Therapy Development For Spinal Muscular Atrophy: Perspectives For Muscular Dystrophies And Neurodegenerative Disorders Part 1

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.

Proximal spinal muscular atrophy (SMA) is a common genetic disorder that affects the body's nervous system, causing the body's muscles to gradually atrophy and decline. People with SMA often face many physical and life challenges, but their memory is as good as most people's.

There is no evidence that SMA affects memory. Many SMA patients exhibit enhanced memory performance, possibly because they have had to face multiple challenges in their lives. SMA patients need to remember information such as medical records, medication dosages, and contraindications to maintain good health and quality of life. They also need to maintain a clear mind to deal with the challenges of daily life, such as managing schedules and handling financial affairs.

While people with SMA may need additional support and assistance to cope with the life challenges they face, this does not mean that their cognitive abilities and memory will be compromised. Their thinking ability, intelligence level, and learning ability are the same as those of the general population, and they can complete various tasks and activities through their efforts and appropriate support.

In the families and communities of SMA patients, we should focus on the support and help they need to help them cope with various challenges. At the same time, we should also view SMA patients positively, understand their condition, and respect their thoughts and wishes. People with SMA have equally powerful minds and memories, and they also need to be respected and appreciated to realize their dreams and wishes. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory, because Cistanche deserticola can also regulate the balance of neurotransmitters, such as increasing the levels of acetylcholine and growth factors. These substances are very important for memory and learning. In addition, Cistanche deserticola can also improve blood flow and promote oxygen delivery, which can ensure that the brain receives sufficient nutrients and energy, thereby improving brain vitality and endurance.

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Main body: Therapies for SMA are designed to interfere with the cellular basis of the disease by modifying pre-mRNA splicing and enhancing the expression of the Survival Motor Neuron (SMN) protein, which is only expressed at low levels in this disorder. 

e 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 on amyotrophic lateral sclerosis, muscular dystrophy, 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 dystrophy, 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.

Keywords: Motoneuron disease, Neurodegenerative disease, Muscular disease, Spinal muscular atrophy, Amyotrophic lateral sclerosis, Muscular dystrophy, Alzheimer's disease, Parkinson's disease, Clinical trial, Gene therapy.

Background

Spinal muscular atrophy (SMA) is the most common form of a lethal pediatric neuromuscular disorder with autosomal recessive inheritance. It is caused by homozygous loss of function (LOF) mutations of the Survival Motor Neuron 1 (SMN1) gene [170] on human chromosome 5(5q13.2). 

Thus, therapeutic approaches so far have focused on the restoration of SMN expression. The specific architecture on human chromosome 5 with a second SMN gene (SMN2) is responsible for the cellular production of low levels of SMN protein that are not sufficient to maintain the structure and function of motoneurons. SMN2 differs from SMN1 by a single C to T transition in exon 7, leading to increased skipping of exon 7 [180, 206]. 

Thus, approaches to suppress alternative splicing of this exon, and AAV9-based gene therapy for enhanced expression of the SMN protein in motoneurons have led to success in treating degeneration of motoneurons in this disease. Restoration of protein expression is also a central goal for therapy development in Duchenne-and Becker-type muscular dystrophies [52, 72, 155]. 

Tus, oligonucleotide-based therapies as well as gene therapies are currently tested in these disorders. Experience with such therapies is rapidly progressing, and this also has an impact on therapy development for other neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS). 

Oligonucleotide therapies do not exclusively offer the chance to increase the expression of proteins such as SMN, but also to repress the expression of mutant proteins with a pathological function in other neurodegenerative disorders. 

This offers further technical opportunities for interference with other neurodegenerative mechanisms. Our review summarizes the development of antisense oligonucleotide (ASO) and gene therapy for SMA, based on the literature search via PubMed.gov and released data from https://clinicaltrials.gov. 

The second part addresses opportunities and challenges associated with further development of these approaches for the treatment of other neurodegenerative disorders and muscular dystrophies.

Spinal muscular atrophy (SMA): disease mechanisms and identification of targets for therapy

Disease presentation and classification of spinal muscular atrophy (SMA)

The severe form of proximal spinal muscular atrophy, also called Werdnig-Hofmann disease [122, 123, 316], is the most common monogenetic lethal pediatric neuromuscular disorder. 

