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

• Status: Recruiting
• Trial end date: 0000-00-00
• Target enrollment: 30
• Participant gender: Both

Summary

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.

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: National Institute of Neurological Disorders and Stroke (NINDS)
• Last Updated: 2016-12-02

Criteria

• 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 < 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. Ongoing medical condition that is deemed by the Principal Investigator to interfere with the conduct or assessments of the study.