Bethesda, Maryland 20892


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 5 and older with GAN. Design: - 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. - 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.

Study summary:

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.


- INCLUSION CRITERIA: In order to participate in this study, the subject must meet the following criteria: 1. Age 5 years or older; however, the first patient will be no younger than 7 years of age. 2. Genetic diagnosis of GAN: Identified mutation(s) on both copies of the GAN gene. If the mutations found are not previously reported, then predictive software tools will be utilized in order to determine the degree of certainty that the mutation is predicted to be pathogenic (disease causing). This will also be evaluated in the context of the clinical and pathological phenotype (see below). 3. Onset of clinical signs and symptoms consistent with GAN, including at least abnormal gait, as well as physical examination findings including at least abnormal gait, abnormal sensation (proprioceptive and/ or vibration sensation and/or positive Romberg), and some quantifiable weakness on manual muscle testing examination (score of < 5/5 strength of at least one tested muscle). 4. 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. 5. 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. 6. Willingness to undergo a nerve biopsy at baseline and at 12 months after treatment. 7. Agree to reside within 100 miles of the study site for at least 2 months following treatment (may include housing on NIH campus). EXCLUSION/DEFERRAL CRITERIA: In order to participate in this study, a patient MUST NOT have the following characteristics: 1. Pregnant or lactating patients 2. Forced vital capacity less than or equal to 50% of predicted value 3. Ventilator dependence to include daytime use of assisted ventilation 4. 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 5. Prior history of bacterial meningitis 6. Unwilling to undergo lumbar puncture at baseline and up to 2 to 3 times during follow up during the first year after treatment. 7. Clinically significant echocardiogram abnormality per PI, anesthesiologist, and cardiologist 8. Clinically significant electrocardiogram (ECG) abnormality per PI, anesthesiologist, and cardiologist 9. History of brain or spinal cord disease that would interfere with the LP procedures, CSF circulation, or safety assessments 10. Presence of an implanted shunt for the drainage of CSF or an implanted CNS catheter 11. Any prior participation in a study in which a gene therapy vector or stem cell transplantation was administered to avoid any ambiguity in the safety assessment resulting from lingering effects from a previous treatment. 12. Participation in an IND, IDE, or equivalent clinical study in the past six months. 13. History of or current chemotherapy, radiotherapy or other immunosuppressive therapy within the past 30 days. Corticosteroid treatment may be permitted at the discretion of the PI. 14. Immunizations of any kind in the month prior to the study to avoid lingering immune effects that could be confusing in the safety assessment of the trial. 15. Current use of medication (e.g., levothyroxine, vitamin A supplementation, oral contraceptive use, tetracycline, Diamox) that could potentially lead to changes in intracranial pressure 16. Known sensitivity or adverse reaction to anesthetic medications likely to be used in the peri-operative period per the anesthesiologist s evaluation 17. GAN subjects without quantifiable weakness or functional loss 18. Evidence of cardiomyopathy on history, exam, or additional testing (echocardiogram or electrocardiogram) or other cardiac disease that in the opinion of the investigator would deem the subject unsafe to participate in the trial 19. History of diabetes or clinically significant abnormality of glucose tolerance test, fasting blood sugar 20. Positive purified protein derivative testing for tuberculosis 21. Abnormal laboratory values considered clinically significant per the investigator: 1. Platelet count < 100,000 / mm3 2. Persistent leukopenia or leukocytosis (Total white blood cell count < 3,000/mm and > 12,000/mm respectively) 3. Significant anemia [Hb <10 g/dL] 4. Abnormal prothrombin (PT) or partial thromboplastin time (PTT) [value] 5. Abnormal liver function tests (>1.5 X ULN or > 2 X the baseline value) 6. Abnormal pancreatic enzymes (>1.5 X ULN or > 2 X the baseline value) 7. Patients with renal impairment defined as urinary protein concentration greater than or equal to 0.2 g/L on 2 consecutive tests 22. Failure to thrive, defined as: 1. Falling 20 percentiles (20/100) in body weight in the 3 months preceding Screening/Baseline 2. In patients below the 3rd percentile, any further drop in body weight percentile in the 3 months preceding Screening/Baseline 23. Weight less than 17kg at Baseline to avoid additional risks from comorbidity 24. Any anticipated need for major surgery in the next 12 18 months (including scoliosis correction surgery) 25. Ongoing medical condition that is deemed by the Principal Investigator to interfere with the conduct or assessments of the study.



Primary Contact:

Principal Investigator
Carsten G Bonnemann, M.D.
National Institute of Neurological Disorders and Stroke (NINDS)

Carsten G Bonnemann, M.D.
Phone: (301) 594-5496

Backup Contact:


Location Contact:

Bethesda, Maryland 20892
United States

For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL)
Phone: 800-411-1222

Site Status: Recruiting

Data Source:

Date Processed: June 25, 2018

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