Category Archives: Gene therapy

Xconomy Boston

Gene therapy offers the potential for a long-lasting, if not permanent, treatment for an inherited disease, but cells that divide rapidly, such as those in the liver, present a thorny problem. Because of how they insert themselves in the cells, some forms of gene therapy get diluted as the cells divide.

Its a particular problem in growing children. Cambridge, MA-based LogicBio says it has developed a workaround by combining gene editing with gene therapy. The firm has raised $45 million in additional capital to help bring this technology into human testing, and it is moving from California to the LabCentral shared incubator space in Cambridges Kendall Square.

LogicBio calls its technology GeneRide. The company says its approach can transfer genetic material to specific sites to repair a faulty genetic sequence. The companys focus is metabolic disorders that affect the liver in children. Published research shows that metabolic disorders of the liver can progress to injury affecting other organs. In rare cases, the severity of the disease requires a pediatric liver transplant.

If GeneRide works as the company envisions, the gene therapy would offer a one-time treatment that avoids side effects.

London-based Arix Bioscience (LSE: ARIX) led the Series B round of investment, which was joined by new investors OrbiMed, Edmond De Rothschild Investment Partners, Pontifax, and SBI Japan-Israel Innovation Fund. Earlier investor OrbiMed Israel Partners also joined in the latest investment. In total, LogicBio says it has raised approximately $50 million in financing to date.

Gene therapy remains largely experimental. UniQure (NASDAQ: QURE) received the Western worlds first gene therapy approval in 2012 for alipogene tiparovec (Glybera), a treatment for a rare metabolic disorder. But earlier this year, the company, split between the Netherlands and Lexington, MA, announced it would not seek renewal of its conditional approval, set to expire in October. Patient demand for the drug was limited and the company did not expect that to change.

The first U.S. approval could come soon. Philadelphia-based Spark Therapeutics (NASDAQ: ONCE) is awaiting an FDA decision on a gene therapy for an inherited form of blindness. Cambridge-based Bluebird Bio (NASDAQ: BLUE) last week released early data from a Phase 3 study in patients with beta-thalassemia, a rare blood disorder.

The technologies underlying LogicBios approach were developed at Stanford University by company co-founders Mark Kay, Adi Barzel, and Leszek Lisowski. In addition to its Cambridge site, the company also has scientists in Tel Aviv, Israel.

Frank Vinluan is editor of Xconomy Raleigh-Durham, based in Research Triangle Park. You can reach him at fvinluan [at] xconomy.com

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LogicBio Lands $45M for Gene Therapies in Rare Pediatric Diseases - Xconomy

Inherent Complexity

The inherent complexity of viral vector-based products, due to their physical size, formulation, and the fact that they often utilize a combined drug targeting/delivery vehicle function, makes their physical and biological characterization highly challenging from a regulatory perspective. Consequently, a fallback approach is adopted where the product is defined by the manufacturing process. This approach then makes the introduction of potentially product-impacting process changes difficult to implement and by default, the process becomes locked down within the early stages of development, severely restricting the scope for process improvement and scale up.

Classical process scale up tends to be via a vertical approach, with a focus on increasing the size of single operations (such as fermentation vessels) while keeping similar labor levels, subsequently achieving reduction in cost. This approach is valid if the process is well understood and amenable to linear scale up. The reality is that a large number of the key operations in the production of viral vectors are neither well characterized nor easily scaled. Lack of time and analytical tools will eventually direct developers to take a more horizontal approach to process scale up.

It seems likely that scale up will be based on limited vertical scale up, with multiple and overlapping production streams, potentially exploiting options around the adoption of closed single-use production systems to maximize outputs from production facilities. While this may not be the most efficient approach with regard to labor and facility costs and end-product testing, it is likely to be the only realistic option for many product development groups.

It is inevitable that some process changes will need to be introduced, for example, the requirement to replace purification of vectors by ultracentrifugation, as these processes are perceived as not only being unscalable, but also as highly operator-dependent with regard to yield and purity. The challenge becomes how engineers replace this type of operation. From a regulatory perspective, the key is an understanding of the critical quality attributes (CQAs) that impact product safety, purity, and potency; the critical process parameters (CPPs) required to control them; and the availability of the tools to measure CPPs.

This approach then, in theory, will allow process development groups to develop strategies for introducing and verifying the impact of desired process changes. However, the successful process development of these legacy processes will be dependent on the availability of suitable in-process and final-product assays. There is a clear regulatory, as well as operational, need for drug developers to invest in the analytical tools required to achieve greater understanding of AAV vectors and the processes used to make them for the products to receive commercial licensing.

