Short and Long Term Treatment With 4-AP in Ambulatory SMA Patients

Spinal muscular atrophy (SMA) is a genetically determined neuromuscular disorder that results
in muscle weakness and impaired functional mobility. Fatigue is a common symptom in SMA with
a resultant impact on physical function and quality of life however the precise mechanisms
are unknown. At present there is no treatment for SMA. There is evidence that 4-AP improves
function in SMA animal models. In patients with multiple sclerosis, 4-AP was found to improve
walking ability and diminish fatigue. The purpose of the study is to determine whether
treatment with 4-AP is associated with an increase in walking speed and endurance compared to
placebo and whether the duration of treatment affects outcome. The study comprises a short
term treatment trial in which participants are treated for 2 weeks with 4-AP and placebo in
random sequence followed by a long treatment trial of 6 weeks in which patients are also
treated with placebo and 4 AP. The primary outcome measure of the clinical study will be the
six minute walk test (6MWT), which has been documented to be a valid and sensitive instrument
to identify fatigue among ambulatory SMA patients. We will also assess the effect of 4-AP on
muscle and nerve electrical function via electromyography (EMG) during the short term trial.
Results of this study may provide support for larger clinical trials.

Inclusion Criteria:

1. Aged 18 to 50 years at the time of enrollment

2. Have genetically confirmed SMA 3 (homozygous absence of SMN1 exon 7)

3. Ability to walk at least 25 meters without assistance

4. Be free of major orthopedic deformities (i.e. scoliosis, contractures)

5. Normal Cystatin C clearance (> 80 ml/min)

Exclusion Criteria:

1. Patients with a history of seizures

2. Patients with any renal impairment

3. Inability to comply with the study procedures

4. Unstable medical illness

5. Any ventilatory assistance

6. Taking experimental medication for SMA other than under this protocol

7. Pregnancy or lactation

8. Menstruating women, not sterilized or not using effective birth control

9. Planning to undergo scoliosis surgery within the next 10 months

10. Inability to give informed consent