Restoring SMN Expression Report Summary

Introduction to SMA:

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder and is one of the leading genetic causes of infant mortality. The disease manifests as progressive muscle weakness, loss of ambulation, and death due to respiratory complications. SMA arises from the homozygous deletion or mutations in the survival of the motor neuron 1 (SMN1) gene. Humans have a nearly identical copy known as the SMN2 gene. The severity of SMA is inversely related to the number of SMN2 copies present. However, SMN2 cannot fully compensate for the loss of SMN1 as it produces only a fraction of functional SMN protein.

Role of SMN Protein:

SMN protein is universally expressed in the body and plays multiple roles, including RNA metabolism, DNA repair, cellular homeostasis, and more. Motor neurons in the anterior horn of the spinal cord are particularly vulnerable to the loss of SMN protein, although the exact reason remains unknown.

Therapeutic Approaches:

Due to SMN2's ability to produce small amounts of functional SMN, two FDA-approved treatments have been developed. These are:

• Nusinersen: An antisense oligonucleotide (AON) that targets SMN2 to produce more functional SMN.
• Risdiplam: A small molecule that also targets SMN2.

Onasemnogene abeparvovec (Zolgensma): An FDA-approved gene replacement therapy that delivers a copy of the human SMN1 gene.

Challenges in SMA Treatment:

The article discusses the challenges associated with the approved therapies for SMA treatment. For instance, while Nusinersen was a breakthrough, it comes with high treatment costs and potential side effects. Gene therapy using Zolgensma has raised concerns about the long-term effects of SMN overexpression and the immune response to the viral vector. Moreover, patients with late-onset SMA (older than 2 years) are not eligible for this treatment. Risdiplam, although advantageous over Nusinersen as it avoids invasive injections, still needs further investigation regarding its long-term efficacy.

Summary of Approved Treatments:

• Nusinersen (Spinraza): An antisense oligonucleotide approved by the FDA in 2016.
• Onasemnogene abeparvovec (Zolgensma): A gene therapy approved by the FDA in 2019.
• Risdiplam (Evrysdi): A small molecule approved by the FDA in 2020.

The article provides a comprehensive overview of SMA, its molecular characteristics, and the current treatments available. It also touches upon alternative treatment strategies that are under research to improve the disease phenotype.