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

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.