In June, the Phelan-McDermid Syndrome Foundation hosted a webinar in collaboration with the American Society of Gene & Cell Therapy (ASGCT). Dr. Kimberly Goodspeed, a child neurologist and Medical Director at Ultragenyx, presented on the fundamentals of gene therapy and what it means to participate in a clinical trial.
Dr. Goodspeed began by explaining the basics of DNA and RNA. DNA is like an encyclopedia, with different sections responsible for producing proteins or regulating how those proteins are made. RNA is transcribed in the nucleus and then moves to the cytoplasm, where it temporarily carries out its functions.
She outlined three main types of gene therapies:
- DNA therapies: These introduce a gene that codes for a specific RNA or protein. Often delivered once, they aim for long-lasting effects.
- RNA therapies: These influence cell behavior and typically require repeated dosing. Delivery systems include viral vectors (e.g., adeno-associated viruses or AAVs) and lipid nanoparticles.
- Antisense Oligonucleotides (ASOs): These are short strands of RNA-like molecules that can silence or modify gene expression. ASOs also need to be administered regularly due to their short lifespan in cells.
Dr. Goodspeed also discussed various therapeutic strategies:
- Gene addition: Adding a functional gene
- Gene silencing: Turning off a faulty gene
- Gene editing: Correcting mutations within the gene itself
- Genetically modified cell therapy: modifying a patient’s cells outside the body and reintroducing them
She reviewed different delivery methods for these therapies:
- Intravenous (IV) – where the therapy is given through a vein (usually in the arm)
- Intrathecal – via lumbar puncture, where the therapy is administered directly into the fluid around the brain and spinal cord (called cerebrospinal fluid) using a needle
- Intracerebroventricular (ICV) – administration directly into the brain
Additionally, Dr. Goodspeed addressed the potential risks associated with gene therapy. These include:
- Procedural risks
- Immune or inflammatory responses
- Unknown long-term effects.
She also noted that participation in a gene therapy trial may limit eligibility for other gene therapy options in the future, a factor families should carefully consider.
Dr. Goodspeed also presented the basics about clinical trials. She explained the journey from early research to FDA approval. This begins with preclinical studies and Investigational New Drug (IND) applications, which include:
- Toxicology: Is the therapy safe?
- Biodistribution: Where does it go in the body?
- Dose-finding: What amount should be given?
She then described the clinical trial phases:
- Phase I/II: Focus on safety and initial signs of efficacy (how well a therapy works under ideal, very controlled circumstances) in small groups
- Phase III: Larger trials to evaluate effectiveness (how well a therapy works in real-world conditions) and side effects
- Phase IV: Post-approval studies to monitor long-term safety
Dr. Goodspeed underscored the critical role of clinical trial readiness and thoughtful study design. For example, selecting meaningful biomarkers and/or outcome measures is critically important to accurately evaluate a therapy’s effectiveness.
She also highlighted the demanding nature of clinical trial participation, noting that families must be fully committed, attending all appointments, and remaining readily available for ongoing engagement with the study team.
We are very grateful to the American Society of Gene & Cell Therapy (ASGCT) for their partnership in hosting this webinar, and to Dr. Goodspeed for her clear, informative, and comprehensive presentation on the science and realities of gene therapy and clinical trials.