Phase I/IIa Trial of scAAV1.tMCK.NTF3 for Treatment of CMT1A

This clinical trial is an open-label, one-time injection ascending dose study in which
scAAV1.tMCK.NTF3 will be administered by intramuscular injections into medial and lateral
heads of gastrocnemius and tibialis anterior muscles in both legs in CMT1A subjects with
PMP22 gene duplication. Nine CMT1A patients, 15 to 35 years of age will be enrolled into one
of two cohorts in this trial. The first cohort will consist of subjects that are 18 to 35
years of age. The first three adult subjects will be enrolled at a low-minimally effective
dose (2e12 vg/kg) distributed bilaterally between both limbs in Cohort 1. An additional six
subjects, ages 15 to 35, will be enrolled with a 3-fold dose escalation (6e12 vg/kg) in
Cohort 2. Post-gene transfer monitoring will include follow up visits on days 7, 14, 30, 60,
90, 120, and months 6, 9, 12, 15, 18 and 24 following gene transfer. Safety is the primary
endpoint for this clinical gene transfer trial. Stopping criteria are based on development of
unacceptable toxicity defined as the occurrence of any one Grade III or higher,
unanticipated, treatment-related toxicity. The secondary endpoint is efficacy defined as
halting of the decline in abilities measured by the CMT Pediatric Scale (CMTPedS) at 2 years
post gene transfer. The CMTPedS is an 11-item scale comprised of the Functional Dexterity
Test, Nine-Hole Peg Test (9HPT), hand grip, foot plantarflexion, and foot dorsiflexion
strength using handheld myometry, pinprick and vibration sensation, the Bruininks Oseretsky
Test- Balance assessment, gait assessment, long jump, and six-minute walk test (6MWT).
Exploratory outcome measures will include 100 meter timed test (100M), peroneal and ulnar
CMAP amplitude and sensory and motor conduction velocities, a revised sensory testing to
increase sensitivity for pinprick, touch-test and vibration assessments, visual analogue
scales for pain and fatigue, Short Form Health Survey (SF-36) as Quality of Life measure, and
circulating NT-3 levels.

Inclusion Criteria:

- Subjects 15- 35 years old inclusive with CMT1A will be enrolled (Cohort 1 will only
include subjects that are 18 to 35 years of age)

- Must exhibit a 1.5 Mb duplication at 17p11.2 inclusive of the peripheral myelin
protein 22 (PMP22) gene

- Males and females of any ethnic or racial group

- Must exhibit weakness of the ankle dorsiflexion muscle (but has full ROM against
gravity and is able to stand on heels 3 seconds or greater)

- Abnormal nerve conduction velocities

- Ability to cooperate for clinical evaluation and repeat nerve conduction studies

- Willingness of sexually active subjects to practice a reliable method of contraception
during the study

Exclusion Criteria:

- Active viral infection based on clinical observations or serological evidence of HIV,
or Hepatitis B or C infection

- Ongoing immunosuppressive therapy or immunosuppressive therapy within 6 months of
starting the trial (e.g., corticosteroids, cyclosporine, tacrolimus, methotrexate,
cyclophosphamide, intravenous immunoglobulin)

- Persistent leukopenia or leukocytosis (WBC ≤ 3.5 K/µL or ≥ 20.0 K/µL) or an absolute
neutrophil count < 1.5K/µL

- Subjects with AAV1 binding antibody titers ≥ 1:50 as determined by ELISA immunoassay

- Subjects with circulating anti-NT-3 titers ≥ 1:50 as determined by ELISA immunoassay

- Treat with any investigational medication within 30 days before the infusion of study
drug

- Abnormal laboratory values considered clinically significant (GGT > 3XULN, bilirubin ≥
3.0 mg/dL, creatinine ≥ 1.8 mg/dL, Hgb < 8 or > 18 g/Dl; WBC > 15,000 per cmm)

- Any medical condition or extenuating circumstance that, in the opinion of the
investigator, might compromise the subject's ability to comply with the protocol
required testing or procedures or compromise the subject's wellbeing, safety, or
clinical interpretability

- Ankle contractures or surgeries preventing proper muscle strength testing

- Pregnancy or lactation (females subjects will be tested for pregnancy)

- Limb surgery in the past six months

- Severe infection (e.g. pneumonia, pyelonephritis, or meningitis) within 4 weeks before
gene transfer visit (enrollment may be postponed)

- Anyone unwilling to disclose study participation with primary care physician and other
medical providers.