known to cause early-onset Alzheimers. However, she did not develop signs of the disease until her 70s, nearly 30 years after the expected onset. Researchers suspect she may have been protected because she also had two copies of the APOE3 Christchurch (APOE3ch) gene variant. Findings of a case study published in Nature Medicine suggest that two copies of the APOE3ch variant may protect against Alzheimers.

Early-onset Alzheimers is rare, representing less than 10% of all people who have the disease. Risk for both early- and late-onset Alzheimers disease is affected by genetic factors.

For the study, investigators at Massachusetts General Hospital, in collaboration with other researchers from Colombia, Boston, and Phoenix, looked at genetic data from a Colombian family with more than 6,000 living members. Family members who carry a rare gene mutation called Presenilin 1 (PSEN1) E280A have a 99.9% risk of developing early-onset Alzheimers disease.

This woman carried the PSEN1 E280A mutation. However, she also had two copies of the APOE3ch gene variant, unlike any other affected relative. Imaging tests showed that she had large amounts of amyloid protein deposits, a hallmark of Alzheimers disease, in her brain. But the amount of tau tangles, another hallmark of the diseaseand the one more correlated with how thinking and memory are affectedwas relatively low.

Experiments as part of the study showed that the APOE3ch variant may reduce the ability of APOE to bind to certain sugars called heparan sulphate proteoglycans (HSPG). APOE binding to HSPG has been implicated as one mechanism that may contribute to the amyloid and tau protein deposits that destroy the brain. The research suggests that a drug or gene therapy that could reduce APOE and HSPG binding has the potential to be a new way to treat or prevent Alzheimers disease.

The study was funded in part by the National Institute on Aging.

Source: NIH, November 4, 2019

See the original post:
Her Genes Cause Early Alzheimer'sSo How Did She Avoid It? - Managed Care magazine

These Five Life Science Organizations are Striving to Cure HIV

For those that lived through the devastation and horror of the HIV/AIDS epidemic of the early 1980s, effective treatment, let alone a cure for Human Immunodeficiency Virus (HIV), seemed unimaginable.

Some three decades later, a host of Maryland life science companies and research organizations are getting closer to making what was once unthinkable, real.

So little was known about this devastating immune disorder in the early phases of the HIV/AIDS epidemic.

In the early days of the HIV/AIDS crisis, the BioHealth Capital Region was the epicenter of HIV/AIDS research, with much of this groundbreaking research occurring within the lab of the now famed NIH researcher, Dr. Robert Gallo. In 1983 and 1984 Gallo and his collaborators co-discovered and confirmed that the virus responsible for the killer disease known as AIDS was human T lymphotropic virus type III (HTLV-III). Gallo and the company went on to develop the first test that identified the virus in humansthe HIV-antibody blood test.

By 1983 the disease had started to spread globally. By 1999, approximately 33 million people across the globe were living with HIV and an estimated 14,000,000 million people had died from AIDS since the epidemic began.

The 1995 approval of Highly Active Antiretroviral Treatment (HAART), which was the result of the remarkable, collaborative efforts of the scientific community, led to the reduction of AIDS-related deaths and hospitalizations by 60-80%. A short time later what was once a three-drug cocktail had been transformed into a pill taken once daily by HIV sufferers.

As of 2017, 19.5 million people are estimated to be receiving antiretroviral treatment globally. While one of the greatest achievements in medical history, HAART and subsequent treatment forms do not cure HIV. Within just weeks of stopping treatment, the virus returns to full strength and chronic inflammation caused by suppressed HIV can lead to adverse health effects over the long term. Current HIV treatments control it but do not cure it; in fact, research shows that those being treated for HIV are more susceptible to other diseases and health risks at an earlier age.

Despite the amazing advancements in HIV/AIDS treatments, HIV/AIDS continues to be a major global health threat.

It would be a fitting conclusion for an HIV cure to emerge from the state where the virus was first linked to AIDS and where the first human diagnostic was developed.

Multiple Maryland companies and research institutions are on the leading-age of HIV research and development, making the state a hotbed of potential next-generation HIV therapies and, possibly, the source of a cure for this devastating global health issue. Some of the most promising cure candidates are coming out of Marylands thriving cell and gene therapy cluster.

Lets take a look at some of the amazing progress thats happening right now across Maryland and take a deeper dive into five of the leading organizations that are on a mission to develop the first HIV cure.

AGT is a gene and cell therapy company with a proprietary gene-delivery platform to rapidly develop gene and cell therapies to cure infectious diseases, cancers and monogenic disorders.

One of its lead gene therapy products is a potential functional cure for HIV. AGT just announced that it has submitted the IND to the FDA for a Phase I trial of its autologous cell therapy for HIV.

While HIV has become a manageable chronic virus for many, in less developed countries HIV/AIDS is still a devastating illness. Developing an HIV cure would relieve millions from the side effects of antiretrovirals used to suppress HIV and prevent AIDS, avoid the serious quality-of-life issues of long-term treatment, and potentially save the lives of countless others.

AGT is currently developing a highly innovative HIV treatment strategy that uses the tools of genetic medicine for immunotherapy to potentially create a functional cure for HIV.

If we are successful, patients will be able to throw away their medication, will not progress to AIDS, and will be immune to future HIV exposures.

The potential single-dose treatment would be delivered as a genetically-modified cell product made from a patients own cells. AGTs strategy is unique because it focuses on the key immune cells responsible for catalyzing strong immunity against a virus. AGTs treatment strategy seeks to protect these cells; one of the first cell subsets to be disabled by HIV. This subset of cells is understood to be critical to building an immune response to any virus. If achieved, the cells natural process of immunity is restored and any future rise of HIV in the body will be attacked by an individuals own immune system.