A milder form of proximal spinal muscular atrophy also exists that originally has been considered as a distinct neurological disease [160]. However, after the identification of the underlying gene defect [170], it became apparent that both diseases are caused by homozygous deletion of the Survival Motor Neuron 1 (SMN1) gene on human chromosome 5q13.2. 

All forms of 5q-SMA (type 1–4) have an incidence of 1/6000– 10,000 worldwide [77, 229, 231, 305]. 

SMA follows autosomal recessive inheritance. Dysfunction and loss of spinal motoneurons are the most prominent pathological features causing weakness and atrophy, notably in proximal muscle groups, and respiratory failure. Depending on disease onset and severity, SMA is classified into four types ranging from the most severe type 1 to intermediate type 2 and milder types 3 and 4 (with adult-onset) [69, 70, 78, 230]. 

This classification mainly focuses on achieved motor milestones with the disadvantage of frequent overlap between different types. Thus, an additional classification has been introduced to cover dynamic changes in the clinical phenotype after therapy as well. This new classification distinguishes non-sitters (type 1–2), sitters (type 2–3), and walkers (type 3–4) [197], summarized in Table 1.

SMA genetics

The two survival motor neuron genes: SMN1 and SMN2

Humans carry two SMN genes (SMN1 and SMN2) within a duplicated region on chromosome 5q. Homozygous loss or mutations of SMN1 cause SMA, whereas loss of SMN2 is usually not associated with the disease. During evolution, the duplication of the SMN gene occurred at the stage of non-human primates [251]. In laboratory mice and other rodents, the Smn gene is not duplicated [263, 264]. 

SMN1 and SMN2 differ only in a few nucleotides. Of particular importance is the C to T transition in exon 7 of the centromeric SMN2 which causes alternative splicing of exon 7. Most transcripts from the SMN2 gene lack exon 7-encoded domains, resulting in only 5–10% full-length SMN protein in comparison to 100% full-length SMN protein from SMN1 transcripts (Fig. 1). 

Therefore, SMN2 can only partially compensate for SMN1 loss [180, 206, 207]. Most SMA patients carry 2–3 SMN2 copies. This allows cellular production of approximately 10–30% full-length SMN protein in comparison to healthy controls with intact SMN1 gene copies. Thus, the SMN2 copy number is the most important genetic modifier of SMA disease severity [85, 319]. 

The majority of the severely affected SMA patients bear homozygous deletions of SMN1 whereas most SMA type 2 and 3 patients show a homozygous absence of SMN1 due to a gene conversion of SMN1 into SMN2 [37, 318]. 

Gene conversion is a common cause for SMN2 gene copy number variations, increasing the SMN2 gene copy number from 2 to 3 or 4 [40]. Four copies of SMN2 usually generate sufficient functional SMN protein for a milder disease phenotype [85, 185] in SMA type 3 patients. In about 5% of SMA patients, point mutations are detected in the SMN1 gene mostly in exons 6 and 7 [320]. 

Such cases are termed "compound heterozygotes"-with a deletion/conversion in one allele and a point mutation in the other. 

Apart from 5q-SMA, other forms of spinal muscular atrophies exist which can be classified into the following categories based on disease phenotype and genetic inheritance: autosomal recessive and autosomal dominant distal spinal muscular atrophies (DSMAs); autosomal dominant proximal spinal muscular atrophies; autosomal recessive non-5q spinal and bulbar muscular atrophies; X-linked recessive SMAs.

Genetic modifers in SMA

A transcriptome-wide differential expression analysis of total RNA from lymphoblastoid cells, derived from SMN1-deficient siblings with discordant disease phenotype, revealed a significant association between disease severity and Plastin 3 (PLS3) expression [224]. 

PLS3 maps to Xq23 [282]. The gene is located on the X-chromosome and appears as a sex-specific modifier of SMA. Plastins are evolutionarily conserved and function as modulators of the actin cytoskeleton. 

Tus plays an important role in cell migration, adhesion, and exo- and endocytosis [321]. Additional genetic modifiers in SMA include Neurocalcin delta (NCALD) and Calcineurin-like EF-hand Protein 1 (CHP1). 

Both proteins act as Ca2+-sensors and Ca2+-binding proteins [124, 143, 246]. 

All three SMA protective modifiers are not active in the assembly of spliceosomal snRNPs. Since they are involved in modulating various cellular processes including the rescue of impaired endocytosis in Smn-deficient cells and animal models [64, 124, 143, 246], these SMA modifiers turned into potential therapeutic targets.

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