• Change in SMAFRS [ Time Frame: 13 months ] [ Designated as safety issue: No ]
• Change in strength assessed by hand-held dynamometer [ Time Frame: 13 months ] [ Designated as safety issue: No ]
• Change in MUNE and CMAP [ Time Frame: 13 months ] [ Designated as safety issue: No ]
• SMN2 copy number [ Time Frame: 13 months ] [ Designated as safety issue: No ]
• Change in PFTs, including forced vital capacity (FVC) and negative inspiratory force (NIF) [ Time Frame: 13 months ] [ Designated as safety issue: No ]
• Change in lean body mass through DEXA scanning [ Time Frame: 13 months ] [ Designated as safety issue: No ]
• Change in distance walked in 6 minutes [ Time Frame: 13 months ] [ Designated as safety issue: No ]
• Change in time to climb four standard stairs [ Time Frame: 13 months ] [ Designated as safety issue: No ]
• Change in health-related QOL assessed through the modified sickness impact profile (SIP) [ Time Frame: 13 months ] [ Designated as safety issue: No ]

• Change in SMAFRS [ Time Frame: 13 months ]
• Change in strength assessed by hand-held dynamometer [ Time Frame: 13 months ]
• Change in MUNE and CMAP [ Time Frame: 13 months ]
• SMN2 copy number [ Time Frame: 13 months ]
• Change in PFTs, including forced vital capacity (FVC) and negative inspiratory force (NIF) [ Time Frame: 13 months ]
• Change in lean body mass through DEXA scanning [ Time Frame: 13 months ]
• Change in distance walked in 6 minutes [ Time Frame: 13 months ]
• Change in time to climb four standard stairs [ Time Frame: 13 months ]
• Change in health-related QOL assessed through the modified sickness impact profile (SIP) [ Time Frame: 13 months ]

The primary objective of this proposal is to determine whether oral VPA is effective in treating SMA in adult patients.

Participation in this study entails six visits and seven to eight blood draws over 13 months. Each visit entails a stay of two days and one night at the General Clinical Research Center (GCRC).

Subjects who live within driving distance will be allowed to participate in the study without an overnight stay through two consecutive outpatient visits. All subjects will be evaluated at two screening visits 2-4 weeks apart to determine eligibility for participation. Eligible subjects will be randomized to receive VPA or placebo for the first six months. At the six-month visit, patients will be evaluated and crossed over to the other regimen.

• Drug: Valproic Acid (VPA)
• Drug: Placebo

• Placebo Comparator: For six months, half of patients are randomized into placebo . After 6 months, all patients are on treatment.
• Active Comparator: Cohort 1b patients are randomized onto treatment. After 6 months, all patients are on drug.

Inclusion Criteria:

1. Ambulatory adults with SMA 3 ages 18-60. The diagnosis of SMA must be documented by the homozygous deletion of both SMN1 genes on standard genetic tests for the disorder. Patients must be able to walk thirty feet without assistance (i.e. no canes, walkers).
2. Interest in participating and the ability to meet the study requirements.
3. Women of child bearing age are required to be on birth control or abstain while participating in the study.

Exclusion Criteria:

1. Non-ambulatory type 3 adults and all type 2 adults.
2. Patients with co-morbid conditions that preclude travel, testing or study medications.
3. Patients who have participated in a treatment trial for SMA in the 3 months prior to this trial, or plan on enrolling in any other treatment trial during the duration of this trial.
4. Patients who are, in the investigator's opinion, mentally or legally incapacitated from providing informed consent for the study, or are otherwise unable to meet study requirements or cooperate reliably with study procedures, especially strength testing.
5. Patients with a need for non-invasive ventilatory support (e.g. BiPAP) for > 12 hours/day
6. Transaminases, amylase or lipase > 3.0 x normal values, WBC < 3.0 or neutropenia < 1.0, platelet count < 100 K, or hematocrit < 30 persisting over a 30 day period
7. Use of medications or supplements which interfere with VPA metabolism and increase the potential risks of the medications, or are hypothesized to have a beneficial effect in SMA animal models or human neuromuscular disorders within 3 months of study enrollment. These agents include riluzole, creatine, butyrate derivatives, growth hormone, anabolic steroids, daily albuterol use, anticonvulsants, or other HDAC inhibitors.
8. Women who are pregnant or who intend to become pregnant while participating in the research study or who are breastfeeding.

• Families of Spinal Muscular Atrophy
• Abbott