Spinal muscular atrophy - onasemnogene abeparvovec and other therapeutic options

Abstract

Farmacja Polska, ISSN 0014-8261 (print); ISSN 2544-8552 (on-line) Spinal muscular atrophy -onasemnogene abeparvovec and other therapeutic optionsSpinal muscular atrophy (SMA) is a neuromuscular disorder that results in the loss of motor neurons. SMA is caused by mutations in the SMN1 gene, leading to the decreased synthesis of the SMN protein, necessary for motor neuron survival. In the past, SMA was considered to be an incurable disease, and therapy was limited only to symptomatic treatment. However, currently there are drugs which effectively inhibit the development of the disease, and even give hope for its cure. Their mechanism of action involves either delivering of a functional copy of the SMN1 gene, or modification of the alternative splicing of the SMN2 gene. Moreover, amelioration of muscle growth and increasing muscle contractility serves as a way of relieving the symptoms of the disease. The functional copy of SMN1 gene is delivered by onasemnogene abeparvovec (Zolgensma). The drug contains cDNA sequences, which correspond to the missing SMN1 gene. It is administered in the form of adeno-associated viral vector serotype 9 (AAV9)-based gene therapy, as a single intravenous infusion, to treat children less than 2 years old. Currently, the drug is approved only in the USA, and its cost exceeds PLN 2,000,000. SMN2 has nearly identical sequence as SMN1, however due to alternative splicing, only around 10% of its transcript results in a full-length, functional SMN protein.Modification of the alternative splicing of the SMN2 pre-mRNA by the drug nusinersen (Spinraza) results in an increased level of the SMN protein. Nusinersen is administered as intrathecal injections and is available both in the USA as well as in Europe. Also risdiplam and branaplam -small-molecule drugs with similar mechanism of action are now being tested in clinical trials. The inhibition of proMyostatin cleavage and slowing calcium release, leads to the increased muscle growth and contractility, respectively. So far, three promising drugs are being evaluated in clinical trials: SRK-015, which is a selective and local inhibitor of the activation of myostatin, as well as reldesemtiv (CK-2127107) and tirasemtiv (CK-2127107), both being the fast skeletal muscle troponin activators. These drugs do not affect the genetic cause of SMA, but relieve the symptoms of the disease. Early diagnosis and treatment gives hope for halting the progress of SMA, preserving motor function and extending patient's life.To jest artykuł o otwartym dostępie, na licencji CC BY NC https://creativecommons.org/licenses/by-nc/4.0/

SMA Therapy in Poland: New Hopes and Challenges

“…Spinal muscular atrophy was once considered as an incurable disease, and therapy was limited to symptomatic treatment. However, medications are now available that effectively halt the progression of the disease and even offer hope for a cure [10]. Being a monogenetic neuromuscular disease, the resulting phenotypic spectrum is complex, and SMA is generally viewed as a systemic disease.…”

Alternative Splicing Role in New Therapies of Spinal Muscular Atrophy

“…This prevents the formation of a complex that would inhibit detection of the exon/intron boundary. Subsequently, the split between exon 7 and intron 7 is detected, resulting in the incorporation of exon 7 into the mature transcript [ 74 ]. The use of appropriate ASOs to treat spinal muscular atrophy allows exon 7 to be incorporated into the transcript of the SMN2 gene.…”