Spinal Muscular Atrophy: from the study of molecular mechanisms to the identification of new therapeutic targets

In a study published in Brain in February, the researchers at Centro Dino Ferrari, University of Milan, IRCCS Fondazione Ca’ Granda, Ospedale Maggiore Policlinico identified NRXN2 and SYNCRIP as alternative therapeutic targets to SMN for Spinal Muscular Atrophy (SMA), demonstrating their possible rule as modifiers of disease phenotype.
Spinal muscular atrophy (SMA), due to autosomal recessive mutations in the SMN (Survival Motor Neuron) gene, is a serious neurodegenerative disease, characterized by the death of motor neurons in spinal cord, the neurons that carry the signals from the Central Nervous System to the muscles, controlling their movement. The type1 SMA represents the most common genetic cause of infant mortality; there are other forms with a later onset defined SMA type 2 and 3. The disease causes progressive weakness, muscle atrophy, deficiency in swallowing and difficulty in breathing. The only currently approved drug (an antisense oligonucleotide) and other clinical trials are focused on increasing the production of SMN, the protein deficient in SMA, in several ways. However, these types of treatments are effective only if administered early and it has not yet been clarified whether they are also suitable for less severe forms of SMA.
A better understanding of the molecular mechanisms underlying this complex pathology is needed to improve the therapeutic strategy. The study of gene expression in patients’ cells compared to those of healthy subjects can provide a turning point to identify non-SMN new therapeutic targets for SMA.

The principal investigator of the research is Prof. Corti, MD, PhD, chief of the Neural Stem Cell Laboratory in the Neuroscience Section, Department of Pathophysiology and Transplantation. The research group included also members of her lab and researchers of the Centro Dino Ferrari, University of Milan, IRCCS Fondazione Ca’Granda, Ospedale Maggiore Policlinico and collaborated with Computational Biology lab of Scientific Institute IRCCS E. MEDEA, , Bosisio Parini, Italy and with Institute of Bioscience and BioResources, IBBR, CNR, Naples, Italy.

Terapia per Atrofia Muscolare Spinale

Figure Legend

University of Milan scientists demonstrated the improvement of the disease phenotype into induced pluripotent stem cell-derived motor neurons reprogrammed from fibroblast of SMA patients following increase of NRXN2 (A) and SYNCRIP (B) expression.
Rizzo et al., Brain February 2019

“A complex analysis of gene expression, carried out in induced pluripotent stem cell-derived motor neurons reprogrammed from fibroblast of SMA patients and healthy subjects, allowed the identification of additional genes altered in this disease”,- Dr Federica Rizzo and Dr Monica Nizzardo affirmed, first co-authors of this study-“and the discovery of common elements in these genes”.

The research showed that the increasing of the identified genes expression improved the disease phenotype in patient cells, as well as in SMA murine and worm models.
“This remarkable result”, Prof. Stefania Corti concluded, “demonstrated the need to deepen the neurodegeneration mechanisms in SMA to identify new molecular markers useful for disease understanding, to evaluate the therapeutic response to available molecules and to contribute to the optimization of present and future therapeutic strategies.

For other information:
Prof. Stefania Corti
Centro Dino Ferrari, Department of Pathophysiology and Transplantation (DEPT),
University of Milan, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico,
Tel. +3902 55033817