AGTs treatment includes the production of an autologous cell product that is highly enriched for HIV-specific CD4+ T cells that are then transduced with a lentivirus vector known as AGT103 to protect against HIV-mediated T cell depletion. The combination of these enriched cells and the lentiviral vector forms a cell product AGT has dubbed AGT103-T. This cell product is delivered intravenously to HIV patients. AGT103-T should control viremia and work to remove infected cells from the body, thus eliminating the need for lifelong antiretroviral treatment.

AGT is currently collaborating with the Institute of Human Virology, University of Maryland Baltimore to collect leukapheresis specimens from HIV positive individuals for an ongoing observational study performing and qualifying the cell process, which is explained in greater detail here. The company expects its potential HIV cure to move into clinical trials in the next six months.

IHV is part of the University of Maryland School of Medicine and is a recognized leader in the virology field. IHV was founded by Dr. Robert C. Gallo who co-discovered HIV and developed the first HIV blood test.

IHV is heavily focused on HIV/AIDS research and the organization is currently progressing a promising HIV/AIDS vaccine through its pipeline. IHV01 (FLSC-001) has completed a Phase I trial and was supported, in part, from funding provided by the Bill and Melinda Gates Foundation.

This potential HIV/AIDS treatment seeks to neutralize the different strains of HIV found across the globe from the moment of infection. IHVs HIV/AIDS research is focused on the CCR5 chemokine receptor that plays a crucial role in HIV-1 infection and as such offers an important potential therapeutic target. (IHV Website). IHV is striving to develop biological HIV/AIDS treatments that are less expensive, have fewer adverse impacts and are more accessible to patients around the globe.

Lentigen is a leading provider of custom lentiviral vectors used in cell and gene therapy research and development. For HIV, Lentigen is at the forefront of efforts to use Chimeric Antigen Receptors (CAR) T-Cell therapy to improve the treatment of HIV and possibly cure it.

Lentigen, along with researchers at the University of Pittsburgh in Pennsylvania and the Albert Einstein School of Medicine, has been conducting a promising study of the use of CAR T in the treatment of HIV. The researchers developed duoCAR T cells that were able to kill white blood cells infected with a range of HIV variants. Testing in mice also produced promising results. Mice with humanized immune systems were simultaneously injected with CAR T cell and HIV-infected human cells into their spleens. When the spleens were examined a week later, five of the six mice had no identifiable HIV DNA and their viral levels had decreased by 97.5% (source: Science).

The study hopes to test the duoCAR T approach in HIV-infected people in the near future.

IBBR is a joint research enterprise of the University of Maryland, College Park and the National Institute of Standards and Technology (NIST). Last year IBBR received $3.9M from the National Institutes of Health (NIH) to develop a multi-specific, single-agent antibody therapeutic against HIV-1 to block virus infection and to clear the reservoir of HIV-infected cells from the body, according to an IBBR press release from November 2018.

The project is led by Dr. Yuxing Li, Associate Professor, Department of Microbiology and Immunology, University of Maryland School of Medicine, and Fellow at the Institute for Bioscience and Biotechnology Research (IBBR), in collaboration with Dr. Qingsheng Li, University of Nebraska-Lincoln, and Dr. Keith Reeves, Harvard Medical School/Beth Israel Deaconess Medical Center.

IBBRs research has focused on overcoming some of the limitations of existing antiretroviral (ARV) HIV treatments, including adverse side effects, ARV treatment drug resistance and how HIV integrates into the human genome, creating pockets of HIV that ARV cannot eliminate. Dr. Li and his group have produced bi and tri-specific antibodies that demonstrated neutralization of 95% of circulating HIV-1 viruses. These bi and tri-specific antibodies can also bind to multiple locations on the HIV-1 surface glycoprotein Env, which could potentially thwart treatment resistance via mutation. The team is now working to optimize their multivalent antibody constructs to recognize Env proteins on the surface of latently infected host cells, and to signal other immune system components to destroy those cells that contain the hard-to-reach viral pockets, or as the team calls them, a viral reservoir. (IBBR press release)

NIAID has been at the forefront of HIV research for decades and continues to be a major player in the research and development of possible HIV treatments and potential cures. NIAIDs research into HIV played a critical role in developing ARV drugs that transformed HIV into a chronic condition rather than a fatal infection.

NIAID-supported research has led to many ARV drug improvements, including reducing the number of pills required, diminishing adverse impacts and identifying the best drug combinations. The organization works with many leading global HIV/AIDS research organizations to identify and develop better HIV treatments.

NIAID is focused on both developing new HIV treatments as well as supporting other researchers and research organizations investigating new therapies. The ultimate goal is to potentially make HIV treatment a single dose, lifetime treatment, and, eventually, the complete eradication of HIV. NIAID is involved in many research and development projects focused on HIV and there are too many to dig into in a single article. Some of their current HIV research and development efforts are focused on investigational long-acting HIV drugs, rilpivirine LA and cabotegravir LA, for patients that have had difficulty following conventional antiretroviral therapy programs. Another NIAID study will test combining monthly injections of cabotegravir LA and infusions of an NIAID-discovered broadly neutralizing antibody called VRC01LS to see if the combination can keep HIV suppressed in people whose infection was previously controlled by antiretroviral therapy.

The organizations support has also helped in the discovery of the experimental drug islatravir (also known as EFdA or MK-8591) and maturation inhibitors. NIAID also has partnered with the Maryland industry, including a research collaboration agreement with AGT for research studies on the companys cell and gene therapy for HIV/AIDS.

A partnership between NIAID, Frederick National Labs for Cancer Research (operated by Leidos Biomedical Research, Inc.) and a team of collaborators recently developed 38 new simian/human immunodeficiency viruses (SHIVs) for prevention and treatment studies. These new SHIVs have closed a gap that previously existed in HIV research. These SHIVs are pathogens engineered in the lab that can help in the investigation of potential new HIV therapies as well as other treatments and vaccines.

