Intrathecal Administration of scAAV9/JeT-GAN for the Treatment of Giant Axonal Neuropathy

Title: Intrathecal Administration of scAAV9/JeT-GAN for the Treatment of Giant Axonal Neuropathy Background: \- The Gigaxonin gene lets the body make a protein chemical called Gigaxonin. Nerves need Gigaxonin to work properly. Giant Axonal Neuropathy (GAN) causes a shortage of functional Gigaxonin. Nerves stop working normally in people with GAN. This causes problems with walking and sometimes with eating, breathing, and many other activities. GAN has no cure. Over time, GAN can shorten a person s life. Researchers want to see if a gene transfer treatment may help people with GAN. Objectives: \- To see if a gene transfer is safe and shows potential to help people with GAN. Eligibility: \- People age 3 and older with GAN. Design: * For 1 month following gene transfer participants must live full-time within 100 miles of the NIH. * Participants will be screened by phone and in person. They will take many tests. Some are listed below. Their medical records will be reviewed. Their caregivers may be contacted. * Participants will have a total of about 27 visits, weekly, monthly, and then yearly over 15 years. They will include many of the tests below. * Physical and nervous system exams. * Blood, urine, and stool samples. * Nerve, lung, heart, and eye tests. * Questionnaires. * MRI scans, nerve biopsies, and spinal taps. Participants will be sedated for some tests. * Speech, memory, muscle, and mobility tests. * Skin biopsy (small sample removed). * Participants will take many medicines. Some require intravenous lines. * Participants will get the gene transfer through an injection by spinal tap into their cerebrospinal fluid, which flows around the brain and spinal cord. The genes are packed in a modified virus that carries the genes to cells in their body. Participants safety is not guaranteed.

This is an open-label and non-randomized first-in-human (Phase 1) clinical trial which incorporates an escalating single dose paradigm to assess safety of the gene transfer vector scAAV9/JeT-GAN administered intrathecally to target the brain and spinal cord of individuals with genetically confirmed Giant Axonal Neuropathy (GAN, OMIM #256850). GAN is a chronic neurodegenerative autosomal recessive disease pathologically characterized by enlarged axons with disordered intermediate filaments and microtubules. The disease pathology is due to loss-of-function variants in the GAN gene, which encodes the protein gigaxonin. Gigaxonin plays a major role in the maintenance of orderly and functional intermediate filament (IF) architecture, which is critical for axonal function. Onset of symptoms, usually at three to four years of age, generally manifests with a clumsy and unsteady gait (sensory ataxia). In the peripheral nervous system, the disease progressively affects predominantly sensory and motor nerves. By the end of the second decade of life, patients typically are wheelchair dependent with limited use of the arms and little to no use of their legs. During the second decade a tracheostomy or other means of ventilation, as well as a feeding tube, are often necessary. Death normally occurs in the second or third decade of life. We recently identified a sub-cohort of patients with a milder and later onset, yet progressive form of GAN characterized by a prolonged preservation of ambulation and less extensive white matter changes on brain MRI restricted to the infratentorial regions. These individuals are good trial candidates given the increased prospect of benefit at milder disease stages. There are no statistics on the incidence of GAN, but it is considered extremely rare and does not have an approved treatment aside from supportive care. Intrathecal delivery of a gene transfer vector carrying a normal copy of the GAN to the spinal cord and brain offers a potentially effective treatment for GAN. Primary objective: To assess the safety of scAAV9/JeT-GAN following intrathecal administration. Primary endpoint: Incidence of SAEs and treatment emergent adverse events at least possibly related to scAAV9/JeT-GAN treatment. Secondary objectives: 1. to assess motor and sensory disease symptoms pre- and post-treatment, 2. to examine neuropathology in peripheral nerve biopsies in response to treatment, 3. to examine cerebrospinal fluid (CSF) and to conduct CSF studies to assess response to treatment, and 4. to assess vector shedding following vector administration. Secondary endpoints: include clinical and physiological assessment of motor and sensory function, possible rescue of disease pathology in peripheral nerves, examination of CSF in response to treatment, and assessment of vector shedding following administration. The primary efficacy endpoint is the Motor Function Measure 32 (MFM-32). Summary of progress through protocol version 23 A total of 14 trial participants (all \>= five years of age) have received a single dose of scAAV9/JeTGAN ranging from 3.5 x 10\^13 vg (1x dose) to 3.5 x10\^14 vg (10x dose). Dosed individuals include those predicted to be cross-reactive immunological material (CRIM) positive (residual gigaxonin expression, n= 10) or CRIM-negative (absence of gigaxonin expression, n= 4), based on their respective GAN variant(s). In CRIM-positive individuals, residual protein expression may allow for transgene immune tolerance whereas in CRIM-negative individuals, immune modulation is required. Since GAN is a progressive neurodegenerative condition, younger and milder affected individuals have a higher prospect of benefitting from treatment with scAAV9/JeT-GAN. The study will explore the safety and efficacy in up to 21 patients with GAN ages 3 years and older, with an emphasis on enrollment of patients who are younger or with a milder phenotype and are independently ambulant.