Trial of Sodium Valproate in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating disease characterized by progressive degeneration of motor neurons leading to muscle weakness.

The pathogenesis of ALS is unknown, but there is convincing evidence that several molecular mechanisms play a role. Previous studies investigated the role of the Survival Motor Neuron (SMN) gene in ALS. Recent data suggest that SMN genotypes producing less SMN protein increase susceptibility and severity of ALS. This leads to the hypothesis that the clinical expression of ALS is influenced by the total SMN protein level in affected patients. In a population of ALS patients in the Netherlands we found that SMN genotypes producing less SMN protein appear to increase susceptibility and severity of ALS. It was shown that the HDAC inhibitor sodium valproate (SVP) increases levels of SMN protein in vitro. From these results and from data suggesting neuroprotective properties of SVP, it is hypothesised that SVP could extend survival of patients with ALS. In addition, sodium valproate significantly prolonged the disease duration in the animal model for ALS, the SOD1 transgenic mouse. Given that SVP is a FDA-approved compound with well-known pharmacokinetic and toxicity profiles, it is an attractive candidate for a clinical trial in ALS patients.

Inclusion criteria

• Definite, probable, or probable-laboratory supported ALS according to the revised El Escorial World Federation of Neurology criteria.
• Intake of riluzole 50 mg twice a day (bid)
• A disease duration at inclusion of more than 6 months and less than 36 months [inclusive] (disease onset is defined as the date of first symptoms excluding muscle cramps and fasciculations)
• Vital capacity (VC%) ≥ 70% of normal value (slow expiration, best of a minimum of three and a maximum of five measurements, with a respiratory function validly assessable and a spontaneous, non-assisted ventilation)
• Ages 18 - 85 years (inclusive)
• Capable of thoroughly understanding the trial information given; has signed the informed consent.

Exclusion criteria

• Tracheostomy, tracheostomal ventilation of any type, non-invasive ventilation more than 16 hours/ day, or supplemental oxygen during the last three months prior to inclusion.
• Any medical condition or intoxication known to have an association with motor neuron dysfunction, which might confound or obscure the diagnosis of ALS.
• Presence of any concomitant life-threatening disease or any disease or impairment likely to interfere with functional assessment.
• Confirmed hepatic insufficiency or abnormal liver function (ASAT, ALAT greater than twice the upper limit of normal range).