Off-target Effects of Spinal Muscular Atrophy (SMA) Therapeutics Gillette, Benjamin
dc.contributor.department Biomedical Sciences 2024-04-19T16:16:14Z 2024-04-19T16:16:14Z 2022-12
dc.description.abstract Spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by a mutation in or deletion of the Survival Motor Neuron 1 (SMN1) gene that produces SMN, a multifunctional protein. The near identical copy of SMN1, SMN2, produces a truncated SMN due to skipping of exon 7 during pre-mRNA splicing. The low levels of full-length SMN generated from SMN2 is insufficient for the body’s needs. Since most SMA patients carry the SMN2 gene, modulation of SMN2 exon 7 splicing constitutes an excellent therapy for the disease. Two small compounds, risdiplam and branaplam, promote SMN2 exon 7 inclusion. Importantly, they achieve body-wide distribution and can cross blood-brain barrier promoting SMN2 exon 7 inclusion in motor neurons, the primary “targets” of SMA. However, it has been shown that these drugs also produce off-target effects that could be potentially harmful to SMA patients. The full scope and degree of these off-target effects remain unknown, so we aimed to identify them. Results of RNA-Seq revealed multiple splicing errors caused by low and high doses of risdiplam or branaplam. To understand the mechanistic aspect of these splicing errors, we generated minigenes containing the affected exons. These minigenes were transfected into HeLa cells which were then treated with risdiplam and branaplam. Cells were collected 24 hours post-transfection followed by analysis of splicing. Our results reveal multiple mechanisms of splicing errors caused by risdiplam and branaplam.
dc.subject.disciplines DegreeDisciplines::Life Sciences::Biology
dc.title Off-target Effects of Spinal Muscular Atrophy (SMA) Therapeutics
dc.type Presentation
dspace.entity.type Publication
relation.isOrgUnitOfPublication 184db3f2-d93f-4571-8ad7-07c8a9e6a5c9
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