Intrathecal Administration of scAAV9/JeT-GAN for the Treatment of Giant Axonal Neuropathy
- Conditions
- Giant Axonal NeuropathyGene Transfer
- Interventions
- Genetic: scAAv9/JeT-GAN
- Registration Number
- NCT02362438
- Lead Sponsor
- Taysha Gene Therapies, Inc.
- Brief Summary
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.
- Detailed Description
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 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.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 21
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description 1X scAAv9/JeT-GAN Lowest dose in the escalation scheme 3.3X scAAv9/JeT-GAN 2nd dose increase in escalation scheme 10X scAAv9/JeT-GAN Highest dose in the escalation scheme 5X scAAv9/JeT-GAN 3rd dose increase in escalation scheme
- Primary Outcome Measures
Name Time Method To assess the safety of the vector 12 months Adverse event reports will be used to assess safety
- Secondary Outcome Measures
Name Time Method Assessment of motor and sensory disease symptoms compare to baseline 12 months Physical therapy assessments will be used for motor symptoms. Nerve conduction studies will be used to assess sensory symptoms.
Determine safety and tolerability of gene transfer in patients with null mutations receiving immunosuppression 12 months Adverse event reporting will be used to assess the safety of gene transfer in CRIM-negative patients.
Examination of neuropathology in peripheral nerve biopsies following treatment 12 months Nerve biopsies will be collected and analyzed to examine neuropathology.
Examination of cerebrospinal fluid following treatment 12 months CSF will be collected via lumbar puncture and analyzed to monitor for inflammatory markers.
Assessment of vector shedding following treatment 12 months Biospecimens will be collected to analyze vector shedding.
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center, 9000 Rockville Pike
🇺🇸Bethesda, Maryland, United States