Investigational Gene Therapy May Help Patients With Rare Neurodegenerative Disease

An investigational gene therapy appeared to be well tolerated and showed signs of therapeutic benefit in a first-in-human trial of children with giant axonal neuropathy (GAN), a rare and progressive neurodegenerative disease. Investigators from the National Institutes of Health led the study and published their findings March 20 in the New England Journal of Medicine.

The dose-escalation study included 14 patients aged 6 to 14 years. Patients received a single dose of the gene therapy (called scAAV9/JeT-GAN) through an injection into the spinal fluid, allowing the therapy to target the motor and sensory neurons affected in GAN. Investigators tested four dose levels, and patients were followed for a median of 68.7 months to assess safety.

During the follow-up period, investigators observed 682 adverse events and 48 serious adverse events. Among serious adverse events, only one – a fever – was possibly related to treatment. Among 682 less serious adverse events, 129 were possibly related to treatment. These included headache, back pain, irregular heart rhythms and inflammation in spinal fluid.

The trial also assessed motor function scores and tests of nerve function on year after treatment. While responses varied depending on dose level, 6 of 14 patients regained sensory nerve response after treatment; electrical measures increased, stopped declining or became measurable after being absent. The three patients who received the highest dose (3.5×10¹⁴ vector genomes [VGs]) showed a notable slowing of decline one year after treatment, with a 99% probability of efficacy. The two patients who received the lowest dose (3.5×10¹³ total VGs) died during the study period due to events related to their underlying disease.

While the results suggest a possible benefit for motor function scores and other measures at some vector doses, investigators noted that further research is needed to determine the safety and efficacy of intrathecal gene therapy in GAN. According to the NIH, investigators next plan to test whether the GAN gene transfer is more effective when given to younger children or those in an earlier stage of the disease.