Valproate is a drug that is approved by the U.S. Food and Drug Administration (FDA) for the treatment of epileptic seizures, episodes associated with bipolar disease, and for the prevention of migraines.

A Phase 3 clinical trial (NCT01671384) is currently studying the effects of valproate (a histone deacetylase inhibitor) in conjunction with Levocarnitine (a supplement) for the treatment of infants with spinal muscular atrophy (SMA).

How does valproate work in SMA patients?

Histones are critical proteins in our cells that bind to the genetic material (DNA) and help it achieve the correct three-dimentional structure.

The binding of histones to DNA is accomplished through a group of proteins called histone deacetylases. Valproate stops histones from binding to the DNA by inhibiting histone deacetylases.

In doing so, valproate exposes several portions of the DNA (genes) to cellular agents that are able to read them and to form their corresponding proteins.

Patients with SMA have low levels of the survival motor neuron (SMN) protein, which leads to the symptoms associated with the disease.

Previous research has shown that when valproate was added to cells from SMA patients under laboratory conditions, the levels of the SMN protein increased.

Why supplement with levocarnitine?

Carnitine is a compound that is essential to degrade fats and generate cellular energy in the mitochondria. Valproate induces a deficit in carnitine and leads to toxicity in the liver, a known side effect of this drug. For that reason, levocarnitine is indicated as a supplementary drug in this treatment.

Studies with valproate and levocarnitine in SMA patients

Initial clinical studies performed in infants (NCT00227266) and adults (NCT00481013) with SMA showed that the use of valproate and levocarnitine was generally well-tolerated. However, the treatment was not effective in improving strength or function.

Blood samples collected from the adults enrolled in the trial were used to evaluate the levels of the SMN protein throughout a 12-month treatment period with valproate and levocarnitine. The study showed that there was no evidence that the treatment increased SMN protein levels in the patients’ cells.

Nonetheless, a Phase 3 clinical trial to treat SMA patients with the valproate and levocarnitine mix (NCT01671384) is currently recruiting participants at the Myopathy Clinic, All India Institute of Medical Sciences, in New Delhi, India.

The double-blinded, randomized, placebo-controlled trial aims to evaluate changes in muscle power and in the functional motor scale of the participants while they receive the treatment and undergo regular physiotherapy sessions.

The study, which began in August 2013, is following 60 children, ages 2 to 15 (30 infants with SMA and 30 healthy patients) for 52 weeks. No results from the trial have been published yet.