These SHIVs target HIV subtype C, which causes approximately half of all HIV infections, and were created using HIV samples from people recently infected, allowing better modeling of more current forms of HIV subtype C circulating globally. The stronger modeling will increase pre-clinical researchs ability to predict effectiveness. Other SHIVs had used samples acquired from patients that had been infected long before the sample was pulled, limiting the SHIVs effectiveness against more current strains of HIV. While improvements are still needed, including challenges with replication, these new tools for HIV research and discovery hold tremendous promise.

In the late 1970s and early 1980s finding a cure for HIV/AIDS wasnt even on the radar. The scientific community was racing to understand the fundamentals of a virus that was rapidly spreading devastation and death across the globe. The speed with which the medical community came to understand the disease and to develop treatments like HAART is one of the truly amazing stories of the 20th century.

One or several of these Maryland companies and research institutions have a real chance to achieve what was once unthinkablefinding a cure for HIV that could help tens of millions of people across the globe live better, healthier and longer lives.

If an HIV cure emerges from Maryland, the BHCR community will have helped write the final chapter of HIV/AIDS terrible yet hopeful story.

Steve has over 20 years experience in copywriting, developing brand messaging and creating marketing strategies across a wide range of industries, including the biopharmaceutical, senior living, commercial real estate, IT and renewable energy sectors, among others. He is currently the Principal/Owner of StoryCore, a Frederick, Maryland-based content creation and execution consultancy focused on telling the unique stories of Maryland organizations.

Link:
Heres Why the First Cure for HIV Could Emerge from Maryland - BioBuzz

A woman in Colombia was destined to develop Alzheimers disease in middle age due to a genetic mutation. But she never did. In fact, she made it into her 70s showing no signs of dementia.

A few years back, the woman partook in a study at the University of Antioquia in Colombia that looked at 6,000 people that she was distantly related to. About a fifth of these participants, including the woman in question, had a genetic predisposition to Alzheimers. She carried a mutation in the gene responsible for a protein called presenilin 1, giving her a greater than 99 percent risk of developing dementia and cognitive issues in her 40s or 50s. But she remained in good cognitive health.

To satisfy the curiosity of baffled scientists, she headed to Boston in 2016 to have her brain, blood, and genome examined. Scans of her brain revealed high levels of amyloid protein, a hallmark of Alzheimers disease. However, she was symptom-free, suggesting something mysterious was protecting her from its effects.

Next, the researchers sequenced her genome, finding that she had a very rare mutation of a gene called APOE. This gene has previously been implicated in Alzheimers one variation can increase risk, another can decrease it, while the most common type has no effect. However, the woman had two copies of another variant, known as Christchurch, which was discovered in 1987 in Christchurch, New Zealand. The findings are reported in Nature Medicine.

The researchers think that the Christchurch mutation might prevent the APOE protein from binding with certain sugars, a process implicated in the build-up of amyloid proteins and tau proteins, another Alzheimers hallmark, in the brain. Therefore, a drug that inhibits this process could stave off the disease, although such a drug likely would not be available soon.

Early-onset Alzheimers affects a small minority of people and only about 5 percent of Alzheimers patients are diagnosed with it. The condition can have substantial impacts on a persons life as it tends to develop during your 40s or 50s, decades before Alzheimers symptoms usually start to set in. Alzheimers is a progressive disease, meaning that symptoms like memory loss, confusion, and delusions get worse over time. Theres currently no cure, so gaining a better understanding of what causes the condition is key.

Sometimes close analysis of a single case can lead to a discovery that could have broad implications for the field, said National Institute of Aging Director Richard J. Hodes in a statement. We are encouraged that as part of our wide array of studies, this research in the unique genetic makeup of an exceptional individual can reveal helpful information.

Read more here:
Colombian Woman In Her 70s Immune' To Alzheimer's Thanks To Rare Genetic Mutation - IFLScience

Dashing through the snow at 25 miles an hour,Heather Huson97 got her first thrill as a musher at age 7. From then on, she was hooked on dog sledding, and raced competitively for almost 30 years throughout North America.

By the end of her racing days, she had competed twice in sled dog racings equivalent to the Olympics the International Federation of Sleddog Sports World Championships. And she ended her racing career with a bang, winning an extremely competitive six-dog class race at the 2004 Tok Race of Champions in Tok, Alaska.

Heather Huson shares time with a sled dog at the Baker Institute.

Now an assistant professor of animal science, Huson is co-leader of a $4.2 million project studying close to 100 Alaskan sled dogs between the ages of 8 and 13, former athletes past their glory days. The study, which began in 2018, is a quest for one of the holy grails of medicine: how to slow aging.

This project allows me to work with sled dogs again, but now Im studying their aging and health, said Huson, a molecular geneticist in the College of Agriculture and Life Sciences.

Huson and co-leaderDr. John Loftus, assistant professor of small animal medicine in the College of Veterinary Medicine, are trying todetermine whether a drug that inhibits an enzyme called reverse transcriptase can mitigate aging and extend life in older dogs. Private donations fund the project through the Vaika Foundation, a nonprofit group of scientists and veterinarianson a mission to extend the health and life span of domestic animals.

The project will serve as a proof of principle for whether reverse transcriptase inhibitors could be an elixir. If confirmed, new finely tuned drugs could be developed for both dogs and humans.

While we love dogs, and we care about extending the life span of dogs for its own right, this is also a really good model for people, hopefully, in the future, Loftus said.

Genetics of aging

Other researchers, including project collaborators at the Roswell Park Comprehensive Cancer Center in Buffalo, New York, have found evidence in mice that reverse transcriptase inhibitors suppress tumors and extend life span.

The next step was to go to a model organism thats more closely related to humans in similar environments, and more similar to the types of diseases that people get, Huson said.

While we love dogs, and we care about extending the life span of dogs for its own right, this is also a really good model for people, hopefully, in the future.