The production of vectors through transient production routes entails a complex materials supply chain. At the front end is the supply of plasmid DNA constructs used to generate the vectors; clearly the quantities required will not only increase proportionally with the increased scale of vector manufacturing, but also, the associated quality requirements will be increased, moving from materials made to traceable standards to those made to GMP-grade standards (Figure 2). For early-phase development, non-GMP-grade plasmids may be used for the production of material for proof-of principle clinical studies. However, this may not be the case for commercial vectors, where GMP-grade plasmids may be required. One consequence of this will be the potential need for manufacturers to align with suppliers that have large-scale GMP capabilities to ensure the timely and secure delivery of plasmid supplies to support late clinical and commercial production.

At the end of the supply chain is the production of the viral vector drug product. For early-stage development, relatively little focus is given to either the product formulation or the filling process. There is often good reason for this, as material for such development studies is in very short supply, with all available material often directed into clinical studies to demonstrate product efficacy.

The result of this is that the basic formulations used in early-stage development are carried forward into late-stage trials, with the products 0.2-m filtered and hand filled into glass vials and stored at 80C.

Future development activities in the AAV field will need to be focused on identifying formulations that provide long-term stability, potentially moving to +28C storage, and generating meaningful stability data. Fully defining the drug product manufacturing process will also ensure the retention of product titers and activity throughout the manufacturing process, including activities such as inspection and labeling.

In conclusion, we are in exciting times with a number of these potentially life-changing products coming through to clinic. However, if we are to bring these products efficiently to the market, developers will need to adopt pragmatic and informed solutions for the manufacturing challenges that lie ahead.

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Manufacturing of AAV Vectors for Gene Therapy - Genetic Engineering & Biotechnology News

An 11-year-old girl in Massachusetts is at the forefront of a disease so rare, that it is believed only 22 people worldwide have been diagnosed with it. Talia Duff, who was born with Down syndrome and later diagnosed with Charcot-Marie-Tooth Neuropathy Type 4J (CMT4J), is slated to be among the first to enroll in a clinical trial that is awaiting FDA approval after her parents refused to watch her fall victim to the degenerative genetic disease.

Its a horrible feeling to go to a doctor and be told that theres nothing that can be done that the best you can do is try to make your child comfortable and enjoy the time you have together, John Duff, Talias dad, told PEOPLE. I learned to cherish moments in life that I would otherwise take for granted.

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The Duff family, which includes mom Jocelyn and older sister Teaghan, had noticed Talia struggling to crawl at around age four, and a regression in a number of other motor skills that at the time was attributed to her Down syndrome, and later to Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP). Subsequent failed therapies and a diagnoses of osteoporosis due to prescribed steroids caused her parents to push for another diagnosis at Boston Childrens Hospital, according to a post on the familys Cure CMT4J Foundation website.

We learned that Talia did not in fact have CIDP but instead had an extremely rare form of Charcot Marie Tooth Disease a degenerative, genetic disease called CMT4J, the post read.

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The family learned the disease would slowly take over Talias body like a form of amyotrophic lateral sclerosis (ALS), eventually causing paralysis and robbing her of her ability to breathe. In the two years since her diagnosis, Talia lost her ability walk or even raise her arms.

We were supposed to sit back and watch our child live her life in reverse, the post on Cure CMT4J Foundation read. I decided not to accept this. I stayed up late nights pouring over scientific papers and booked appointments with the top CMT doctors in the world. We traveled to the University of Iowa and then Vanderbilt University, where we met Dr. Jun Li.

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It was at the meeting with Li that the Duffs learned of a genetic therapy that could potentially cure Talias disease, but that it was eight-to-ten years away from production. Knowing that time was of the essence for Talia, Jocelyn began connecting with other parent advocates and the family started the Cure CMT4J Foundation with a goal of raising $1 million for research. She met with a team of eight researchers in Maryland, who concluded that the gene therapy would have a lasting effect on Talia, and they are now working to attain proof of concept approval from the FDA, PEOPLE reported.

With approval expected to come later this summer, Jocelyn is prepared to then push for approval of a human clinical trial, with Talia expected to be among the first to receive the gene therapy intravenously.

We feel hope now, Jocelyn told PEOPLE. People have said to me, This is a lot of work for you, and my response is, Hey, you would do this for your child, too. I simply cant stand by and do nothing.

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Massachusetts girl may be among first-ever to receive gene therapy for rare disease after parents push for cure - Fox News

Dimension Therapeutics is winnowing out 25% of its staff as it concentrates on three gene therapy programs, including one partnered with Bayer that has the potential to generate some badly needed milestone cash.

