Title: Combining bioinformatic and drug repurposing approaches to develop second-generation therapies for spinal muscular atrophy
Funder: The Academy of Medical Sciences

Abstract: The aim of this project is to develop targeted treatment strategies to improve intrinsic muscle pathologies in spinal muscular atrophy (SMA). SMA is a devastating childhood neuromuscular disease caused by loss of the survival motor neuron 1 (SMN1) gene. The first SMN gene-based therapies have recently been approved by the Federal Drug Administration and European Medicines Agency. However, results from clinical trials highlight the need for combinatorial approaches that include SMN-dependent and -independent as well as central nervous system (CNS)- and non-CNS treatments for optimal therapeutic benefit. We have recently reported that administering the synthetic glucocorticoid prednisolone to SMA mice significantly improved disease phenotypes such as muscle health, weight and survival. Whilst these results are promising, chronic use of prednisolone can actually lead to muscle wasting. We therefore hypothesize that identifying the molecular effectors of prednisolone will allow us to develop more targeted muscle-specific therapies that can eventually be used in combination with SMN treatments. We have thus performed RNA-Sequencing on muscle from prednisolone-treated and untreated SMA mice to identify the molecular targets of prednisolone. We then used several publically available databases to generate a list of commercially available drugs and/or pharmacological compounds predicted to target similar genes and/or pathways as prednisolone. We have selected three drug candidates to be further investigated in SMA cellular and animal models, laying the foundation for future follow up projects where these drugs, as well as others from our list, will be evaluated alongside SMN gene therapies and in other muscle-wasting conditions.

Lay abstract: Spinal muscular atrophy (SMA) is a devastating childhood disease caused by loss of function of the survival motor neuron (SMN) gene, leading to the death of nerve and muscle cells. The first SMN gene replacement therapies have recently been approved by the regulatory bodies in the United States of America and Europe. These drugs, aimed at putting SMN back into cells, provide significant improvements in quality of life and life expectancy of SMA patients. However, it is now clear that SMN gene replacement treatments are unfortunately not a cure and their success is highly dependent on the age and disease severity of the SMA patient. Furthermore, SMN gene replacement therapies are extremely expensive, which has limited their availability to all patients worldwide, including in the UK. Therefore, additional affordable treatments need to be developed that can be used alongside SMN gene replacement therapies. We have recently shown that treating SMA mice with the steroid-like drug prednisolone improves their muscle health, weight and survival. However, long-term use of high doses of prednisolone can have unwanted side effects. We have therefore identified additional commercially available and affordable drugs that have the same predicted effects as prednisolone in muscle but with less reported negative side effects. We thus propose to evaluate the therapeutic potential of our top three drug candidates in cell and animal models of SMA. Our ultimate goal is to develop muscle-specific therapies that can be combined with existing SMN gene replacement treatments to improve the health of all SMA patients.

Research activity codes: 5.1 PHARMACEUTICALS;5.2 CELLULAR AND GENE THERAPIES
Health categories: MUSCULOSKELETAL