John Loftus

In mammals, viruses that infected distant ancestors left behind some of their DNA, which are called genetic elements.

As we age, were finding these normally dormant DNA elements get turned on and then behave like viruses in the body, said Loftus, a veterinarian and researcherwho leads the immune system analysis on this project.When DNA elements get turned on, they can encode [for] a number of proteins, and reverse transcriptase is one of them.

In turn, reverse transcriptase plays a role in duplicating more of these genetic elements, which become randomly inserted in the genome and can lead to mutations and cancer.

And since these elements act like viruses in cells, they also trigger an immune response, which creates inflammation.

The federally approved drug being tested in the sled dog project is commonly prescribed to people for viral infections.

Our approach is going to be to give the dogs a reverse transcriptase inhibitor to turn the transcriptase off, Loftus said, and hopefully reduce inflammation, reduce the incidence of cancer and other diseases related to mutations and DNA damage, and ideally increase life span.

Heather Huson watches as a sled dog runs during play time in a fenced field at the Baker Institute for Animal Research at Cornell.

Why Alaskan sled dogs?

Dogs offer many advantages over mice as research subjects. They share with humans similar lifestyles and aging-related diseases like cancer and cognitive dysfunction, and serve as a model for studying Alzheimers disease.

Originally, the researchers proposed to study pet dogs. But maintaining a uniform diet for all participants and trusting owners to administer the drug consistently proved too unreliable.

We had the idea instead to create a colony of dogs we had control over, Huson said. They realized athletic dogs were housed in groups, in kennels, and as they age, owners kept their best dogs and often sold the rest to hobbyists or as pets.

So that gave us an avenue for how we could get these dogs, Huson said.

For her doctorate, Huson studied the genetics and selective breeding in Alaskan sled dogs at the University of Alaska, Fairbanks. She discovered that sled dogs are a genetically distinct breed. They have undergone intense selection for such traits as athleticism, but at the same time are subject to an open breeding scheme,with a diverse gene pool that makes for fewer genetic issues and diseases than pure breeds.

John Loftus greets a sled dog at the Baker Institute for Animal Research.

Yet they create a unique population that is still homogenous that we can study and say, this response to the drug is potentially related to the drug and not because its a poodle versus a beagle, Huson said.

In late May 2018, Huson and Loftus began acquiring dogs, which they kenneled at the Baker Institute for Animal Research at Cornell. Huson traveled twice to Alaska, and she and others, including students, picked up dogs from Canada, Michigan, Minnesota, Oregon, Washington and other states.

Locating dogs and bringing them to the Baker Institute required countless cross-country trips on planes and by vehicle. By September 2018, they had 102 dogs for the study. In March 2019, the researchers collected the firstbaseline data.

Testing aging over time

To test the drugs effectiveness, Huson and Loftus have been quantifying aging in the dogs every six months through three avenues immune function, behavior and physical condition. All the tests are noninvasive or minimally invasive.

They are testing two types of immune responses: adaptive responses that react quickly to infections; and innate responses where the immune system recognizes and delivers specific antibodies to fight a pathogen that previously entered the body. They are also checking blood for increases in markers for inflammation.

Four cognitive dysfunction behavioral tests involve an empty behavioral testing room with a video camera to record lone dogs as they encounter such things as a stranger sitting still in a chair, a familiar or novel toy, or a mirror.

Heather Huson racing in an Alaska Dog Mushers Association Challenge Series race in 2005 at the Jeff Studdard Sled Dog Race Track in Fairbanks, Alaska.

For physical tests, dogs are fitted with a racing harness and are trained to run on a treadmill with heart rate and electrocardiogram monitors. The treadmill has special sensors under the belt to record the pressure of each footfall, to detect limping that could come with arthritis. Another test times dogs as they pull one-and-a-half times their weight a distance of 40 yards using a pull harness.

It will take years to gather enough data for the researchers to make a definitive statement about the drugs effects. But funds have already been allotted to provide the dogs with a high quality of life until they die of natural causes.

Twice a day the dogs go outside for play time. As soon as the kennel doors open, the dogs, tongues flapping, scurry excitedly down a long hallway toward the light of an open door that leads to three separate fenced fields where they play, run, sniff the grass and greet the student volunteers outside.

It reminds Huson of her childhood, when her family owned as many as 50 sled dogs.

I used to train dogs to run all the time, Huson said. Now were training them to run in a slightly different scenario. Its fun and rewarding. And, its therapy for us.

Read the original post:
Sled dogs lead the way in quest to slow aging - Cornell Chronicle

Dylan Stoll |Health Editor

Featured Image:Olaparib discovered to have stopped the spread of prostate cancer in patients than standard treatments. |Courtesy of Pixabay

With the recent start to the Movember month of prostate cancer awareness, it is fit to recognize the newfound use for olaparib a precision drug used to treat prostate cancer and the incredible results it has shown in its third phase of randomized clinical trials.

The trial involved 400 men split into two groupings based on their genetic mutations. The first group had mutations in the genes referred to as BRCA1, BRCA2, and ATM, while the second group had mutations in select genes involved in DNA repair.

The aim of the trial was to compare how effective olaparib was at fighting prostate cancer compared to the standard treatments used today. Overall, it was found that olaparib halted the cancers spread in more patients than standard treatments by approximately 8.5 per cent.

However, the difference was found to be significantly larger in the group that had BRCA1, BRCA2, and ATM genetic mutations: a difference of 18.6 per cent.

Interestingly, olaparib was originally developed as a treatment for breast and ovarian cancer. Olaparib, and similar drugs, seem to respond most effectively to BRCA genetic mutations, or what are often referred to as breast cancer genes. Though these genes are well known to be associated with breast cancer, they are also seen as a high risk factor in developing prostate cancer for men.

