RSRT has announced Roadmap to a Cure, a 3-year research plan featuring gene therapy as the lead program. Gene therapy fixes the cause of a genetic disorder instead of alleviating the symptoms, essentially representing a cure.
The theory is simple - replace defective genes with healthy copies. However, it is a challenge to deliver the right amount of a gene to the desired organ, ensure it stays activated and produces product, and guarantee safety of the patient. Hundreds of clinical trials are underway but there is no gene therapy commercially available in the US yet. This is about to change.
History of Gene Therapy
The field of gene therapy has experienced ups and downs throughout the years. The first successful gene therapy was used in 1990 at the National Institutes of Health to cure two girls of adenosine deaminase (ADA) deficiency. Then in 1999, 18-year-old Jesse Gelsinger died four days after he began gene therapy to treat his liver condition. The adenovirus used to deliver the therapeutic gene triggered a fatal immune reaction. This was a major setback for gene therapy, particularly in the US, prompting many clinical trials to be shut down.
Another setback occurred a few years later after children with severe combined immune deficiency (SCID) participated in a gene therapy clinical trial. The treatment cured the syndrome in almost all participants, but several children went on to develop leukemia and one died. It was discovered that the retrovirus carrying the therapeutic gene had inserted itself near a cancer-causing gene, turning it on.
These tragedies triggered fears that significantly hindered progress in the field. At the same time, they provided scientists with specific problems to address in their research. After a tumultuous first few decades, the field of gene therapy is finally taking off. Gene therapies have now been successfully used to treat a wide range of diseases, including but not limited to cancer, immune deficiencies, blindness, and hemophilia.
There are now several different approaches to gene therapy:
- Traditional: healthy genes are delivered into cells in the human body using a vector like a virus.
- Ex vivo: cells are removed from the body, healthy genes are introduced, then the cells are put back into the body.
- RNA therapeutics: mutations are corrected at the mRNA level in order to increase or reduce protein levels.
- CRISPR/Cas9: defective genes are corrected by editing the DNA in cells in the body.
- Cancer gene therapy (eg., CAR-T): cells are removed from the body and genetically engineered to target and kill tumor cells, then put back into the body.
Approvals In Europe and Asia
Europe and Asia have led the world in commercializing gene therapy. In 2003, China was the first to approve a gene therapy for commercial use - Gendicine to treat cancer. Russia followed after with Neovasculgen to treat peripheral artery disease in 2011. In the years since, Europe has approved Glybera in 2012 to treat a rare disorder that causes fat to accumulate in the blood and Strimvelis in 2016 to treat ADA-SCID, the first treatment to come with a money-back guarantee.
Progress In The US
Gene therapy startups in the US have exploded in number recently, indicating the country’s readiness to embrace this new technology. Companies such as AveXis, Voyager Therapeutics, Spark Therapeutics, uniQure, Editas Medicine, CRISPR Therapeutics, Sangamo BioSciences, Calimmune, Caribou Biosciences, Orgenesis, to name just a few, are racing to develop new therapies for a wide range of disorders at this very moment.
Several gene therapies are predicted to gain FDA approval within the next year. Spark Therapeutics has developed a treatment for inherited retinal disease called voretigene neparvovec that is able to restore vision with no adverse effects. Bluebird Bio was granted “breakthrough therapy designation” by the FDA for their treatment for severe sickle cell anemia, LentiGlobin BB305, and recently reported encouraging results from their Phase 3 trial. Novartis and Kite Pharma are both hurrying to gain FDA approval for CAR-T cell therapy to treat cancer, and GlaxoSmithKline is seeking approval in the US for Strimvelis (already approved in Europe) to treat ADA-SCID.
Outlook For Rett Syndrome
Rett Syndrome is a candidate for gene therapy because it is caused by a single gene, it is not degenerative, and symptoms may be reversible at any age. Studies in mouse models of Rett Syndrome demonstrate that a single dose of gene therapy can significantly improve symptoms even after the syndrome has progressed. However, translating this to humans is challenging.
MeCP2 is needed in all regions of the brain so the gene must be delivered broadly. At the same time, some cells already have healthy copies so overexpression is a risk. Choosing the correct dose and vector is vital. In addition, MECP2 is elaborately regulated so ideally the introduced copy would incorporate these checks and balances. The RSRT Gene Therapy Consortium is currently working to optimize vectors, gene constructs, dose, and delivery route.
With RSRT’s new Roadmap to a Cure, the plan is to launch the first ever gene therapy clinical trial for children with Rett Syndrome.
To learn more about gene therapy read this Gene Therapy Primer.