Giant axonal neuropathy (GAN) is a rare, autosomal recessive neurodegenerative disorder, characterized by a spectrum of symptoms and a challenging prognosis. Now, a study published recently in the New England Journal of Medicine (NEJM) presents promising treatment results in the form of gene therapy.
GAN is primarily caused by biallelic loss-of-function variants in the GAN gene, which encodes gigaxonin, a crucial protein involved in regulating intermediate filament turnover within the nervous system. The absence of functional gigaxonin leads to the pathological accumulation of intermediate filaments, resulting in the formation of abnormal axonal swellings, colloquially termed "giant axons." These structural abnormalities are central to the disease's progression and manifestation of symptoms.
GAN typically manifests in patients as sensorimotor neuropathy, cerebellar dysfunction, and progressive loss of motor function, often leading to loss of independently being able to walk by early adolescence. Unfortunately, GAN's relentless progression often leads to a fatal outcome by the third decade of life, primarily due to complications like respiratory failure.
The new study conducted a phase 1 clinical trial to investigate the safety and efficacy of intrathecal gene transfer using a self-complementary adeno-associated virus (scAAV9) vector carrying the GAN transgene (scAAV9/JeT-GAN). Using viruses to transport gene therapies is a novel but growing methodology.
The trial indicated mixed results regarding safety and efficacy. While adverse events were observed, most were attributed to disease manifestations or immunosuppressive treatments.
Electrophysiological changes post-gene transfer showed some improvement in sensory nerve responses in the upper extremities, although motor nerve responses continued to decline. Postmortem analysis of nerve pathology and biodistribution revealed broad distribution of the vector DNA and GAN transgene throughout the nervous system, albeit with limited distribution in the brain.
The phase 1 trial of intrathecal gene transfer with scAAV9/JeT-GAN in children with GAN offers promising insights into the potential of gene therapy for treating this rare neurodegenerative disorder. While safety concerns and variable efficacy outcomes underscore the need for further research, these findings represent a significant step forward in the quest to combat GAN and improve the quality of life for affected individuals.
Sources: New England Journal of Medicine, Pfizer