The reason that this drug is capable of treating two seemingly very different and very gender-oriented cancers is because in both cases, olaparib is focused on blocking the PARP enzyme an enzyme involved in repairing faulty DNA. Though it seems counter-intuitive, their aim is to stop DNA repair so cancer cells can be pushed into apoptosis, or cellular suicide.

Maha Hussain, an oncologist at Northwestern University Feinberg School of Medicine, showcased these discoveries at an oncology meeting.

Essentially, its going after the same target: PARP, Hussain said.

The FDA has approved olaparib for breast and ovarian cancers, but has yet to approve for prostate cancer. If they do, it will be a first in the use of precision medicine; in other words, it will be a first in producing a medicine based on an individuals genetic make-up.

Prostate cancer therapy has been, generally, a one-size-fits-all approach, Hussain said. With regard to precision medicine, I think that weve opened up the door.

Read more:
Olaparib breast/ovarian cancer treatment found to be effective against prostate cancer - Excalibur Online

MONTREAL A "surprising" and "provocative" study of two cohorts of women who developed peripartum cardiomyopathy (PPCM) in Canada and in the United States suggests that socioeconomic factors differences in the healthcare systems rather than genetics may explain racial disparities in outcomes.

The findings should be viewed as only hypothesis-generating, the authors caution.

Maxime Tremblay-Gravel, MD, from Universit de Montral, Canada, who is now a heart failure fellow at Stanford University, Palo Alto, California, presented findings from a study that involved 114 women in Canada and the United States (including 24 African Americans) who developed PPCM. The study was presented here at the Canadian Cardiovascular Congress 2019.

"It's been pretty accepted in the literature...that African American women who have PPCM have a worse prognosis," Tremblay-Gravel told theheart.org | Medscape Cardiology.

But contrary to previous research, their study showed that in Canada, recovery of left ventricular ejection fraction (LVEF) among black women after PPCM was similar to that among women of other ethnicities.

On the other hand, LVEF recovery among the African American women in the American cohort was dampened, consistent with prior findings.

"I don't think African American women are different between the United States and Canada," said Tremblay-Gravel. He noted that it's probably the healthcare delivery that's different.

This is "clearly only a hypothesis," he continued, but many socioeconomic factors may explain why African American women with PPCM in the United States fared worse than their counterparts in Canada.

In the United States, women who developed PPCM may have had "less insurance, less education, [and] less trust in the medical care system...whereas here, we have a universal healthcare system."

This is very topical, he noted, as candidates for the Democratic Party leadership are proposing that the United States adopt Medicare for all, "which is basically a system that would be a little bit more similar to Canada."

"This small study is interesting and provocative in suggesting both that the differences in outcomes between African American vs nonAfrican American women relates to socioeconomic status rather than race and that healthcare in Canada addresses these issues better than in the US," Zolt Arany, MD, PhD, Perelman School of Medicine, University of Pennsylvania, Philadelphia, told theheart.org | Medscape Cardiology in an email.

Arany, who was senior author of a previously reported US study involving 121 African American and 99 nonAfrican American women with PPCM, cautioned that "the numbers are very small, however, making a false positive conclusion not unlikely, and larger studies are needed."

The findings "indicate that the differences in genetic background are not the main reasons for differences observed in LV recovery," Johann Bauersachs, MD, professor and director of the Department of Cardiology and Angiology, Hannover Medical School, Germany, told theheart.org | Medscape Cardiology in an email

Bauersachs, who wrote a commentary that accompanied the article by Arany and colleagues, agreed that the cohorts in the current study were small.

However, PPCM is rare, and "even the US, 'big' Investigations of Pregnancy-Associated Cardiomyopathy (IPAC Study)," he noted, "report on only a few more than 100 patients.

"I suspect," he suggested, that black women "have better access to healthcare services in Canada than African Americans in the US."

According to Bauersachs, the results "clearly indicate that all efforts should be made to guarantee the same optimal care for African American as for nonAfrican Americans with PPCM, both in the acute and the chronic phases."

He is lead author of a recently published position statement from the Heart Failure Association of the European Society of Cardiology that summarizes diagnosis and optimal care for patients with suspected PPCM.

Peripartum cardiomyopathy is "a potentially life-threatening condition typically presenting as heart failure with reduced ejection fraction (HFrEF) in the last month of pregnancy or in the months following delivery in women without another known cause of heart failure.

"It is a very rare disease, affecting 1 in 4000 young women who are pregnant," Tremblay-Gravel noted.

"Most women recover, but some don't," he said, "and it's a very underrecognized disease.

"As shortness of breath, fatigue, and leg [edema] are common in the peripartum period, a high index of suspicion is required to not miss the diagnosis," the authors of the European position paper advise.

"We were interested in knowing whether being an African American portends a worse prognosis because of socioeconomic factors or because the disease itself is worse in African Americans," Tremblay-Gravel said.

The Canadian cohort comprised 62 women, including 16 African American women (35%), who were treated for PPCM in hospitals in the province of Quebec during 19942015.

The American cohort consisted of 52 women with PPCM, including eight African American women (15%), who were seen at Stanford Hospital during 19912017.

The mean ages of the women in each of the cohorts were similar, at around 32 years.

In the Canadian cohort, improvements in LVEF were similar among African American and nonAfrican American women, from 30% to 55% and from 28% to 52%, respectively (P = .27).

In the American cohort, improvement in LVEF among the nonAfrican American women was similar to that of the Canadian women (going from around 30% to 50%), although for African American women, recovery of LVEF function was less (from around 25% to 38%; P = .02).

The next steps in their ongoing research, Tremblay-Gravel said, is to see whether insurance coverage and social status (estimated from ZIP codes) play a role in prognosis. They are also performing whole-exome sequencing for more than 100 women with PPCM to see whether African American women have a different genotype.

Canadian Cardiovascular Congress 2019: Abstract 060, presented October 24, 2019.

