Gene therapy is a cutting-edge medical approach aimed at treating diseases caused by genetic mutations. Over the years, scientists have been exploring the potential of this technology to cure a wide range of health conditions, including rare and untreatable diseases. One such condition is Niemann-Pick disease type C (NPC), a rare neurodegenerative disorder that affects only one in every 150,000 people worldwide. A promising new study has shown early success in using gene therapy to treat NPC patients, providing hope for those suffering from this debilitating condition.
Researchers, including scientists from the National Institutes of Health (NIH), have developed a potential gene therapy for hereditary spastic paraplegia 50 (SPG50), a rare childhood-onset neurodegenerative disorder that leads to developmental delays, cognitive impairment, and eventual paralysis. The condition is caused by mutations in a single gene known as AP4M1. The team designed an investigational therapy to deliver a functioning AP4M1 gene to the cells of the central nervous system.
Scientists in the Bonifacino Lab at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) worked with cells derived from patients with SPG50 to establish the experimental therapy’s potential to restore typical AP4M1 gene function. These findings, along with results from experiments in animal models, provide the foundation for an early-stage clinical trial to evaluate the gene therapy in people with SPG50.
The AP4M1 gene provides instructions for one of the four proteins comprising the adaptor protein 4 (AP-4) complex. AP-4 helps direct certain proteins to different locations within the cell, and loss of function in any of its four protein subunits leads to a form of hereditary spastic paraplegia. AP-4-associated hereditary spastic paraplegias are classified as “ultrarare” diseases. Approximately 300 cases have been identified worldwide, of which 90 are the SPG50 type. Although disease severity can vary, most individuals with SPG50 are non-verbal; never acquire the ability to walk, often becoming reliant on a wheelchair by the age of 10; and have microcephaly, epilepsy, and significant cognitive impairment.
The scientists first developed a version of the gene therapy that could deliver a functional copy of AP4M1 to cultures of cells derived from patients with SPG50. Biochemical analyses suggested that the treatment effectively restored AP-4 levels and function in the cells. Independent experiments at Boston Children’s Hospital using cells from three additional SPG50 patients with different AP4M1 mutations yielded comparable results.
The research team next moved to animal studies, packaging the AP4M1 gene into a carrier, or vector, called adeno-associated virus type 9 (AAV9). Prior studies have suggested that AAV9, a non-disease-causing virus, serves as a safe and effective vector for gene therapies targeting the central nervous system. Treating mice lacking AP4M1 with AAV9/AP4M1 partially improved the animals’ behavioral issues. The benefits were greatest when the mice received high doses of AAV9/AP4M1 at a young age. Toxicology studies in mice, rats, and monkeys suggested that AAV9/AP4M1 is safe at doses predicted to be effective in humans with SPG50.
The work identified a potential treatment for SPG50 and laid the groundwork for a clinical trial to evaluate its safety and efficacy in people with the disease. The authors also hope that their work may provide a roadmap for researchers designing gene therapies for other neurological conditions. A clinical trial evaluating the experimental gene therapy in people with SPG50 is currently underway.
In conclusion, the potential of gene therapy to treat rare neurodegenerative diseases is a promising development in the field of medical science. While this research is still in the early stages and more testing is needed, the early results are encouraging. The innovative use of AAV9 vectors to deliver functional copies of the faulty gene may provide a long-term solution for patients suffering from these rare diseases. Continued research and advancements in gene therapy could ultimately have a tremendous impact on the lives of individuals and families affected by these devastating conditions.