The biotech says it has enough revenue in hand to operate for another year, adding that it can extend the runway out to the end of 2018, provided it bags about $15 million in cash in its deal with Bayer. Three years ago Dimension inked a $252 million pact with Bayer, with $20 million of that upfront.

Annalisa Jenkins

Counting milestone money in your business plan isnt likely to generate much confidence among investors, especially after some disappointing results and evidence of liver toxicity for its initial lead gene therapy for hemophilia B in January crushed the biotechs stock price. DTX101 which faced more advanced competitors with better data has now been shoved out of the spotlight.

The biotechs market cap has now shrunk to $38 million.

The lead program in the clinic now is DTX301 for rare cases of ornithine transcarbamylase (OTC) deficiency. The biotech is lining up two more programs for INDs, including DTX201 allied with Bayer.

Dimension was one of several gene therapy companies to get started with a technology licensing deal with ReGenX, a spinoff from the University of Pennsylvania which is working with AAV technology developed by scientific founder James Wilson.

Our key focus is to deliver initial data from our ongoing Phase I/II clinical trial for DTX301 in OTC deficiency, advance two proof-of-concept studies for glycogen storage disease type Ia (GSDIa) and hemophilia A, the latter in collaboration with Bayer, and advance our unique HeLa 2.0 manufacturing platform, says CEO Annalisa Jenkins. We believe we can deliver these important objectives in 2017-2018 with our current financial position.

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Hammered on a gene therapy setback, Dimension cuts staff and circles the wagons - Endpoints News

LogicBio Therapeutics has got off a $45 million series B funding round as it eyes the cash for disease-modifying gene therapies in rare childhood diseases.

London-based investment firm Arix Bioscience led the oversubscribed round in the semi-stealth biotech, with new investors OrbiMed, Edmond De Rothschild Investment Partners, Pontifax, and SBI, along with previous investors OrbiMed Israel Partners, also stumping up cash.

Arix Bioscience's investment manager, Daniel OConnell, M.D., Ph.D, will join Cambridge, Massachusetts-based LogicBios board as part of the raise. This brings its total raised to $50 million, much of which will be put toward finishing off preclinical work and moving them into human tests.

The biotech sets itself up as a breakthrough gene therapy company targeting lifelong cures for serious, early-onset rare diseases by combining the best of gene therapy and gene editing in a one-time treatment.

It was founded in 2014 with platform technologies discovered by Adi Barzel, Tel Aviv University, Dr Leszek Lisowski, Childrens Medical Research Institute, Australia, and Professor Mark Kay at Stanford University School of Medicine.

The first platform, GeneRide, is a technology that uses homologous recombination that is designed to allow site-specific transfer of therapeutic genetic material without the use of promoters or nucleases. The company says it also has access to a library of synthetic, non-pathogenic, recombinant adeno-associated viral (rAAV) vectors developed at Stanford that allows for better predictability of vector performance in clinical trials.

Joe Anderson, CEO of Arix Bioscience, said: Early intervention for rare genetic disorders in children is important and LogicBio is uniquely positioned at the forefront of this research area with its proprietary genetic therapy technology to deliver a durable cure for young patients with life-threatening genetic diseases and otherwise limited options. LogicBio has huge potential and, alongside its excellent team and investors, we look forward to supporting the company to achieve continued success in this area.

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Arix leads $45M series B for gene therapy biotech LogicBio - FierceBiotech

U.K. firm NightstaRx raised $45 million in a Series C financing round to support continued clinical development of its pipeline of retinal gene therapies, including a pending Phase III study with lead candidate NSR-REP1 for treating choroideremia. The new funds will also be used to support an ongoing Phase I/II study with NSR-RPGR in patients with X-linked retinitis pigmentosa (RP), and a proposed Phase I/II trial with a gene therapy product targeting an inherited form of macular dystrophy. Nightstar projects starting the macular dystrophy clinical trial during late 2018.

Investors in the Series C round included Nightstars existing investors Syncona and New Enterprise Associates (NEA) and new investors Wellington Management Company and Redmile Group. As an original investor in Nightstar, our goal from day one was to build a global gene therapy leader with the capability of developing multiple programs for inherited retinal diseases, commented Chris Hollowood, Ph.D., chairman of the board of Nightstar and chief investment officer of Syncona, which is funded by The Wellcome Trust. We welcome Wellington Management and Redmile Group as investors and look forward to working with them and NEA to fulfill Nightstars potential.

Founded in 2014 by researchers at the University of Oxford, Nightstar is developing a pipeline of one-time potentially curative treatments for rare inherited retinal diseases. Lead candidate NSR-REP1 is an adeno-associated virus (AAV) vector-based gene therapy in development for treating choroideremia, a rare X-linked inherited retinal dystrophy for which there are currently no disease-modifying therapies. The AAV vector is administered by injection under the retina, using standard surgical procedures performed under local anesthetic. Nightstar says a Phase I/II study carried out by the University of Oxford confirmed long-term benefits of the treatment including vision improvement or stabilization.