For more from theheart.org | Medscape Cardiology , follow us on Twitter and Facebook

Continued here:
Peripartum Cardiomyopathy Recovery in Blacks Better in Canada? - Medscape

Aniridia is a congenital disorder that causes severe eye problems, and also affects metabolism sometimes resulting in severe obesity. It is associated with mutation of a major developmental gene, called PAX6. People born with aniridia have no irises in their eyes, often are legally blind, and whatever eyesight they have continually worsens with age. The disease is uncommon, but disorders associated with genetic mutations can involve common eye problems, including cataracts and glaucoma.

To better understand and treat aniridia and other disorders involving the PAX6 gene, researchers and clinicians at the University of Virginia are combining clinical research, patient treatment and powerful basic science investigations.

They have organized for this weekend a major symposium focused on congenital eye disorders and the PAX6 gene, bringing together top researchers from the University and around the nation and Europe, along with patients living with aniridia and their families.

The organizers are Rob Grainger, W.L. Lyons Brown Professor of Biology, and Dr. Peter Netland, Vernah Scott Moyston Professor and Chair of Ophthalmology. Both are members of UVAs Brain Institute, and are research collaborators.

In his studies, Grainger uses frogs that are mutated to mimic aniridia and other eye disorders. Netland treats congenital eye disorders and conducts clinical research.

Here, the two colleagues explain for UVA Today readers their research and the goals of the 2019 John F. Anderson Symposium, Aniridia-PAX6 and Beyond

Q. Why did you organize this particular kind of symposium, connecting how eyes develop before birth and genetic diseases that can follow?

Grainger: Each of us works on different perspectives concerning eye formation. In my lab, we focus on how the eye is constructed during embryonic development; in Peter Netlands practice, on how to treat diseases that affect these processes.

These are complementary approaches two sides of the same coin. In one case we focus on the assembly of the eye, and in the other, what occurs when the eye is not constructed properly, leading to multiple serious consequences for the patient.

This interplay highlights the importance of looking at these two perspectives together, a collaboration in this case between the two of us (one in the School of Medicine and the other in the College of Arts & Sciences) each providing insights for the other.

Netland: The value of this kind of interaction has motivated us to bring together many of the worlds experts who pursue these two perspectives, including as well a third group: patients and their families who want to learn more about these diseases and treatments. There are few meetings held with this sort of three-way interaction in mind, and we anticipate that many fruitful insights and collaborations will emerge.

Q. Dr. Netland, why is aniridia an area of particular interest to you?

Netland: More than 20 years ago, I spent an extended period of time in the Middle East and India, where there are high rates of consanguinity and congenital eye disorders, which led to a book I produced about pediatric glaucomas, other scholarly contributions and development of my clinical skills. About 20 years ago, I cared for an infant with aniridia and the family of that patient. The potentially disabling issues for the patient, which involved all parts of the eye, and the compelling issues that the family were dealing with drew me toward this condition.

Another patient was very influential to me, because she was a patient advocate and mother of an affected child. I began to see increasingly larger numbers of patients with congenital eye disorders and aniridia, and I developed further clinical and academic interests in the topic.

Around 20 years ago, we started biannual meetings with the patient advocacy group Aniridia Foundation International, and developed connections with other patient support groups, which helped shape the direction of our efforts. With increasing contact with the patients and their families, I became deeply interested in trying to help these patients.

About 20 years ago, I cared for an infant with aniridia and the family of that patient. The potentially disabling issues for the patient, which involved all parts of the eye, and the compelling issues that the family were dealing with drew me toward this condition.

- Dr. Peter Netland

This is a disease that results from damage to the gene PAX6, already known to be perhaps the most fundamental gene involved in eye formation overall and consequently affecting the entire visual system. However, we knew much less about how to treat the many facets of this disorder; for example, cataract, glaucoma and corneal opacification (scarring), which are frequently acquired by patients. Some of these problems are common in the general population, and have broad significance. Many advances have been made in the past, but there is much more progress that is needed for the future.

Q. Why do you use frogs in your eye research, Professor Grainger?

Grainger: We have been examining eye development in frog embryos for over 20 years in my lab, initially because so much embryology, going back to the beginning of the 20th century, was done on these large, easy-to-obtain-and-raise embryos.

In the early days, we were learning how the different parts of the eye, notably the lens and retina, are formed by interactions between parts of the embryo to form a coordinated whole organ exactly the interactions that are disturbed when things go awry in aniridia patients.

Q. Six years ago the Grainger lab developed a gene-editing technique that allows you to mimic human lesions. How is this advancing eye research?

Grainger: While the utility of the frog system for understanding embryological processes is undisputed, during the decades that we have been doing research, the techniques allowing us to manipulate and understand gene function have blossomed, including genome projects and more recently gene editing the ability to inactivate genes of interest to learn how they function during normal development.

In 2013, we published our first paper using this new technology to inactivate genes critical for eye formation in frogs and to follow in precise detail how things go awry. This has allowed us to make important clarifications in how these genes contribute to development of the eye. Because the frog eye develops much as the human eye, these mutations help us look in detail in a way not feasible in human embryos; thereby allowing us to understand how these genetic errors lead to the problems that occur in human patients. Specifically, we have made mutations in frogs in the PAX6 gene that lead to frogs having aniridia, with features of the animals strikingly similar to those in human patients.

These are complementary approaches two sides of the same coin. In one case we focus on the assembly of the eye, and in the other, what occurs when the eye is not constructed properly, leading to multiple serious consequences for the patient.

- Robert Grainger

Q. What kind of clinical research and therapies are UVA conducting that connect with the basic research?

Netland: We have looked at many of the vision-threatening eye problems in our aniridia patients. We have also found that their mutation is linked with obesity, and have performed clinical trials to evaluate the causes of this. We have performed studies to better understand the mechanisms for some of their clinical problems, such as glaucoma.

