Intraneural Administration of scAAV9/JeT-GAN Into the Vagus Nerve for Patients With Giant Axonal Neuropathy (GAN)

A Phase I/II Open-label Intraneural Administration of scAAV9/JeT-GAN Into the Vagus Nerve to Determine the Safety and Efficacy for Patients With Giant Axonal Neuropathy (GAN) Caused by a Mutation in the GAN Gene

Giant axonal neuropathy (GAN) is a rare pediatric disorder caused by autosomal recessive mutations in the GAN gene. GAN is a multisystem, neurodegenerative disorder affecting the peripheral nervous system (PNS), central nervous system (CNS) and autonomic nervous system (ANS).

GAN is a fatal disease with many patients not surviving past early adulthood due to aspiration pneumonia and pulmonary complications. Currently, there are no approved drugs or other therapies for the treatment of GAN; and only supportive care therapies exist, leaving an unmet medical need to treat this rare, progressive, and ultimately fatal neurodegenerative disease.

The drug used in this study (scAAV9/JeT-GAN) has been studied in a previous gene therapy clinical trial by which the drug was administered as a single injection into the spinal canal (intrathecal [IT] administration) to treat the symptoms associated with the CNS and PNS neurodegeneration; however, this administration method did not address the symptoms associated with neurodegeneration of the ANS.

To treat the symptoms associated with ANS, this study has been designed to evaluate the safety and tolerability of a single dose of scAAV9/JeT-GAN administered directly into the left vagus nerve (intraneurally) in participants who have previously received scAAV9/JeT-GAN administered intrathecally.

This study involves the use of an investigational drug called scAAV9/JeT-GAN "Investigational" means that the drug has not been approved by the U.S. Food & Drug Administration (FDA) for the treatment of GAN and the progression of neurodegeneration to the CNS, PNS and ANS.

This is the first study in humans to administer the drug directly into the left vagus nerve. We want to find out what effects, good and/or bad, scAAV9/JeT-GAN has when administered directly into the vagus nerve.

The safety of intrathecal (IT) administration of scAAV9/JeT-GAN has been established in a prior research study; however, the people in this study will be the first people to receive the drug intraneurally. As a result, information about the safety and effectiveness of the route of administration is incomplete and all of the possible side effects are not yet known.

Study Overview

• Status: Recruiting
• Conditions: Giant Axonal Neuropathy (GAN)
• Intervention / Treatment: Genetic: scAAV9/JeT-GAN

• Study Type: Interventional
• Enrollment (Estimated): 4
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Samantha Bridges, BSN; Phone Number: 214-456-3696; Email: samantha.bridges@utsouthwestern.edu
• Study Contact Backup: Name: Kristy Riddle, BSN; Phone Number: 214-456-9501; Email: Kristy.Riddle@UTSouthwestern.edu

Study Locations

• United States
  • Texas
    • Dallas, Texas, United States, 75235
      • Recruiting
      • Children's Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Confirmed diagnosis of GAN disease by:

   1. Genomic DNA mutation analysis demonstrating homozygous or compound heterozygous, pathogenic and/or confirmed pathogenic variants in the GAN gene;
   2. Clinical history or symptoms to ANS dysfunction.
2. Previously treated with IT AAV/GAN and completion of 5 year follow up prior to enrollment.
3. Parents/l LAR willing to accompany the participant to all study visits and who will provide consent for their child's participation.
4. Subject able to comply with all protocol requirements and procedures.
5. Up to date on childhood vaccinations according to Centers for Disease Control (CDC) guidelines. Annual influenza and COVID-19 vaccinations are highly recommended.
6. Female participants of child-bearing potential must have a negative urine and/or negative serum pregnancy test at screening/baseline; (a) Female participants must agree to use an effective form of birth control during study participation.

Exclusion Criteria:

1. Inability to participate in study procedures (as determined by the site investigator).
2. Inability to be safely sedated in the opinion of the clinical anesthesiologist.
3. Concomitant illness or requirement for chronic drug treatment that in the opinion of the Principal Investigator (PI) creates unnecessary risks for gene transfer.
4. The presence of significant non-GAN related CNS impairment or behavioral disturbances that would confound the scientific rigor or interpretation of results of the study.
5. Have received an investigational drug within 30 days prior to screening or plan to receive an investigational drug (other than this gene therapy) during the study.
6. Currently participating in another interventional (drug/device) clinical trial.
7. Experienced an SAE (serious adverse event) related to scAAV9/JeT-GAN while participating in the first GAN IT study.
8. Contraindication to scAAV9/JeT-GAN or any of its ingredients.
9. Contraindication to any of the immune suppression medications used in this study.
10. Clinically significant abnormal laboratory values (GGT, ALT, and AST, or total bilirubin > 3 × ULN, creatinine ≥ 1.5 mg/dL, hemoglobin [Hgb] < 6 or > 20 g/dL; white blood cell [WBC] > 20,000 per cmm) prior to gene replacement therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Open Label administration of scAAV9/JeT-GAN; Patients will receive a single injection of scAAV9/JeT-GAN, given directly into the left vagus nerve. scAAV9/JeT-GAN is an injectable drug that contains optimized human gigaxonin (the protein that is mutated in GAN) DNA. scAAV9/JeT-GAN is delivered to cells through a modified viral vector. The vector is the vehicle that transports the gigaxonin DNA to cells. The vector used to transport gigaxonin DNA, is virus called adeno-associated virus serotype 9 (AAV9); however, this virus has been modified so as not cause an illness or infection.

