Science update: Gene therapy for rare neurodegenerative diseases shows early promise | NICHD

Illustration depicting an AAV9 vector delivering a gene to cells.
Credit: NIH/National Human Genome Research Institute

A research team including National Institutes of Health scientists has developed a potential gene therapy for hereditary spastic paraplegia 50 (SPG50), a rare childhood-onset neurodegenerative disorder that causes developmental delays, cognitive impairment and eventual paralysis. The condition is caused by mutations in a gene known as AP4M1. The team created a research therapy to ensure functioning AP4M1 gene to cells of the central nervous system.

Scientists in the Bonifacino Laboratory at NIH Eunice Kennedy Shriver The National Institute of Child Health and Human Development (NICHD) is working with cells obtained from patients with SPG50 to help establish the experimental therapy’s potential to restore typical AP4M1 gene function. These findings and results from experiments in animal models provide the basis for an early-stage clinical trial to evaluate gene therapy in humans with SPG50.

The research was led by Xin Chen, MD, Ph.D., and Steven Gray, Ph.D., of Texas Southwestern University and was funded by the CureSPG50 Foundation and NICHD. The study appears in Journal of Clinical Research.


The AP4M1 gene provides instructions for one of the four proteins that make up the adapter protein 4 (AP-4) complex. AP-4 helps direct certain proteins to different locations in the cell, and loss of function in any of its four protein subunits results in a form of hereditary spastic paraplegia. AP-4-related hereditary spastic paraplegias are classified as “ultra-rare” disorders. Approximately 300 cases have been identified worldwide, of which 90 are of the SPG50 type. Although the severity of the disease can vary, most people with SPG50 are nonverbal; never acquire the ability to walk, often becoming dependent on a wheelchair by the age of 10; and have microcephaly, epilepsy, and significant cognitive impairment.


Scientists first developed a version of gene therapy that could deliver a functional copy of AP4M1 to cultures of cells derived from patients with SPG50. Dr. Bonifacino and his NICHD colleagues Raffaella De Pace, Ph.D., and Rafael Mattera, Ph.D., conducted experiments with cells from two SPG50 siblings. Biochemical analyzes suggest that the treatment effectively restores AP-4 levels and function in cells. Independent experiments at Boston Children’s Hospital using cells from three additional SPG50 patients with different AP4M1 mutations give comparable results.

The research team then moved on to animal studies, packing AP4M1 gene in a carrier — or vector — called adeno-associated virus type 9 (AAV9). Previous studies have shown that AAV9, a virus that does not cause disease, serves as a safe and effective vector for gene therapies targeting the central nervous system. Treatment of mice is missing AP4M1 with AAV9/AP4M1 partially improved the animal’s behavioral problems. Benefits were greatest when mice received high doses of AAV9/AP4M1 at a young age. Toxicological studies in mice, rats and monkeys suggest that AAV9/AP4M1 is safe at doses thought to be effective in people 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 their work can provide a road map for researchers designing gene therapies for other neurological conditions.

next steps

A clinical trial evaluating the experimental gene therapy in humans with SPG50 is underway.


Chen H and others. Intrathecal AAV9/AP4M1 gene therapy for hereditary spastic paraplegia 50 shows safety and efficacy in preclinical studies. Journal of Clinical Research DOI: 10.1172/JCI164575 (2023)

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