We are excited about precision medicine trials identifying patients who can benefit from a specific gene-based therapy and we recently completed a two-year clinical trial evaluating targeted gene therapy. In parallel, similar problems are under study in the frog to complement and build on the work with human patients.

Q. What future do you see for patients with eye disease as this research moves forward?

Netland: We are working with patients with known mutations of a specific gene, so naturally we are excited about precision medicine approaches to these patients. We believe that genetic-based approaches will continue to increase understanding of these diseases and will provide the basis for rational therapy for affected patients, and more broadly for others in the general population who are suffering from the same clinical problems. We believe that new imaging techniques will produce new insights in this area.

Grainger: In the frog, our lab has developed a method for efficiently creating exact patient mutations, again amplifying the opportunities for an integrated approach to precision medicine. There are opportunities with in situ gene modification and other gene-based therapies for addressing problems and improving the quality of life of patients.

Continued here:
Patients, Physicians and Researchers Gather to Probe Genetic Eye Disorders - University of Virginia

In celebration of our 15 Year Anniversary, Academic Editor Ronald CW Ma highlights advancements published in PLOS Medicine in diabetes research and care, including improved precision medicine.

Happy 15th Birthday to PLOS Medicine! I still remember reading about the PLOS journals and the idea of making science accessible to all back when PLoS was first launched. It is amazing how far the Open Access movement has developed, how far that idea has advanced and how scientific publishing has been revolutionized. Congratulations PLOS Medicine on this important milestone!

Among the many articles that I have enjoyed reading in PLOS Medicine over the years, I would like to highlight two for sharing with other readers on this special occasion.

1) Event Rates, Hospital Utilization, and Costs Associated with Major Complications of Diabetes: A Multicountry Comparative Analysis

This paper by Philip Clarke and colleagues from the ADVANCE Collaborative Group, published back in 2010, highlighted the significant economic burden of diabetes and rates of hospitalization resulting from diabetes co-morbidities, using data from the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) study, a landmark multi-centre trial on the treatment of diabetes conducted in 20 countries. Within the ADVANCE trial settings, the study demonstrated important differences in the rates of hospitalization for different diabetes complications in different regions of the world (Asia, Eastern Europe, and established market economies such as Australia, New Zealand and Canada), mirroring epidemiological observations of comparative higher nephropathy rates, higher stroke risk, and lower risks of coronary artery disease among Asians (mostly from Chinese centres in this particular trial) with type 2 diabetes, thereby highlighting the heterogeneity of risk of diabetes complications (and costs) in different populations.

This study also provided important tools to facilitate estimation of healthcare expenditure associated with diabetes in different healthcare settings. At the time of the study, it was estimated that the average annual per capita health expenditure was approximately 216 international dollars in China, and 698 international dollars in Russia, but that the annual hospital costs for people with diabetes experiencing major macrovascular complications such as coronary or cerebrovascular events would be around four and ten times these average per capita expenditures. Perhaps not fully appreciated at the time was the significant burden associated with hospitalization with heart failure, which is a topic of much current interest in relation to recent advances in the treatment of type 2 diabetes.

Although the work was focused on evaluating the economic burden of diabetes in different parts of the world, this work can be considered as an important example of early attempts to deconstruct the heterogeneity of type 2 diabetes. As the diabetes epidemic continues unabated, the healthcare burden of diabetes complications has become a major concern globally.

2) Type 2 diabetes genetic loci informed by multi-trait associations point to disease mechanisms and subtypes: A soft clustering analysis

The second article, by Jose Florez and colleagues, utilized a state-of-the-art multi-omics approach to use available genetic and epigenomic data to probe the issue of heterogeneity of diabetes. The authors showed that identified genetic loci linked to diabetes can be segregated according to underlying biological mechanisms which can be used to classify individuals, to provide a way forward for individualized diagnosis, monitoring and treatment. The study highlighted the potential role of genetic variants related to the beta cell, pro-insulin, obesity, lipodystrophy and liver/lipid traits in accounting for different patient characteristics, as well as long-term diabetes outcomes.

What was particularly interesting is the soft-clustering approach adopted by the authors, which did not require genetic variants to fit into only one pathway, or for individuals to be classified to have diabetes due to only one specific pathophysiological defect, but instead, for individuals to be identified to have scores in each of the above-mentioned categories, and thereby accepting that individuals may have developed diabetes with different contribution from the different underlying pathophysiology. The use of such genetic risk scores may be useful in selecting the most appropriate therapies for individualized care in the future.

Over the last 15 years, the global burden of diabetes has more than doubled, from less than 200 million people affected back in the early 2000s to now more than 422 million people affected globally (with the majority in LMICs). These 2 articles represent important advances in our understanding of type 2 diabetes over the last decade. Whilst the ADVANCE study was a landmark study that generated much interest, the Clarke paper highlighted much of the burden of diabetes complications, and our lack of understanding regarding the heterogeneity in risk of diabetes complications. Together with the Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Veterans Affairs Diabetes Trial (VADT) studies, these landmark studies, published between 2008-2010, have highlighted the potential dangers of hypoglycaemia, and heralded the debate and call for more individualized treatment in type 2 diabetes, and contributed to the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) to propose in their joint position statement on management of hyperglycaemia in type 2 diabetes in 2012 to move away from a one-size-fit-all approach to treatment, but instead adopt a treatment strategy that is more tailored to individual patient profile, disease duration, co-morbidities and expectations. This represented a major watershed moment in the evolution of diabetes research and care.

With recent advances in genomic medicine and the genetics of type 2 diabetes, some of which have been reported in PLOS Medicine, the era of precision medicine in diabetes is very much here to stay. We, as diabetes researchers and clinicians caring for people with diabetes, look forward to further advances in our understanding of how best to treat individuals with diabetes based on their underlying genetics, pathophysiology, and needs, and to improving outcomes for people with diabetes.

