Intrathecal Administration of scAAV9/JeT-GAN for the Treatment of Giant Axonal Neuropathy
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|ClinicalTrials.gov Identifier: NCT02362438|
Recruitment Status : Recruiting
First Posted : February 13, 2015
Last Update Posted : May 21, 2020
- 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.
- To see if a gene transfer is safe and shows potential to help people with GAN.
- People age 5 and older with GAN.
- For 2 months 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 30 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.
- 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.
|Condition or disease||Intervention/treatment||Phase|
|Giant Axonal Neuropathy Gene Transfer||Drug: Intrathecal Delivery of scAAV9/JeT-GAN||Phase 1|
This is a non-randomized, phase I, escalating single dose study to assess the safety of the gene transfer vector scAAV9/JeT-GAN through intrathecal delivery to the brain and spinal cord of patients with Giant Axonal Neuropathy (GAN, OMIM No.256850). The primary objective of this study is to assess the safety of the vector following intrathecal delivery in 10-12 GAN patients who are five years of age or older and have mutations which result in positive cross-reactive immunological material (CRIM) status. This terminology is used in other genetic disorders with residual protein expression that would allow for immunotolerance, amenable to enzyme or gene replacement such as in Pompe disease. Mutations which could result in CRIM-positive status include missense mutations, in-frame deletions or duplications or hypomorphic mutations (such as regulatory domain mutations which are leaky such as incomplete splice site mutations). This protocol was amended to include a single GAN patient, 5 years or older CRIM negative patient ('null mutation patient'). Secondary objectives of this study are 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. The first eligible CRIM positive patient will have a genetic diagnosis of giant axonal neuropathy, will be seven years of age or older, and will have a forced vital capacity of greater than or equal to 50 percent predicted value on pulmonary function testing. This study will be the first-in-human trial of intrathecal delivery of scAAV9/JeT-GAN. The primary endpoint will be safety, based upon adverse events and standard laboratory safety evaluations. Secondary endpoints will 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.
GAN is a chronic neurodegenerative autosomal recessive disease pathologically characterized by enlarged axons with disordered microtubules and intermediate filaments. The disease pathology is due to loss-of-function mutations 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 3-4 years of age, generally manifests with a slightly awkward gait (sensory ataxia). In the peripheral nervous system the disease progressively affects predominantly sensory and motor nerves. By the end of the 2nd decade of life, patients typically are wheelchair dependent with limited use of the arms and little to no use of their legs. During the 2nd decade a tracheostomy or other means of ventilation, as well as a feeding tube, are often necessary. Death normally occurs in the 2nd or 3rd decade of life. There are no statistics on the incidence of the disease, but it is considered extremely rare and there are no effective treatments for the disease. Intrathecal delivery of a gene transfer vector carrying a normal copy of the GAN Gene to the spinal cord and brain offers a potentially effective treatment for GAN.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||30 participants|
|Intervention Model:||Sequential Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase I Study of Intrathecal Administration of scAAV9/JeT-GAN for the Treatment of Giant Axonal Neuropathy|
|Actual Study Start Date :||April 24, 2015|
|Estimated Primary Completion Date :||June 30, 2022|
|Estimated Study Completion Date :||April 1, 2030|
- Drug: Intrathecal Delivery of scAAV9/JeT-GAN
Intrathecal transfer of scAAV9/JeT-GAN, with escalating doses at 3.5x10^13 vg, 3.3 x higher dose of 1.2 x10^14 vg, and the 5x higher dose of 1.8 x10^14 vg and the 10x higher dose of 3.6x10^14 vg.
- To determine the relative safety of intrathecal administration of scAAV9/JeT-GAN in the treatment of Giant Axonal Neuropathy [ Time Frame: Following vector administration: during weeks 1-4; months 3, 6, 9, 18; and, years 1 to 15; primary initial window for safety is within the first 1 year post gene transfer. Long term safety follow up will be evaluated for up to 15 years. ]The primary objective is to assess the safety of the vector as the incidence of serious adverse events at least possibly related to the investigational treatment, following intrathecal administration. The safety of scAAV9/JeT-GAN, measured by quantitative and qualitative descriptive statistics of the incidence of Adverse Events. Additional safety studies include: CSF studies, blood work, MRI brain/ spine.While the primary objective is safety, this study also evaluates safety, with the primary efficacy endpoint being MFM32. Additional supporting efficacy measures of interest include: FARS, myometry, NIS, NCS, and ophthalmology evaluation.
- To determine the efficacy of scAAV9-JeT-GAN, measured by improvement of pathologic, histologic, physiologic, function, and clinical markers of Giant Axonal Neuropathy [ Time Frame: post-vector administration during first four weeks, months 3, 6, 9, and 18; and years 1 to 15 ]Secondary objectives include:-Assessment of motor and sensory disease symptoms compared to baseline, based upon standardized testing and investigational Non Significant Risk testing methods before and after administration of the investigational agent;-Examination of neuropathology in peripheral nerve biopsies after investigational treatment, in comparison to biopsies obtained prior to treatment;-Examination of cerebrospinal fluid after investigational treatment, in comparison to CSF samples obtained prior to treatment; and-Assessment of vector shedding following IT administration.-Determine if a patient with null mutations in the GAN gene (CRIM-negative patient) can safely tolerate gene transfer with immunosuppression (to include transient corticosteroids, as well as a longer course of tacrolimus and rapamycin)All secondary outcome measures will be compared to baseline using simple descriptive statistics.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02362438
|Contact: Carsten G Bonnemann, M.D.||(301) firstname.lastname@example.org|
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Recruiting|
|Bethesda, Maryland, United States, 20892|
|Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR) 800-411-1222 ext TTY8664111010 email@example.com|
|Principal Investigator:||Carsten G Bonnemann, M.D.||National Institute of Neurological Disorders and Stroke (NINDS)|