Therapy Development For Spinal Muscular Atrophy: Perspectives For Muscular Dystrophies And Neurodegenerative Disorders Part 8

Muscle‑directed strategies

Muscle-autonomous disease mechanisms in SMA could contribute to the course of the disease, in particular at later stages in SMA type 2 and 3 patients [50]. SMN levels in muscle and other tissues are very low in adult SMA mice and patients [50, 138]. 

Muscle autonomic diseases are disorders of the nervous system and muscle tissue that include many types of conditions, such as multiple sclerosis, amyotrophic lateral sclerosis, myasthenia, and others. These disorders not only affect muscle movement but may also negatively impact cognitive function.

However, a positive attitude can have a positive impact on muscle autonomic disorders and memory. First, research shows that a positive attitude can reduce the severity and duration of illness. When patients actively confront these illnesses, they are more willing to accept treatment and recovery, which helps speed up the recovery process. In addition, a positive attitude can reduce patients' anxiety and depression about the disease, which hurts memory and cognitive function.

In addition, lifestyle adjustments can also be beneficial. Proper physical exercise can improve the condition of muscles, and promote blood circulation and oxygen supply, which helps promote cognitive functions of the brain. Also, a healthy diet is a key factor. Nutritious foods can provide large amounts of vitamins and minerals, which can help improve the body's immunity and resistance, thereby reducing the risk of other diseases.

With the help of a positive mindset and a healthy lifestyle, people with muscle autonomic disorders can live with more vigor and energy. While these diseases are unavoidable, a healthy lifestyle can help reduce their negative impact on us and go a long way in improving memory and cognitive function. Therefore, we should stay optimistic, face challenges, and try to live as healthily as possible and move in the direction of positive development. 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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To prevent loss of muscle mass, myostatin inhibition has been proposed as an option since this secreted growth/differentiation factor acts as a negative regulator of skeletal muscle fiber growth and size [169, 191, 332]. 

Myostatin activity is normally inhibited by follistatin and myostatin propeptide [118]. First studies with myostatin inhibition in models of severe SMA did not show significant effects [248, 284]. 

Interestingly, the effects of myostatin inhibition were stronger in mouse models of milder forms of SMA. In particular, at later stages of the disease, myostatin inhibition seems to have a positive effect on motor function and survival as well as muscle and bone atrophy [86, 179, 331]. 

SRK-015/Apitegromap is a selective monoclonal antibody that blocks myostatin [86, 236]. It is currently under investigation in the phase 2 TOPAZ study for 57 type 2 and type 3 SMA patients who already received Nusinersen (ambulatory cohort; 2–20  mg/ kg). 

In the non-ambulatory cohort (20  mg/kg), it is tested both as a monotherapy and in combination with Nusinersen. Along the same line, the troponin activator Reldesemtiv (CK-2127107) is considered another modulator of muscle atrophy and loss of muscle strength. This molecule acts by slowing down calcium release from the troponin complex and thus sensitizes the sarcomere response to calcium [130], resulting in enhanced contractility. 

Most importantly, it amplifies the skeletal muscle force–frequency response upon nerve stimulation [9]. Reldesemtiv has been studied in a double-blind, randomized, placebo-controlled, phase 2 study (NCT02644668) in two cohorts. Oral application of a single dose of Reldesemtiv has been well tolerated. Whether this treatment also improves motor function is currently investigated with larger cohorts of SMA patients [258]. 

Human Insulin-like growth factor 1 (IGF1), which has already shown neuroprotective potential in mouse models for SMA, was also tested in SMARD1/DSMA1 mouse models (Nmd2J mouse). Nmd2J mice are IGF-1-deficient and show an upregulation of the IGF-1 receptor in the gastrocnemius muscle and diaphragm, which is not observed in the spinal cord [159]. 

Te IGF-1 deficiency can be compensated by the pharmacological application of human pegylatedIGF-1. This external application normalizes muscle fiber differentiation in the diaphragm and leads to a partial rescue in the gastrocnemius muscle [159]. Unfortunately, the compensatory effect of PEG-IGF-1 could not counteract atrophy. The cell body and axon loss of motoneurons are not diminished by IGF-1 treatment in Nmd2J mice [159].

Oligonucleotide and gene therapies beyond SMA for other neurodegenerative and muscular disorders

Most oligonucleotide therapies focus on gene silencing and transcriptional and splice modulation. Since oligonucleotides usually interact with their target molecules via complementary base pairing, gene-specific lead compounds can be derived from the primary sequence of the target gene. 

Also modifications for increasing bioavailability, such as for properly passing the plasma membrane and increased resistance to nucleases are feasible and have been successfully introduced [182]. 

In addition, bioinformatics tools allow for avoiding predictable of-target effects. In terms of the ASO applications for individualized therapies, it is also possible to target patient-specific sequences in specific alleles such as single nucleotide polymorphisms (SNPs) or expanded repeat-containing mutant transcripts that are causative for rare diseases. This appears as an advantage over conventional screening for small molecules based on effects on defined cellular target mechanisms. 

Although small molecules also bear the advantage of systemic application, they usually need extensive toxicological analyses and chemical optimization to lower off-target effects. ASOs are classified into RNase H-competent ASOs and steric block ASOs without RNase H activity. 

Steric block oligonucleotides can interfere with transcript RNA–RNA and/or RNA–protein interactions and mask specific sequences within a target transcript [250]. They are mostly used for modulation of alternative splicing to exclude (exon skipping) or retain specific exon(s) (exon inclusion). In these cases, the oligonucleotide 'masks' a splicing signal converting it invisible to the spliceosome. 

This ultimately leads to alterations in splicing events e.g. for SMN2 exon 7 retention [277]. In the following, we will give an overview of current ASO applications in neurodegenerative and muscular disorders beyond SMA. 

ASO therapies in amyotrophic lateral sclerosis (ALS) Amyotrophic lateral sclerosis is a fatal motoneuron disorder, predominantly with adult onset. 10% of ALS cases are familial (fALS), whereas the remaining cases are considered ''sporadic'' (sALS) without a clear familial history [150]. Extended genetic analyses discovered all major genes for monogenetic forms of ALS [42]. 

However, the question concerning how the relevant mutations affect the function of the corresponding gene products is in almost all cases not appropriately answered. This has consequences on the development of genetically based therapeutic strategies. In case such mutations cause loss of function (LOF), relevant approaches need to be designed for re-establishing this function. 

Gain of function (GOF) mutations would require the blockade/inhibition of the mutated gene and its product. However, downregulation of the expression of the mutated gene usually also affects the expression of the unaffected allele. Most of the mutations described for the familial forms of ALS show dominant inheritance patterns and imply GOF mechanisms such as protein aggregates or altered protein properties affecting essential cellular processes [290]. 

However, there is evidence that GOF and LOF come together in some ALS-causing gene mutations such as the intronic expansion of C9ORF72 [278, 290]. This situation then requires strategies that only affect the mutant gene and transcript. Herein we will exemplify ASO application in cases of SOD1, C9ORF72, and FUS and genetic ALS modifiers.

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