The firms AAV-vector-based NSR-RPGR gene therapy for X-linked RP is designed to deliver a normal copy of the RP GTPase regulator (RPGR) gene, which Nightstar says is mutated in more than 70% of cases of X-linked RP. The procedure similarly involves injecting the gene-carrying vector under the retina. The ongoing Phase I/II study with NSR-RPGR was started in March.

Nightstar has ongoing collaborations with the University of Oxford, the Bascom Palmer Eye Institute, and the Institute for Ophthalmic Research, Tbingen University Hospital. In February, the firm inked a collaboration with Netherlands-based Preceyes to develop a subretinal drug delivery technology based on the latters high-precision robotic device for ocular surgery.

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NightstaRx Raises $45M to Fund Phase III Study with Retinal ... - Genetic Engineering & Biotechnology News (blog)

Many Helpers Make Light Work

Targeting cancer cells that have spread to several organs of the body is difficult. Targeted radiation therapy or chemotherapy tends to destroy not only the cancer cells but also normal cells. Turning to gene therapy to selectively deliver therapeutic genes into these cancer cells on a larger scale and eliminating them in one fell swoop is the ultimate goal of Tocagen.

Using two products, Toca 511 and Toca FC, the company plans on developing an effective combination therapy that could hit the cancer hard. Toca 511 is an injectable retroviral replicating vector (RRV) that provides the genetic material to encode a prodrug activator enzyme, cytosine deaminase (CD), which is derived from yeast and has no human counterpart. It is selectively delivered to only cancer cells, thus producing the CD protein in each cell.

Part two of this therapy involves a pill called Toca FC, which contains 5-fluorocytosine (5-FC) that converts to the anticancer agent 5-FU in the presence of CD protein. Toca FC kills not only the cancer cells, but also the myeloid-derived suppressor cells (MDSCs), which suppress the immune system, and tumor-associated macrophages (TAMs).

Harry Gruber, M.D., cofounder and former CEO of Tocagen, talks about the use of gamma-retroviruses: The advantage of using a gamma-retrovirus (as opposed to the lentivirus) is that it cannot enter the nucleus on its own. This makes it selective to dividing cells only, and since cancer cells are rapidly dividing, [gamma-retroviruses] help in spreading the virus and its genetic information. They live in defective cells that lack an innate immunity, and due to this selectivity, they are designed to be universally geared toward only cancer cells.

Dr. Gruber also mentioned that Toca 511/FC received the FDAs Breakthrough therapy designation, which expedites drug development.

The field of gene therapy has come a long way since its inception. Early failures and setbacks forced researchers back to the drawing board to figure out how viral vectors could be accepted by the human body, which ordinarily rejects foreign particles. Researchers also had to learn how such vectors could reach specific targets and deliver foreign DNA that could be integrated into the genome. This dance between therapy and the innate immune system is getting more complex, but is also showing its true beauty within the complexity.

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Gene Therapy: A New Twist on an Old Helix - Genetic Engineering & Biotechnology News

What Is Gene Therapy?

Explore the what's and why's of gene therapy research, includingan in-depth look at the genetic disorder cystic fibrosis and how gene therapy could potentially be used to treat it.

Gene Delivery: Tools of the Trade

Explore the methods for delivering genes into cells.

Space Doctor

You are the doctor! Design and test gene therapy treatments with ailing aliens.

Challenges In Gene Therapy

Researchers hoping to bring gene therapy to the clinic face unique challenges.

Approaches To Gene Therapy

Beyond adding a working copy of a broken gene, gene therapy can also repair or eliminate broken genes.

Gene Therapy Successes

The future of gene therapy is bright. Learn about some of its most encouraging success stories.

Gene Therapy Case Study: Cystic Fibrosis

APA format:

Genetic Science Learning Center. (2012, December 1) Gene Therapy. Retrieved September 23, 2016, from http://learn.genetics.utah.edu/content/genetherapy/

CSE format:

Gene Therapy [Internet]. Salt Lake City (UT): Genetic Science Learning Center; 2012 [cited 2016 Sep 23] Available from http://learn.genetics.utah.edu/content/genetherapy/

Chicago format:

Genetic Science Learning Center. "Gene Therapy." Learn.Genetics.December 1, 2012. Accessed September 23, 2016. http://learn.genetics.utah.edu/content/genetherapy/.

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Gene Therapy - Learn Genetics