G.P.9.02 In vitro evaluation of HDAC inhibitors for the treatment of spinal muscular atrophy

Proximal spinal muscular atrophy (SMA) is one of the most common recessively inherited diseases with an incidence of 1:6000. It is characterized by weakness and atrophy of voluntary muscles due to degeneration of alpha-motor neurons in the anterior horns of the spinal cord. SMA patients are classified into three groups based on age of onset and survival. Type I SMA is the most severe form with clinical onset before 6 months and survival time of less than 2 years. Type II SMA is the intermediate form with onset before 18 months. Patients die usually during the third decade of life. Type III SMA is the mild form of the disease with an onset after 18 months. Patients have a normal life expectancy, but are often wheelchair bound. In most of the cases SMA is caused by loss of protein encoded by the survival motor neuron-1 gene (SMN1). A nearly identical copy of the SMN1 gene, SMN2 is present in all SMA patients; however, SMN2 produces only low levels of functional protein due to alternative splicing. Various reports suggest that treatment with inhibitors of histone deacetylases (HDACs) offers the possibility to increase SMN protein levels from the SMN2 locus, which is likely to improve the disease phenotype. We built up an HDAC inhibitor compound toolbox containing selected HDAC inhibitors that belong to different structural classes, such as hydroxamic acids, amides and cyclic peptides. These were chosen based on their selectivity profiles for HDACs class I, II and III and tested in an ELISA assay on both human fibroblasts from SMA patients and differentiated neuroblastoma cell lines. We demonstrated that in general HDAC inhibitors exert differential effects on SMN up-regulation compared to reference compounds, such as valproic acid or trichostatin A. Our data suggest that the use of HDAC inhibitors remains promising for a potential treatment of SMA.