Valproic acid, or valproate, is a relatively safe drug that improves gross motor function in patients with spinal muscular atrophy (SMA), but fails to improve the functionality of specific muscles, including those involved in breathing, a review finds.
The study, “Efficacy and Safety of Valproic Acid for Spinal Muscular Atrophy: A Systematic Review and Meta‑Analysis,” was published in CNS Drugs.
SMA comprises a group of neurodegenerative disorders characterized by the gradual loss of motor neurons — the nerve cells responsible for controlling voluntary muscles — in the spinal cord, leading to muscle weakness and wasting.
It is divided into several subtypes (ranging from type 0 to type 4), depending on the age of disease onset and symptom severity. Patients affected by the most severe forms of the disease — those that have an early onset and have symptoms during fetal development (type 0) or shortly after birth (type 1) — usually are affected by respiratory complications that can be fatal.
Valproic acid (VPA) is a histone deacetylase inhibitor — essentially a molecule that prevents proteins called histones from binding to DNA. In doing so, VPA increases the exposure of DNA to cellular agents that translate it to functional proteins.
VPA is normally used to treat seizures, manic episodes, and bipolar disorders. However, recent studies have shown that VPA can increase the production of the survival motor neuron (SMN) protein that’s lacking in SMA patients, in cells cultured in a lab dish. In animal models of disease, VPA treatment reduced motor neuron degeneration and increased the production of the SMN protein.
“Several clinical trials have been conducted to investigate the safety and efficacy of VPA in SMA patients. However, … the results of these studies were controversial with no clear-cut evidence, and further evidence asserting the safety and efficacy of VPA for SMA in humans is needed,” the investigators wrote.
Their systematic review focused on gathering and summarizing the main findings of studies that assessed the safety and efficacy of VPA in patients with SMA.
A total of 455 studies were obtained from 11 databases that had been systematically searched to look for clinical trials on the safety and efficacy of VPA for SMA patients. After a full-text review and manual search, a total of 10 reports from nine clinical trials were selected to be included in the review.
The trials’ primary objective was to assess the efficacy of VPA, which was determined by measuring and comparing patients’ gross motor function before and after treatment; the secondary goal was to assess the safety of VPA, based on the frequency and severity of reported adverse events (AEs).
From the 10 reports included in the systematic review, five involving a total of 126 SMA patients were selected to be used in the final meta-analysis.
Results showed an overall significant improvement in gross motor function after VPA treatment, as measured by the Hammersmith Functional Motor Scale, Modified Hammersmith Functional Motor Scale, and MHFMS-Extend. Likewise, in non-randomized controlled studies, patients’ gross motor function was significantly improved after treatment.
On the other hand, no significant differences in gross motor function improvement were found between patients who were treated with VPA in combination with carnitine (a compound essential for cellular metabolism whose levels lower during VPA treatment) or with VPA alone.
In addition, qualitative analysis showed that VPA treatment failed to improve other types of motor functions, including respiratory function, for which results were contradictory.
VPA was generally considered safe and well-tolerated. Most of the studies included in the systematic review did not report any serious AEs associated with VPA treatment. However, in some cases, VPA use was associated with weight gain, gastrointestinal, and respiratory problems.
“Our study suggests that VPA treatment results in an improvement in gross motor functions for SMA patients, but not in other assessments of motor function or, possibly, in respiratory function,” the scientists said.
“Furthermore, although VPA appears to be a relatively safe drug, it may be associated with a wide range of AEs (including body weight increase, fatigue, fever, flu-like symptoms, irritability, and pain),” they added. “Thus, additional double-blind RCTs (randomized clinical trials) are required to obtain more conclusive findings.”