James Wilson is a prominent figure in gene therapy, a medical approach that utilizes genetic material to prevent and treat diseases by addressing their underlying causes. This technique aims to alter genetic material within the body to produce desired proteins or medications, offering potential cures. Wilson’s long involvement in this complex and evolving scientific discipline has shaped its trajectory.
Pioneering Work in Gene Therapy
Wilson’s early contributions established him as a leader in gene therapy research. His laboratory focused on developing viral vectors, particularly adenovirus (AdV), as vehicles for gene delivery. These modified viruses were designed to carry therapeutic genes into target cells, effectively turning the body’s own cells into factories for producing missing or deficient proteins. AdV vectors were promising due to their ability to infect a wide range of cell types, including non-dividing cells, and their high efficiency for in vivo gene therapy.
The Jesse Gelsinger Tragedy and Its Aftermath
The field of gene therapy faced a significant setback with the tragic death of Jesse Gelsinger in a clinical trial led by James Wilson in September 1999. Gelsinger, an 18-year-old with a partial ornithine transcarbamylase (OTC) deficiency, volunteered for the trial, which aimed to correct his metabolic disorder using an adenoviral vector. Four days after receiving the corrective OTC gene, Gelsinger experienced a severe immune reaction to the viral vector, leading to his death.
This event prompted intense scrutiny from regulatory bodies and the public. Investigations revealed that Gelsinger was not fully informed about serious side effects experienced by other patients in the trial, nor about the deaths of three monkeys in preclinical studies after receiving the vector. The U.S. Food and Drug Administration (FDA) suspended the University of Pennsylvania’s gene therapy trials, citing issues with staff training, operating procedures, and informed consent. Wilson faced restrictions on his human research for five years, and the Institute for Human Gene Therapy was eventually shut down. This tragedy underscored the inherent risks of gene therapy and led to substantial regulatory changes to enhance patient safety and oversight in clinical trials.
Reshaping Gene Therapy
In the wake of the Gelsinger tragedy, James Wilson and his team significantly redirected their research focus. They shifted away from adenovirus vectors due to concerns about their immunogenicity, the ability to trigger an immune response, and began concentrating on adeno-associated virus (AAV) vectors. AAVs offered a more favorable safety profile, as they are non-enveloped viruses that typically do not cause disease in humans.
Wilson’s laboratory was instrumental in discovering a new family of primate AAVs, rescuing over 120 new AAV capsids from primate tissues. This work led to a deeper understanding of AAV biology and the development of safer and more effective gene delivery systems. For instance, AAV8 demonstrated improved gene transfer to the liver, muscle, and photoreceptors, while AAV9 showed the ability to cross the blood-brain barrier, enabling it to target the heart and central nervous system. This shift to AAVs has been a significant factor in the resurgence of gene therapy efforts.
Current Contributions and Impact
James Wilson continues to be a highly influential figure in gene therapy, with ongoing research focused on advancing AAV vector technology. His laboratory at the University of Pennsylvania’s Gene Therapy Program and Orphan Disease Center actively works on developing gene therapies for rare diseases. His research has contributed to the development of several clinically approved gene therapies, including Glybera for familial lipoprotein lipase deficiency (using AAV1), Luxturna for RPE65-mediated retinal dystrophy (using AAV2), and Zolgensma for spinal muscular atrophy (using AAV9).
Wilson’s team is also exploring novel applications of the AAV platform, such as AAV-based therapies to treat influenza and central nervous system metastases. He has co-founded several gene therapy companies, including Regenxbio and Passage Bio, demonstrating his commitment to translating research into therapeutic solutions. As of August 1, 2024, Wilson announced his departure from the University of Pennsylvania Gene Therapy Program to establish two new companies, Gemma Biotherapeutics and Franklin Biolabs, with Gemma Biotherapeutics focusing on advanced medicines for rare diseases. This continued work underscores his dedication to addressing unmet medical needs and advancing the clinical development of gene therapies.