GTP-220: A Gene Replacement Therapy Being Advanced for Angelman Syndrome
Dr. Jim Wilson from the University of Pennsylvania announced major progress in the development of a gene replacement therapy for Angelman syndrome. The preclinical research has reached a milestone that supports further advancements towards IND-enabling studies for a first in-human clinical trial. The therapy involves injecting a vector into the cerebrospinal fluid to achieve broad distribution in the brain. The platform technology, called HItap, has shown promising results in lysosomal storage diseases and other neurodevelopmental diseases. The therapy, known as GTP-220, has demonstrated correction of behavioral and motor abnormalities in animal models. Formal pharmacology and toxicology studies are currently underway, and discussions with health authorities are being held to finalize the clinical trial design. Dr. Wilson praised the partnership with FAST and highlighted the importance of disruptive technologies in the field of gene therapy.
In a recent presentation at the 2023 FAST Science Summit, Dr. Jim Wilson from the University of Pennsylvania discussed the progress made in the development of a gene replacement therapy for Angelman Syndrome. This ongoing partnership between Dr. Wilson’s team and FAST has reached a major milestone, paving the way for further advancements in research and the potential for a first in-human clinical trial.
The Challenges of Rare Disease Research
Dr. Wilson acknowledged the challenges faced in developing treatments for rare diseases, particularly in light of diminishing support for genetic medicines. He highlighted the question posed by Goldman Sachs – “Is curing patients a sustainable business model?” – and the unfortunate retreat of support for rare diseases in recent years. Despite these challenges, organizations like FAST play a crucial role in advocating for and supporting research in this field.
The Concept of Disruptive Technology
Dr. Wilson drew upon the concept of disruptive technology, popularized by business leader Clay Christensen, to explain the potential of gene therapy. Disruptive technologies fundamentally change the way business is done, and gene therapy has the potential to revolutionize the treatment of diseases. However, incorporating these technologies into current market structures and addressing questions of pricing and delivery pose significant challenges.
Developing Gene Therapy as a Platform
Dr. Wilson emphasized the importance of thinking about gene therapy not as individual programs, but as platforms. By keeping key elements consistent across different diseases, such as the delivery vehicle, route of administration, and manufacturing process, the development of gene therapy can be simplified and streamlined. This approach increases the probability of success, minimizes the risk of toxicity, and makes the collective impact of multiple programs more attractive from a market perspective.
The Approach for Angelman Syndrome
Dr. Wilson explained the specific approach being taken for the development of gene therapy for Angelman Syndrome. The goal is to deliver the therapeutic gene to the central nervous system, particularly the brain. Traditional methods of intravenous delivery are not feasible, so the team has focused on injecting the gene therapy vector into the cerebrospinal fluid through a technique called intracisterna magna injection. This approach allows for broad distribution of the vector and the potential for correction of the disease.
The HItap Platform
The team has developed a platform called HItap, which encompasses the vector delivery vehicle, the injection technique, and the manufacturing process. This platform has been successfully applied to lysosomal storage diseases and other neurologic diseases, demonstrating promising results in preclinical studies. The same platform can be used for Angelman Syndrome, leveraging the knowledge and experience gained from other diseases to inform the development of gene therapy for this specific condition.
Preclinical Studies and Safety Evaluation
Dr. Wilson discussed the preclinical studies and safety evaluation that have been conducted to ensure the effectiveness and safety of the gene therapy. Animal models, including non-human primates, have been used to assess the distribution of the vector and the expression of the therapeutic gene. These studies have shown promising results with little evidence of toxicity. Further formal pharmacology and toxicology experiments are underway to support the development of the therapy.
Clinical Trial Considerations
Dr. Wilson outlined the considerations for the upcoming clinical trial for Angelman Syndrome. The trial will be open-label, meaning participants will know they are receiving the therapy. It will involve a single intracisterna magna injection, with potentially two different doses being tested. The primary endpoints of the trial will focus on safety and tolerability, while also measuring other indicators of efficacy. Discussions with health authorities are ongoing to ensure the trial design meets regulatory requirements.
Timeline and Future Plans
Dr. Wilson provided a timeline for the next steps in the development of the gene therapy for Angelman Syndrome. Production of the toxicology lot has begun, and monkeys have been identified for the GLP tox study. Discussions with health authorities and the securing of a manufacturing contract are also in progress. Once these steps are completed, regulatory documents will be submitted, leading to the initiation of the clinical trial.
Dr. Wilson expressed his enthusiasm for the partnership with FAST and the progress made in the development of gene therapy for Angelman Syndrome. He commended FAST for their outstanding engagement and their ability to bring the community together. He emphasized the need for disruption in the field of rare disease research and expressed his confidence in the potential of gene therapy to revolutionize treatment. Dr. Wilson looks forward to further updates as the program moves forward and the potential impact it could have on patients with Angelman Syndrome.
- Title: GTP-220: A Gene Replacement Therapy Being Advanced for Angelman Syndrome
- Author(s): James Wilson
- Author(s)’ affiliation: Perelman School of Medicine, University of Pennsylvania
- Publication date: 2023-11-12
- Collection: 2023 FAST Science Summit