Research Description

Spinal Muscular Atrophy (SMA) pathogenesis and treatment.

The Burghes Laboratory is focused on understanding how reduced SMN ( Survival Motor Neuron) protein levels give rise to Spinal Muscular Atrophy (SMA). Increasing SMN protein using gene therapy, small molecule drugs and antisense oligonucleotides ameliorates SMA in cell culture, mouse models and humans. The Burghes laboratory was heavily involved in the development of these FDA approved therapies. Yet, the particular function of SMN that is disrupted remains unknown. To study the biological pathway altered by loss of SMN, the lab has used transgenic mice, pigs, and cell culture to study proteins that are known to physically interact with SMN. These studies will give genetic evidence for the critical pathway and genes disrupted by SMN deficiency.

Currently we are using long-range Oxford Nanopore sequencing techniques to study genetic variation in discordant SMA sibling pairs with identical SMN2 copy numbers. Bioinformatic pipelines and novel methods of variant analysis are used to identify genetic modifiers of SMA severity in humans. Understanding the basic mechanism of SMA and SMN loss can lead to the identification of new therapeutic targets, which can then be tested in the Delta7 SMA mouse model and eventually translated to the clinic. In addition, the lab is developing next-generation gene therapy for SMA through modification of the SMN2 gene using CRISPR technology. The Burghes Lab has expertise in the cloning of the SMN gene, transgenic mouse model creation and the development of therapeutics, including gene replacement therapy for SMA.