Valproic Acid

Disease-Modifying Therapies for Treating SMA

Valproic acid has long been indicated for the treatment of seizures, mania, and migraine prophylaxis and has been used off label for painful diabetic neuropathy, postherpetic neuralgia, and status epilepticus among others. Valproic acid is known to increase levels of the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA). However, this small molecule is also a histone deacetylase inhibitor. It is this mechanism of action that earned valproic acid the attention of spinal muscular atrophy (SMA) researchers.

Long before antisense oligonucleotide and gene therapy were being developed, valproic acid was being tested as a putative treatment for SMA. The idea was that valproic acid could inhibit histone deacetylase and increase the transcription of the SMN2 gene. Higher levels of SMN2 RNA would lead to high levels of survival motor neuron protein in a less severe phenotype in the disease.

Valproic acid was tested in no fewer than five Phase I/II clinical trials (NCT00374075, NCT00227266, NCT00481013, NCT00661453, NCT01033331).1,2,3,4,5,6 In the first clinical trial, patients with SMA types 1, 2, and 3 (age 2-31) received valproic acid as divalproex sodium in divided doses 2 to 3 times per day titrated to maintain a minimum blood level of the drug.1 The treatment was generally well-tolerated, though weight gain was noted. More importantly, plasma levels of carnitine dropped precipitously in some patients, which exacerbated motor symptoms. In this initial trial, patients under the age of five (who maintained blood carnitine levels) had better motor function with treatment despite no perceptible change in full-length SMN RNA levels.

The positive results of this trial were used to design and justify the other clinical trials of valproic acid in patients with spinal muscular atrophy (Patients were also given carnitine supplements along with valproic acid, for example). The results of the additional trials were highly disappointing—valproic acid did not improve strength or motor function compared to baseline or placebo, and there was no improvement in survival.2,3,4,5,6

Given the accumulated results of clinical trials, valproic acid has largely been abandoned as a potential treatment for SMA.7 However, researchers realized that approximately 1/3 of patients with SMA benefited from valproic acid and had increased SMN2 transcript levels.8 Nonresponders, it turns out, had fivefold higher CD36 RNA expression than those who responded to valproic acid treatment, suggesting that CD36 overexpression interfered with treatment. While much of the field has moved to antisense oligonucleotide and gene therapy approaches for the treatment of spinal muscular atrophy, one wonders if valproic acid may be a potential combination treatment for SMA in patients with relatively low CD36 RNA expression.7


1. Swoboda KJ, Scott CB, Reyna SP, et al. Phase II open label study of valproic acid in spinal muscular atrophy. PLoS One. 2009;4(5):e5268.

2. Swoboda KJ, Scott CB, Crawford TO, et al. SMA CARNI-VAL trial part I: double-blind, randomized, placebo-controlled trial of L-carnitine and valproic acid in spinal muscular atrophy. PLoS One. Aug 19 2010;5(8):e12140.

3. Krosschell KJ, Kissel JT, Townsend EL, et al. Clinical trial of L-Carnitine and valproic acid in spinal muscular atrophy type I. Muscle Nerve. Feb 2018;57(2):193-199.

4. Kissel JT, Scott CB, Reyna SP, et al. SMA CARNIVAL TRIAL PART II: a prospective, single-armed trial of L-carnitine and valproic acid in ambulatory children with spinal muscular atrophy. PLoS One. 2011;6(7):e21296.

5. Kissel JT, Elsheikh B, King WM, et al. SMA valiant trial: a prospective, double-blind, placebo-controlled trial of valproic acid in ambulatory adults with spinal muscular atrophy. Muscle Nerve. Feb 2014;49(2):187-192.

6. Darbar IA, Plaggert PG, Resende MB, et al. Evaluation of muscle strength and motor abilities in children with type II and III spinal muscle atrophy treated with valproic acid. BMC Neurol. Mar 24 2011;11:36.

7. Shorrock HK, Gillingwater TH, Groen EJN. Overview of Current Drugs and Molecules in Development for Spinal Muscular Atrophy Therapy. Drugs. Mar 2018;78(3):293-305.

8. Garbes L, Heesen L, Holker I, et al. VPA response in SMA is suppressed by the fatty acid translocase CD36. Hum Mol Genet. Jan 15 2013;22(2):398-407.