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

Abstract

Background 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. Main body 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. Conclusion 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.

Newborn screening research sponsored by the NIH: From diagnostic paradigms to precision therapeutics

“…On the other hand, platforms to develop gene‐targeted therapies for classes of genetic diseases are already under development, and some are used as treatments for NBS conditions, such as two of the therapies available for SMA: the antisense oligonucleotide (ASO) therapy nusinersen (Spinraza) and the gene replacement therapy Zolgensma (Jablonka, Hennlein, & Sendtner, 2022). Customizable “n of 1” treatments have been brought to fruition in under a year for specific variant‐based disorders such as neuronal ceroid lipofuscinosis (Kim et al, 2019), and non‐profit groups such as the n‐Lorem Foundation have pledged to facilitate this process regardless of a family's ability to pay (Crooke, 2022).…”

Спінальна М’язова Аміотрофія: Сучасне Лікування Та Методи Ранньої Діагностики

“…Наразі на терапії цим препаратом перебувають більш як 9300 пацієнтів у світі. Nusinersen (Spinraza®) призначений для дітей віком від 2 до 12 років [2]. Препарат приймають довічно.…”

Spinale Muskelatrophie im Erwachsenenalter

“…Die neuen Therapien für SMA interferieren mit der zellulären Basis der Erkrankung, indem sie das pre-mRNA-Splicen modifizieren und damit die Expression des SMNProteins erhöhen. Die Entwicklung dieser Therapien erfolgte zunächst in Zellkultursystemen und Mausmodellen und wurde in innovativen klinischen Studien "from Bench to Bedside" weitergeführt [6].…”

“…Die häufigsten Nebenwirkungen sind Fieber, Diarrhöe und Hautausschlag; bei Kindern mit SMA wurden respiratorische Infekte, Pneumonie, Bronchiolitis, Hypotonie, Konstipation und Erbrechen beobachtet [6]. Zu beachten sind die teratogene Wirkung der Substanz sowie bei Männern eine zumindest passagere Einschränkung der Fertilität.…”