Spinal Fluid-Based Gene Therapy Shows Promising Results in Early-Stage, Long-Term Study of Giant Axonal Neuropathy


At some dose levels, the treatment appeared to slow the rate of motor function decline and regenerate sensory nerves in patients with giant axonal neuropathy.

Carsten G. Bönnemann, MD, chief of the Neuromuscular and Neurogenetic Disorders of the Childhood Section at the National Institute of Neurological Disorders and Stroke

Carsten G. Bönnemann, MD

In a newly published first-in-human trial (NCT02362438), treatment with scAAV9/JeT-GAN, an investigational gene therapy administered directly into the spinal fluid, was well tolerated and showed signs of therapeutic benefit among children with giant axonal neuropathy (GAN). Published in the New England Journal of Medicine, the investigators observed various rates of slowed motor function decline, with nearly half of the small cohort regaining sensory nerve response.1,2

Led by senior investigator Carsten G. Bönnemann, MD, chief of the Neuromuscular and Neurogenetic Disorders of the Childhood Section at the National Institute of Neurological Disorders and Stroke, the trial featured 14 children with genetically confirmed GAN, aged 6 to 14 years old, who received 1 of 4 intrathecal doses of scAAV9/JeT-GAN at doses of 3.5 x 1013 total vector genomes (vg)(n = 2), 1.2 x 1014 vg (n = 4), 1.8 x 1014 vg (n = 5), and 3.5 x 1014 vg (n = 3). scAAV9/JeT-GAN is a self-complementary adeno-associated viral (AAV) serotype 9 vector that carries a codon-optimized human GAN transgene with expression controlled by the minimal synthetic recombinant JeT promoter consisting of 5 elements.

Initiated in 2015, the study’s primary end point was safety, represented by the incidence of serious adverse events (AEs). The key secondary efficacy end point at 1 year after gene transfer was at least a 95% Bayesian posterior probability of slowing the rate of change in the MFM-32 total percent score, as compared with the mean slope during the pretreatment period, which was determined in the entire cohort during the nature history study.

Over an observation period of 68.7 months, a total of 682 AEs were recorded, 129 of which were related to the study treatment. These included CSF pleocytosis (14 events in 13 patients), an elevated CSF immunoglobulin index (14 events in 13 participants), leukocytosis (12 events in 8 participants), thrombocytosis (11 events in 7 participants), and headache (7 events in 7 participants). In total, 48 serious AEs were observed, namely because of scoliosis (n = 9), urinary tract infection (n = 6), and upper respiratory tract infection (n = 5).

The mean change in the slope of the curve of the MFM-32 total percent score was −0.54 percentage points per year in the 3.5×1013 vg–dose group, 3.23 percentage points per year in the 1.2×1014 vg–dose group, 5.32 percentage points per year in the 1.8×1014 vg–dose group, and 3.43 percentage points per year in the 3.5×1014 vg–dose group. Only the 1.8 x 1014 vg-dose group met the prespecified efficacy threshold at 1 year, with a posterior probability of any change in the slope, as compared with the pretreatment slope across dose groups, of 99% (95% CI, 99-99). Investigators observed varied findings on the mFARS score and Neuropathy Impairment Score, as the highest posterior probability of change, 95%, was observed in the 1.2 x 1014 vg-dose group.

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Between 6 and 24 months after gene transfer, ulnar sensory nerve action potentials (SNAP) amplitudes increased, stopped declining, or became recordable after being absent in 6 participants but remained absent in 8 participants. Motor nerve responses, recorded in the distal upper and lower extremities, demonstrated a decline in compound muscle action potential amplitude both before and after gene transfer. At 1 year after dose administration, 8 patients in a subgroup of obtained nerve-biopsy specimens showed regenerating cluster density in the superficial radial sensory nerve that was 3 to 48 times as high as that at baseline.

"One striking finding in the study was that the sensory nerves, which are affected earliest in GAN, started ‘waking up’ again in some of the patients," Bonnemann said in a statement. "I think it marks the first time it has been shown that a sensory nerve affected in a genetic degenerative disease can actually be rescued with a gene therapy such as this."

In terms of immunologic response, clinically asymptomatic, lymphocyte-predominant CSF pleocytosis was found in 13 participants during routine scheduled CSF examinations by 3 to 6 months after starting therapy. These increases were self-limited and abated by 1 year after dose administration. Notably, a diminished AAV9 capsid interferon-γ response was observed in those who received rapamycin, with or without additional tacrolimus, as compared with those without T-cell immunomodulation.

In the study, 2 participants who received the lowest dose died from events deemed by the principal investigator to be at least possibly related to the underlying disease. In addition, in the immunosuppressive regimen, investigators observed serious AEs such as grade 1 pneumonia, grade 3 skin infection, and grade 3 bone infection that led to hospitalization. All 3 of these serious AEs were resolved within weeks of them being reported.

1. Experimental gene therapy for giant axonal neuropathy shows promise in NIH clinical trial. National Institutes of Health. March 20, 2024. Accessed April 1, 2024. https://www.nih.gov/news-events/news-releases/experimental-gene-therapy-giant-axonal-neuropathy-shows-promise-nih-clinical-trial
2. Bharucha-Goebel D, Todd JJ, Saade D, et al. Intrathecal gene therapy for giant axonal neuropathy. NEJM. 2024;390:1092-1104. doi:10.1056/NEJMoa2307952
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