First Intrathecal AAV Gene Therapy — Targeting Ultra-Rare GAN

Giant Axonal Neuropathy (GAN) is a devastating pediatric disease characterized by the degeneration of both peripheral and central nerves due to a mutation in the GAN gene, leading to a deficiency in the Gigaxonin protein. With a global prevalence of approximately 50 families, and no FDA-approved treatments, current management is limited to supportive care such as physical therapy and assistive devices. Researchers at the National Institute of Neurological Disorders and Stroke (NINDS), led by Dr. Carsten Bönnemann, have been conducting a first-in-human gene therapy clinical trial (NCT02362438) since 2015, using a self-complementary AAV9 vector (scAAV9/JeT-GAN) delivered intrathecally to supplement Gigaxonin. This trial has established a precedent for intrathecal AAV delivery in humans, with implications extending beyond GAN to the broader field of gene therapies for rare neurological disorders.

MFM-32 Slope Reversal Observed at 1.8×10¹⁴ vg

A total of 14 GAN patients (64% female), aged 6-14 years, were assigned to four dose escalation cohorts ranging from 3.5×10¹³ to 3.5×10¹⁴ vg and received a single intrathecal injection. In the primary outcome measure, the motor function measurement (MFM-32) score, the 1.8×10¹⁴ vg dose group showed a reversal of the pre-treatment annual decline of -7.17% to an increase of +5.32%, meeting the pre-specified 95% efficacy threshold (posterior probability 99%). Sensory nerve action potential (SNAP) showed unexpected recovery in 6 of 14 patients (43%), and nerve biopsies revealed a 3- to 48-fold increase in regenerative cluster density in 8 patients, providing biological evidence of peripheral nerve regeneration. Long-term data with a median follow-up of 68.7 months (up to 90.5 months) have been collected, and an update on 72-month long-term efficacy and safety was presented at the MDA 2026 conference.

Safety — One Treatment-Related SAE, No Anti-Transgene T-Cell Response Observed

Among a total of 682 adverse events, 129 were considered potentially treatment-related, and among 48 serious adverse events (SAEs), only one case of fever in the highest dose group (3.5×10¹⁴ vg) was deemed treatment-related. Two deaths (aspiration pneumonia 8 months post-administration, respiratory failure 60 months) were attributed to disease progression. Asymptomatic pleocytosis was observed in 93% (13/14) of participants, but resolved within one year, and no anti-transgene T-cell response was observed, strongly supporting the immune safety of the AAV9 intrathecal platform. The complete data set was published in NEJM (390(12):1092-1104, DOI:10.1056/NEJMoa2307952) in March 2024, after peer review.

No Commercial Partner — Taysha Withdrawal, NIH Sole Sponsor, Platform Expansion Ongoing

Taysha Gene Therapies (TSHA) had planned to commercialize TSHA-120, which is based on the same vector, but discontinued development and returned the IND to NINDS after determining that the double-blind, placebo-controlled design required by the FDA was not feasible in the ultra-rare patient population. Astellas Pharma, which held co-option rights, also waived its license, leaving no commercial sponsor at present. However, the intrathecal AAV9 delivery platform, validated in this trial, is already being expanded to multiple follow-on clinical trials for Batten disease (CLN1/5/7), Rett syndrome, and GM2 gangliosidosis, and a clinical trial (NCT07543991) for intrathecal administration of scAAV9/JeT-GAN is also being registered on ClinicalTrials.gov, demonstrating diversification of the administration route. The GAN therapeutic market is projected to grow from approximately $126.4 million in 2025 to $186.3 million in 2032 (CAGR of 5.7%), and the validated intrathecal AAV9 delivery platform remains a strategically valuable asset for acquisition or licensing by specialized rare disease biotech companies or large pharmaceutical companies, with a platform value exceeding the individual indication sales.