The physiology of alternative splicing

Major efforts have been made in the last decade to develop and improve therapies for proximal spinal muscular atrophy (SMA). The introduction of Nusinersen/Spinraza™ as an antisense oligonucleotide therapy, Onasemnogene abeparvovec/Zolgensma™ as an AAV9-based gene therapy and Risdiplam/Evrysdi™ as a small molecule modifier of pre-mRNA splicing have set new standards for interference with neurodegeneration.Therapies for SMA are designed to interfere with the cellular basis of the disease by modifying pre-mRNA splicing and enhancing expression of the Survival Motor Neuron (SMN) protein, which is only expressed at low levels in this disorder. The corresponding strategies also can be applied to other disease mechanisms caused by loss of function or toxic gain of function mutations. The development of therapies for SMA was based on the use of cell culture systems and mouse models, as well as innovative clinical trials that included readouts that had originally been introduced and optimized in preclinical studies. This is summarized in the first part of this review. The second part discusses current developments and perspectives for amyotrophic lateral sclerosis, muscular dystrophies, Parkinson's and Alzheimer's disease, as well as the obstacles that need to be overcome to introduce RNA-based therapies and gene therapies for these disorders.RNA-based therapies offer chances for therapy development of complex neurodegenerative disorders such as amyotrophic lateral sclerosis, muscular dystrophies, Parkinson's and Alzheimer's disease. The experiences made with these new drugs for SMA, and also the experiences in AAV gene therapies could help to broaden the spectrum of current approaches to interfere with pathophysiological mechanisms in neurodegeneration. 

/pdf/therapy-development-for-spinal-muscular-atrophy-perspectives-2f5tp9kt.pdf

Therapy development for spinal muscular atrophy: perspectives for muscular dystrophies and neurodegenerative disorders

Spinal muscular atrophy.

Mid- and long-term (at least 12 months) follow-up of patients with spinal muscular atrophy (SMA) treated with nusinersen, onasemnogene abeparvovec, risdiplam or combination therapies: A systematic review of real-world study data.

Spinal muscular atrophy (SMA) is caused by reduced levels of survival of motor neuron (SMN) protein due to deletions and/or mutations in the SMN1 gene. Risdiplam is an orally administered molecule that modifies SMN2 pre‐mRNA splicing to increase functional SMN protein.

/pdf/risdiplam-in-types-2-and-3-spinal-muscular-atrophy-a-3j7u4osy.pdf

Risdiplam in types 2 and 3 spinal muscular atrophy: A randomised, placebo‐controlled, dose‐finding trial followed by 24 months of treatment

Background Type 1 spinal muscular atrophy (SMA) is a progressive neuromuscular disease characterized by an onset at 6 months of age or younger, an inability to sit without support, and def...

https://www.nejm.org/doi/suppl/10.1056/NEJMoa2102047/suppl_file/nejmoa2102047_appendix.pdf

Giovanni Baranello

Papers

Risdiplam-Treated Infants with Type 1 Spinal Muscular Atrophy versus Historical Controls.