Congratulations again PLOS Medicine and we look forward to the next 15 years of exciting advances!

Ronald Ma is Professor and Head of Division of Endocrinology and Diabetes at the Department of Medicine and Therapeutics, The Chinese University of Hong Kong, and co-lead of the Chinese University of Hong Kong-Shanghai Jiao Tong University Joint Research Centre in Diabetes Genomics and Precision Medicine. He is a member of the Executive Board, Asian Association for the Study of Diabetes (AASD), and member of the editorial board of PLOS Medicine.

Acknowledgement: RCWM acknowledge support from the Hong Kong Research Grants Council Research Impact Fund (R4012-18).

Image Credit: stevepb, Pixabay (CC0)

See more here:
Charting the evolution of diabetes research and care | Speaking of Medicine - PLoS Blogs

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Beam Therapeutics, a biotechnology company developing precision genetic medicines through base editing, today announced that it has entered into a collaboration and license agreement with a newly-formed company, Prime Medicine, Inc. to research and develop a novel gene editing technology called prime editing, recently developed by one of Beams co-founders, David Liu, Ph.D., and his group at the Broad Institute of Harvard and MIT.

Under the agreement, Beam has the exclusive right to develop prime editing technology for the creation or correction of any single-base transition mutations, as well as for the treatment of sickle cell disease, both of which Beam is already pursuing with its base editing technology. Transition mutations (e.g. A to G, C to T) are the largest single class of disease-associated genetic mutations, and are also potentially treatable with base editing. Beam plans to evaluate prime editing technology for potential use in future programs.

Part of Beams strategy is to continue to access emerging technologies in gene editing and delivery, while finding new ways to create meaningful options for patients. Our collaboration with, and contribution to the formation of, Prime Medicine is a great example of that approach, allowing us to incorporate prime editing into the Beam platform, said John Evans, chief executive officer of Beam. This partnership enables both companies to advance the technology in distinct spaces, with Beam focusing on the kinds of edits that are most similar to our base editing technology.

As part of the collaboration, Beam is providing initial interim leadership to Prime Medicine for the first year of the collaboration, and will have the right to designate a member on Prime Medicines board. The parties will also grant each other non-exclusive licenses to certain CRISPR technology and delivery technology to enable the development of prime editing products.

About Beam Therapeutics

Beam Therapeutics is developing precision genetic medicines through base editing. Founded by leading scientists in CRISPR gene editing, Beam is pursuing therapies for serious diseases using its proprietary base editing technology, which can make precise edits to single base pairs in DNA and RNA. Beam is headquartered in Cambridge, Massachusetts. For additional information, visit http://www.BeamTx.com.

Originally posted here:
Beam Therapeutics Announces Collaboration and Exclusive License Agreement with Prime Medicine for Prime Editing Technology - Business Wire

Your genes can effect how you respond to medicine. Genetic testing can help identify the right drug at the right dose for a patient. Courtesy of Mayo Clinic

Predicting whether a patient like KerriePrettitorewill have a fatal reaction to a chemotherapy drug or even whether adrugwill work at all is the future of medicine, and its coming soon.

Genetic testing can help predict how patients will respond to a drug,whether its designed to combat cancer or other illnesses. Eventually, that will enable doctors to individualize patient treatment, choosing a medication and dose to best match a patients genetic profile. The goal is to maximize benefit while minimizing harm.

Research inseveral areasalready is having an impact:

KerriePrettitore, a Ridgewood woman,suffered from a genetic abnormality called DPD deficiency, which prevents someone from breaking down the chemotherapy drug 5-FU, or fluorouracil.Agenetic test can help identify patients who may be at risk of developing such a reaction.

Frances national drug-regulating agency began recommending last year that all patientsprescribed5-FU and related drugs be screened for DPD deficiency beforehand. Two hundred people a year die in France because they receive the drug and have DPD deficiency, according to a company that performs such tests. The company recommends that the genetic test be combined with a blood test for maximum accuracy, a practice that has been used in the Netherlands for almost a decade.

In theUnited States, testing for DPD deficiency is not currently recommended by major cancer treatment organizations.But some scientists say change will come soon.

AID-IN-DYING LAW: She hoped for death on her own terms. Then NJ's aid-in-dying law was challenged

DANGER OF SURGERY CENTERS: People are dying after procedures in NJ surgery centers and it's not always made public

Genetic testsmust be inexpensive,produce results quickly and provide clinically useful informationto be cost-effective, said RobertDiasio, an authority on DPD deficiency and director of the Mayo Clinic Cancer Center. The tests currently availablefor DPD deficiencydont yet meet that standard, he said.

The testsdont identify everyone atrisk,and they may identify a mutation in a person who turns out to be able to tolerate the drug, he said. Thats because they test for only a handful of mutations. They dont testfor all possible mutations because it is expensive andyieldsinformation that scientists dont yet know how to interpret.

But the cost of a complete genetic analysis is coming downandthe turnaround time is getting quicker, he noted. Moreknowledge is needed, however,about which mutations are important and which are irrelevant to doctorsmakingprescribing decisions,Diasiosaid.

At the Mayo Clinics Center for Individualized Medicine,astudy of 10,000 Minnesota patientsis underway. It will integratepatients genetic informationinto theirelectronic medical recordsto inform physicians about significant linkages when certain medications are prescribed.

As research advances, more linkages will be discovered and included in the individual records. The goal isto help patients get the right drug at the right dose for their disease personalized medicine at its best.

Become a NorthJersey.com subscriber today and get unlimited digital access and support stories like this one.

JOIN TODAY

Read or Share this story: https://www.northjersey.com/story/news/health/2019/10/29/genetic-testing-cancer-treatment-could-find-perfect-drug-you/2450117001/

See the original post here:
Soon, genetic testing for cancer treatment could match you with the perfect drug - NorthJersey.com