SMN Replacement Therapy for Spinal Muscular Atrophy: Clinical Development

Lead Research Organisation: University of Sheffield
Department Name: Neurosciences


SMA is due to premature death of motor neurons which are connected to muscle, and provide the stimulus to initiate muscle contraction. The disease is caused by depletion in the SMN protein levels. We recently showed that genetically modified viruses, making them safe to use in human, can be successfully used to restore the level of SMN both in cells and in a mouse model. The latest experiments showed for the first time that we can replace the SMN gene, reverse the symptoms leading to a dramatic effect on survival in the SMA mouse model. However, further in vivo studies are needed to characterise our strategy before entering clinical application in human. Our major goals are: 1) Optimise a method to produce large quantity of clinical grade vector; 2) select the appropriate dose for further safety studies in rodents; 3) Evaluate the safety and toxicity of our system. These studies represent an important and necessary step towards translation into human treatment.

Technical Summary

Spinal muscular atrophy is caused by mutations of the survival motor neuron (SMN) gene. Gene therapy aimed at restoring the SMN protein expression represents therefore a rationale therapeutic approach to ameliorate the disease phenotype. We recently showed that a gene transfer of self complementary adeno-associated virus serotype 9 expressing a codon optimised version of SMN in SMNdelta7 mice leads to complete correction of the motor deficits in these animals resulting in a substantial extension in their life span. These data provide evidence for the most efficacious therapy observed in this field to date. Our ultimate goal is to progress the SMN replacement approach to a phase I clinical trial in SMA patients. However, progress is limited by the requirement for further pivotal pre-clinical studies and vector production scaling up. The proposed pre-clinical studies will provide essential information about safety and suitability of our vector system for clinical application.


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