Development of a Splice-Switching Antisense Oligonucleotide for the Treatment of Spinal Muscular Atrophy
Abstract
Spinal Muscular Atrophy (SMA), an Area of Encouragement for the CDMRP Medical Technology/Therapeutic Development, is adevastating neurodegenerative disease and is the leading genetic cause of infantile death worldwide, and therefore commonly affects familieswithin the armed services, often with devastating emotional and financial consequences. SMA is marked by severe neurodegeneration andskeletal muscle wasting, similar to the muscle wasting and weakness in active duty soldiers recovering from combat injuries and/orenvironmental toxins. Additionally, SMA is remarkably similar to ALS, a deadly neurological disease that has been shown to have an increasedfrequency in Gulf War veterans. The current project focuses upon the pre-clinical development of a uniquely targeted nucleic acid-basedtherapeutic to treat all forms of SMA. Our strategy is comprehensive and continues to lead toward a therapeutic that could have immediate aswell as longterm positive impacts upon active and retired service members and their families struggling with SMA. The gene responsible forSMA is called survival motor neuron-1 (SMN1). SMN2 is nearly identical to SMN1, however, mutations in SMN2 have no clinical consequence ifSMN1 is retained. The reason why SMN2 cannot prevent disease development in the absence of SMN1 is that the majority of SMN2-derivedtranscripts are alternatively spliced, resulting in a truncated and unstable protein. The presence of SMN2 opens the door to a number ofexciting therapeutic strategies, including alternative splicing modulation of SMN2 exon 7. In this project, we will build upon our previousbasic molecular biology findings that identified Element 1 (E1) as a potent repressor of SMN2 exon 7 inclusion. The molecular geneticcontext makes SMA especially attractive for nucleic acid-based therapeutics designed to modulate pre-mRNA splicing for several reasons
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2019
- Accession Number
- AD1103064
Entities
People
- Christian Lorson