거대 축삭 신경병증 치료를 위한 scAAV9/JeT-GAN의 척수강내 투여

• INCLUSION CRITERIA:

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).

EXCLUSION/DEFERRAL CRITERIA:

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

• Clinically significant electrocardiogram (ECG) abnormality per PI, anesthesiologist, and cardiologist

• History of brain or spinal cord disease that would interfere with the LP procedures, CSF circulation, or safety assessments

• Presence of an implanted shunt for the drainage of CSF or an implanted CNS catheter

• 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.

• Participation in an IND, IDE, or equivalent clinical study in the past six months.

• 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.

• 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.

• Current use of medication (e.g., levothyroxine, vitamin A supplementation, oral contraceptive use, tetracycline, Diamox etc) that could potentially lead to changes in intracranial pressure

• Known sensitivity or adverse reaction to anesthetic medications likely to be used in the peri-operative period per the anesthesiologist s evaluation

• GAN subjects without quantifiable weakness or functional loss

• 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

• History of diabetes or clinically significant abnormality of glucose tolerance test, fasting blood sugar

• Positive purified protein derivative testing for tuberculosis

• Abnormal laboratory values considered clinically significant per the investigator:

  • Platelet count < 100,000 / mm3
  • Persistent leukopenia or leukocytosis (Total white blood cell count < 3,000/mm and > 12,000/mm respectively)
  • Significant anemia [Hb <10 g/dL]
  • Abnormal prothrombin (PT) or partial thromboplastin time (PTT) [value]
  • Abnormal liver function tests (>1.5 X ULN or > 2 X the baseline value)
  • Abnormal pancreatic enzymes (>1.5 X ULN or > 2 X the baseline value)
  • Patients with renal impairment defined as urinary protein concentration >= 0.2 g/L on 2 consecutive tests

• Failure to thrive, defined as:

• Falling 20 percentiles (20/100) in body weight in the 3 months preceding Screening/Baseline

• In patients below the 3rd percentile, any further drop in body weight percentile in the 3 months preceding Screening/Baseline

• Weight less than < 3rd percentile predicted for age and gender based upon WHO criteria

• Any anticipated need for major surgery in the next 12 - 18 months (including scoliosis correction surgery)

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