New publications on SMA

Project co-funded with a grant from Families of SMA and SMA Europe has shown embryonic stem cell-derived neural cells improve SMA in mice. This study was recently published in the journal Brain by lead author Dr. Stefania Corti in the laboratory of Dr. Giacomo Comi at the Centre of Excellence on Neurodegenerative Diseases at the University of Milan.
The authors have previously published that primary neural stem cells derived from spinal cord of mice can ameliorate the spinal muscular atrophy phenotype in mice. However, this primary source has limited value in therapy development. Therefore, the authors have gone on to illustrate that neural cells derived from pluripotent embryonic stem cells show the same potential therapeutic benefit as those derived from spinal cord, offering promise as an unlimited source of neural stem cells for therapeutic transplantation and intervention.

The authors demonstrated in the current study that embryonic stem cell-derived neural stem cells can differentiate into motor neurons. In addition, following their intrathecal transplantation into spinal muscular atrophy mice, the neural stem cells survived and migrated to appropriate areas. Transplantation resulted in improved motor function, enhanced lifespan, and exhibited neuroprotective capability in the mice.
According to the authors, these results suggest translational potential for the use of pluripotent cells in neural stem cell-mediated therapies.

In a recent publication in Human Molecular Genetics “SAHA ameliorates the SMA phenotype in two mouse models for spinal muscular atrophy”, B. Wirth et al. 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 and have already been used in clinical trials for the treatment of SMA. 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 the researchers 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).
The researchers 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.

(source: FSMA website)