The recent funding of Fate Therapeutics as a company dedicated to identification of pharmacological stem cell activators is a great step for the industry. Essentially, the concept of the company is that one day one will be able to activate one's own stem cells through taking various chemical compounds. This concept is not new, companies such as Stem Cell Therapeutics are already in Phase II clinical trials with such approaches.
In the current mini-article, we will discuss the ability of a compound that has been clinically used for decades as potential modulator of endogenous stem cells.
Note: VIDEO OF VALPROIC ACID EFFECTS ON STEM CELLS
Sodium Valproate belongs to a class of compounds called “histone deacetylase inhibitors”, which are known for ability to “desilence” the genome, allowing expression of genes that under normal situations would not be expressed . This “desilencing” activity is believed to allow for increasing ability of stem cells to propagate in vitro without differentiating [2, 3]. Clinically, valproic acid is an established treatment for epileptic seizures and biopolar disorders , whose activity was based upon its upregulation of inhibitory GABA activities .
The potential use of Valproic Acid for ALS comes from three main angles. The first is that valproic has been demonstrated to inhibit microglial cells hyperactivity and production of inflammatory mediators , such hyperactivity has previously been shown to be a factor in ALS progression in animal models [7, 8], and associated with clinical ALS . The second is that valproic acid appears to have protective effects in the superoxide dismutase (SOD) mouse model of ALS . The third is that the stimulation of stem cell activity may allow for regeneration of damaged motor neurons associated with ALS .
To date, a Phase III clinical trial evaluating valproic acid for the treatment of ALS has been reported in the Netherlands . For detailed information on doseages used it may be appropriate to contact the investigator. The investigator, Dr. Leonard H Van den Berg, MD, PhD, from UMC Utrecht (firstname.lastname@example.org) actually put this hypothesis together for why he thinks it may work. “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.”
If patient specific off-label usage of valproic acid (DEPAKENE®) is attempted on a case by case basis, a possible starting regimen may follow the clinically used protocols for bipolar disorders in which patients initiate therapy at 10 to 15 mg/kg/day and dose is increased by 5 to 10 mg/kg/week to achieve plasma concentrations (50 to 100 micrograms/mL).
Various adverse effects associated with valproic acid administration should be discussed with a physician experienced in its use. Primary known adverse effects include Indigestion, nausea, thrombocytopenia, and vomiting during initiation of the drug.
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