Families of SMA Funded Study Shows the HDAC Inhibitor SAHA Ameliorates the SMA Phenotype in Two Mouse Models for Spinal Muscular Atrophy.
January 25, 2010.

Summary by Dr. Brunhilde Wirth:

In our recent publication in Human Molecular Genetics “SAHA ameliorates the SMA phenotype in two mouse models for spinal muscular atrophy” (Human Molecular Genetics, 2010 by Riessland M, Ackermann B, Förster A, Jakubik M, Hauke J, Garbes L, Fritzsche I, Mende Y, Blumcke I, Hahnen E, and Wirth B) we investigated the in vivo efficacy of the FDA-approved drug suberoylanilide hydroxamic acid (SAHA) in two SMA-like mouse models.

SMA develops from the loss of functional SMN1 alleles and failure of the retained SMN2 copies to produce sufficient full-length SMN protein. Histone deacetylase inhibitors (HDACi) such as valproic acid (VPA) have been shown to efficiently up-regulate SMN levels in SMA patients (Brichta et al 2003, Hum Mol Genet) and have already been used in clinical trials for the treatment of SMA (Brichta et al 2006, Ann of Neurology). Since VPA seems to be effective in only about 1/3 of SMA patients whilst the remaining are non- or negative responders showing no change or even a decrease of SMN levels under VPA, the need for further applicable potential SMA therapeutics is of vital importance.

Here we show that one other FDA-approved HDACi, SAHA (Vorinostat for Cancer), can rescue embryonic lethality in one SMA mouse model and significantly prolong survival in another SMA mouse model. Treated animals revealed improvement in motor function, increased number of motor neurons, increased size of neuromuscular junctions and muscle fibers. SAHA significantly elevated expression of SMN protein in the spinal cord (2.7-fold), brain (5.5-fold) and muscle (17.6-fold).  We propose SAHA as a candidate for a potential SMA therapy.

This study was supported by grants provided by Families of SMA (FSMA), the German Initiative “Forschung und Therapie fuer SMA”, Deutsche Forschungsgemeinschaft (DFG), and the Center for Molecular Medicine Cologne.

 Please click here for the paper abstract.