Genetic: scAAV9/JeT-GAN; The drug used in this study (scAAV9/JeT-GAN) has been studied in a previous gene therapy clinical trial by which the drug was administered as a single injection into the spinal canal (intrathecal [IT] administration) to treat the symptoms associated with the CNS and PNS neurodegeneration. This is the first study in humans to administer the drug directly into the left vagus nerve.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety of scAAV9/JeT-GAN when delivered to the Vagus Nerve - Based on the Number and Severity of Adverse Events Attributable to Toxicity	Safety and tolerability will be determine by the number of Incidences of unanticipated treatment-related toxicities, Grade 3 or higher. Toxicity of scAAV9/JeT-GAN i will be determined by the amount of occurrences and severity of serious adverse events (adverse events Grade 4 and 5). Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 details the criteria for classifying adverse events. The requirements for classifying an AE a Grade 3 or higher is the following: Grade 3 Severe: Severe or medically significant but not immediately life- threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL (the ability to care for oneself without assistance).; Grade 4 Life-threatening consequences; urgent intervention indicated.; Grade 5 Death related to AE	3 years post treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Stability or Improvement in Autonomic Nervous Symptoms	Efficacy scAAV9/JeT-GAN will be determined by the stability or improvement in autonomic symptoms measured by the following Patient Reported Outcome Measures (PROM): 1) The COMPASS-31 is a scale used to measure neurodegenerative system symptoms related to autonomic dysfunction. A higher score indicates worse autonomic dysfunction. It consists of 31 patient-reported questions across six weighted domains.: Orthostatic Intolerance (10 points): Assesses symptoms related to standing up, such as dizziness or fainting.; Vasomotor Symptoms (6 points): Evaluates issues like changes in skin color or temperature regulation.; Secretomotor Symptoms (7 points): Focuses on dryness of eyes and mouth.; Gastrointestinal Symptoms (28 points): Covers digestive issues.; Bladder Symptoms (9 points): Assesses urinary symptoms.; Pupillomotor Symptoms (15 points): Relates to pupillary function.	3 years post treatment
Stability or Improvement of Motor Function	The Motor Function Measurement-32 (MFM-32) is a clinician-reported outcome measure used to assess the functional abilities of individuals with neuromuscular diseases. The MFM32 assessment is comprised of 32 items that assess a range of different motor functional abilities across three functional domains: Standing and transfers (D1: 13 items),; Axial and proximal motor function (D2: 12 items); Distal motor function (D3: 7 items). These domains assess a broad spectrum of abilities including gross and distal motor functioning of the upper and lower limbs. Each MFM32 item is scored on a 4-point Likert scale from 0 (cannot initiate the task) to 3 (performs the task fully). Item scores are summed, and the raw score is transformed to an overall total score ranging from 0 (severe functional impairment) to 100 (no functional impairment).	2 Years

Collaborators and Investigators

• Sponsor: University of Texas Southwestern Medical Center

Publications and helpful links

General Publications

• Ding J, Allen E, Wang W, Valle A, Wu C, Nardine T, Cui B, Yi J, Taylor A, Jeon NL, Chu S, So Y, Vogel H, Tolwani R, Mobley W, Yang Y. Gene targeting of GAN in mouse causes a toxic accumulation of microtubule-associated protein 8 and impaired retrograde axonal transport. Hum Mol Genet. 2006 May 1;15(9):1451-63. doi: 10.1093/hmg/ddl069. Epub 2006 Mar 24.
• 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.
• Weber T. Anti-AAV Antibodies in AAV Gene Therapy: Current Challenges and Possible Solutions. Front Immunol. 2021 Mar 17;12:658399. doi: 10.3389/fimmu.2021.658399. eCollection 2021.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2026
• Primary Completion (Estimated): December 31, 2031
• Study Completion (Estimated): June 30, 2032

Study Registration Dates

• First Submitted: March 12, 2026
• First Submitted That Met QC Criteria: April 18, 2026
• First Posted (Actual): April 22, 2026

Study Record Updates

• Last Update Posted (Actual): April 22, 2026
• Last Update Submitted That Met QC Criteria: April 18, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Gene Therapy; Autonomic Nervous System; Neurodegenerative disorder; Giant axonal neuropathy (GAN); scAAV9/JeT-GAN; Hannah's Hope Fund
• Additional Relevant MeSH Terms: Nervous System Diseases; Neuromuscular Diseases; Genetic Diseases, Inborn; Peripheral Nervous System Diseases; Congenital Abnormalities; Heredodegenerative Disorders, Nervous System; Nervous System Malformations; Polyneuropathies; Hereditary Sensory and Motor Neuropathy; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Neurodegenerative Diseases; Giant Axonal Neuropathy
• Other Study ID Numbers: STU20250052

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: At this time, the study team is undecided about sharing any patient related data with anyone outside of the study site. Should it be determined that the information learned in this study will be beneficial to other researchers, we make our data available and will follow all regulations regarding data sharing.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No