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

NCT02362438 | Completed Phase 1 FDA Drug

• 2 other identifiers: 15007315-N-0073
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

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.

Conditions

Giant Axonal Neuropathy; Gene Transfer

Keywords

Intrathecal; AAV9 Mediated Gene Transfer; Phase I; Safety Study; Giant Axonal Neuropathy

Outcome Measures

Primary Outcomes (1)

• To assess the safety of the vector

  Adverse event reports will be used to assess safety

  12 months

Secondary Outcomes (5)

• Assessment of motor and sensory disease symptoms compare to baseline

  12 months

• Examination of neuropathology in peripheral nerve biopsies following treatment

  12 months

• Examination of cerebrospinal fluid following treatment

  12 months

• Assessment of vector shedding following treatment

  12 months

• Determine safety and tolerability of gene transfer in patients with null mutations receiving immunosuppression

  12 months

Study Arms (4)

10X

EXPERIMENTAL

Highest dose in the escalation scheme

Genetic: scAAv9/JeT-GAN

1X

EXPERIMENTAL

Lowest dose in the escalation scheme

Genetic: scAAv9/JeT-GAN

3.3X

EXPERIMENTAL

2nd dose increase in escalation scheme

Genetic: scAAv9/JeT-GAN

5X

EXPERIMENTAL

3rd dose increase in escalation scheme

Genetic: scAAv9/JeT-GAN

Interventions

scAAv9/JeT-GAN GENETIC

scAAV9/JeT-GAN is a biological gene transfer reagent

10X; 1X; 3.3X; 5X

Eligibility Criteria

• Age: 3 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• To participate in this study, subjects must meet the following criteria:
• Age 3 years or older.
• Genetic diagnosis of GAN: Identified pathogenic variant(s) on both copies of the GAN gene. If the variants found are not previously reported, then predictive software tools will be utilized to determine the degree of certainty that the variant is expected to be pathogenic (disease causing). This will also be evaluated in the context of the clinical and pathological phenotype.
• Men capable of fathering a child must agree to use barrier contraception (combination of a condom and spermicide) or limit activity to post-menopausal, surgically sterilized, or contraception-practicing partners, for 6 months after administration of investigational product. Women and girls of childbearing potential (and parents/ guardians for minors \< 18) must agree to have urine human chorionic gonadotropin testing performed to rule out the possibility of pregnancy at each visit. Those women who are sexually active must also agree to use barrier contraception as well or limit activity to surgically sterilized or contraception-practicing partners for 3-6 months after the administration of the investigational product. This limitation is set because of the unknown risk associated with the administration of this vector genome to offspring. There is no known risk of sexual transmission of the vector.
• Willing and able to give informed consent if \>17 years of age and assent if \>7 years of age. For patients ages 7-17, parents or legal guardians must also consent to the child s participation in the study. Adults who lack capacity to consent but who have an appropriate surrogate may be included.
• Willingness to undergo a nerve biopsy at baseline and at 12 months after treatment.
• Agree to reside within 100 miles of the study site for at least 4 weeks following treatment (may include housing on NIH campus).
• To participate in this study, a patient MUST NOT have the following characteristics:
• Pregnant or lactating patients
• Forced vital capacity \<= 50% of predicted value (if patient is \>/= 5 years old; otherwise, baseline FVC is not required in those \< 5 years old at time of enrollment)
• Ventilator dependence to include daytime use of assisted ventilation
• Current clinically significant infections including any requiring systemic treatment including but not limited to Human immunodeficiency virus, Hepatitis A, B, or C, Varicella zoster virus, or HTLV-1
• Prior history of bacterial meningitis
• Unwilling to undergo lumbar puncture at baseline and up to 2 to 3 times during follow up during the first year after treatment.
• Clinically significant echocardiogram abnormality per PI, anesthesiologist, and cardiologist

Sponsors & Collaborators

• National Institute of Neurological Disorders and Stroke (NINDS): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• Bharucha-Goebel DX, Todd JJ, Saade D, Norato G, Jain M, Lehky T, Bailey RM, Chichester JA, Calcedo R, Armao D, Foley AR, Mohassel P, Tesfaye E, Carlin BP, Seremula B, Waite M, Zein WM, Huryn LA, Crawford TO, Sumner CJ, Hoke A, Heiss JD, Charnas L, Hooper JE, Bouldin TW, Kang EM, Rybin D, Gray SJ, Bonnemann CG; GAN Trial Team. Intrathecal Gene Therapy for Giant Axonal Neuropathy. N Engl J Med. 2024 Mar 21;390(12):1092-1104. doi: 10.1056/NEJMoa2307952.

  PMID: 38507752 DERIVED

• Armao D, Bouldin TW, Bailey RM, Gray SJ. Extensive rod and cone photoreceptor-cell degeneration in rat models of giant axonal neuropathy: implications for gene therapy of human disease. Ophthalmic Genet. 2021 Oct;42(5):600-603. doi: 10.1080/13816810.2021.1923036. Epub 2021 May 6.

  PMID: 33955818 DERIVED

• Armao D, Bouldin TW, Bailey RM, Hooper JE, Bharucha DX, Gray SJ. Advancing the pathologic phenotype of giant axonal neuropathy: early involvement of the ocular lens. Orphanet J Rare Dis. 2019 Feb 1;14(1):27. doi: 10.1186/s13023-018-0957-5.

  PMID: 30709364 DERIVED

• Bailey RM, Armao D, Nagabhushan Kalburgi S, Gray SJ. Development of Intrathecal AAV9 Gene Therapy for Giant Axonal Neuropathy. Mol Ther Methods Clin Dev. 2018 Feb 15;9:160-171. doi: 10.1016/j.omtm.2018.02.005. eCollection 2018 Jun 15.

  PMID: 29766026 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Giant Axonal Neuropathy

Condition Hierarchy (Ancestors)

Hereditary Sensory and Motor Neuropathy; Nervous System Malformations; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Peripheral Nervous System Diseases; Neuromuscular Diseases; Polyneuropathies; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn

Study Officials

• Rotem Or Bach, M.D.

  National Institute of Neurological Disorders and Stroke (NINDS)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 12, 2015
• First Posted: February 13, 2015
• Study Start: April 24, 2015
• Primary Completion: April 10, 2026
• Study Completion: April 10, 2026
• Last Updated: April 30, 2026

Record last verified: 2026-04-23

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: At a minimum, the study protocol will be shared with a commercial partner to assist with the BLA. The current CTA requires sharing of data by the end of July 2021; however, there are plans to extend the agreement until July 2023.
• Access Criteria: A relationship has been established with a Taysha Gene Therapies. A data analysis plan has not yet been established by the company because NINDS is the current Sponsor.@@@@@@Safety is the primary outcome measure for this clinical trial.

Locations

US (1)