Gene-Targeting Therapeutics for Neurological Disease: Lessons Learned from Spinal Muscular Atrophy

Abstract

The last few decades have seen an explosion in identification of genes that cause monogenetic neurological diseases, as well as advances in gene-targeting therapeutics. Neurological conditions that were once considered incurable are now increasingly tractable. At the forefront is the motor neuron disease spinal muscular atrophy (SMA), historically the leading inherited cause of infant mortality. In the last 5 years, three SMA treatments have been approved by the US Food and Drug Administration (FDA): intrathecally delivered splice-switching antisense oligonucleotide (nusinersen), systemically delivered AAV9-based gene replacement therapy (onasemnogene abeparvovec), and an orally bioavailable, small-molecule, splice-switching drug (risdiplam). Despite this remarkable progress, clinical outcomes in patients are variable. Therapeutic optimization will require improved understanding of drug pharmacokinetics and target engagement in neurons, potential toxicities, and long-term effects. We review current progress in SMA therapeutics, clinical trials, shortcomings of current treatments, and implications for the treatment of other neurogenetic diseases.

Activation of Muscle-Specific Kinase (MuSK) Reduces Neuromuscular Defects in the Delta7 Mouse Model of Spinal Muscular Atrophy (SMA)

“…The SMA community has witnessed three recent breakthrough gene-targeted treatments for SMA patients: Spinraza (nusinersen), a SMN2-splicing antisense oligonucleotide approved by the US Food and Drug Administration (FDA) in 2016; Zolgensma (onasemnogene abeparvovec), an AAV9-mediated gene replacement therapy in 2019; and Evrysdi (risdiplam), a SMN2 splicing modifier small molecule in 2020 (see recent reviews by [ 43 , 44 , 45 ]). All of these three drugs significantly enhance the production of SMN protein levels and show remarkable efficacy in treating SMA patients.…”

“…All of these three drugs significantly enhance the production of SMN protein levels and show remarkable efficacy in treating SMA patients. However, the clinical outcomes vary, and some patients show only a stabilization in motor function and continued appearance of neuromuscular symptoms [ 41 , 45 , 46 , 47 ]. The spectrum of clinical responses could be explained, in part, by initiation of treatment after symptoms were evident and at different stages of disease, especially for older children and adult patients.…”

The importance of genetic testing for dystonia patients and translational research

“…Although currently unavailable for any of the hereditary dystonia forms, genetic therapeutic approaches, that profoundly and intrinsically rely on precise molecular diagnoses, are crucial for patients for whom hitherto only symptomatic management was feasible. Namely, scientific and technological advances have already allowed the medical application of therapies that can reinstate lost gene function via viral transgenic expression (Li and Samulski 2020;Ravi et al 2021) or alleviate the harmful effect of abnormally functioning genes by neutralizing or modulating their mRNAs through antisense oligonucleotides or RNA interference (Mercuri et al 2018;Levin 2019;Tabrizi et al 2019;Roberts et al 2020). Therapeutic/curative genome editing is emerging as a powerful but extremely costly next-generation therapeutic intervention due to its inherent requirement to be tailored for individual patients (Cox et al 2015;Wilson and Carroll 2019;Doudna 2020).…”

Adeno-associated virus gene therapy to the rescue for Charcot-Marie-Tooth disease type 4J

“…Further, the sophisticated mechanistic and mouse model studies from the Meisler laboratory and others in the field indicate that CMT4J is an optimal target (7)(8)(9)(10)(11)(12). The FIG4 gene codes for a phosphatase involved in phosphatidyl inositol (3,5)P2 (PI [3,5]P2) metabolism, which is affected in several other types of CMT neuropathy (Figure 1). While FIG4 is expressed in many cell types, the clinical manifestations of CMT4J are most prominently displayed in the peripheral nerve.…”

“…Indeed, clinical trials have already commenced for giant axonal neuropathy (GAN) (4), a rare disorder that can be considered a CMT neuropathy. As a result of the cumulative efforts of many laboratories and companies, the safety studies of AAV delivery to motor neurons have provided additional confidence in this approach, and the regulatory path to FDA approval is well mapped (5). It will take some time to fully evaluate the long-term persistence of therapeutic gene expression within AAV-treated individuals, but the single administration of a therapeutic agent is a big advantage of this approach.…”