Therapy Development For Spinal Muscular Atrophy: Perspectives For Muscular Dystrophies And Neurodegenerative Disorders Part 5

In some patients, hydrocephalus has been reported as a potential side effect [10, 83, 100, 199, 232, 287]. 

Hydrocephalus refers to the accumulation of fluid in the brain caused by obstruction of the circulation or absorption of cerebrospinal fluid. There are many causes of hydrocephalus, including birth defects, infections, trauma, tumors, and other factors. Although hydrocephalus can have a certain impact on the human body, it can still be relieved with appropriate treatment.

At the same time, many people worry about the negative impact hydrocephalus can have on memory. However, generally speaking, hydrocephalus does not directly damage our memory. This is because human memory is mainly controlled by neurons and neural circuits in the brain. Hydrocephalus generally only causes compression of the spinal fluid around the brain and has no direct impact on the neurons and circuits within the brain.

However, if hydrocephalus is not treated in time, or if the condition is severe, it may cause irreversible damage to brain function. At this time, symptoms such as headache, blurred vision, and muscle weakness will appear, affecting our life and work. Therefore, when symptoms such as headache, dizziness, nausea, etc. occur, you should seek medical treatment promptly for examination and treatment.

In short, hydrocephalus does not directly affect memory. However, if hydrocephalus is left untreated, it can cause a variety of physical problems and cause permanent damage to brain function. Therefore, we should adopt a positive attitude towards the treatment of hydrocephalus, seek medical help in time, and not delay the condition. Only in this way can we protect our bodies and brains, maintain good physical and mental health, and maintain good living and working conditions. 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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The most commonly occurring side effects include lower respiratory infection and constipation in SMA infants whereas headache, vomiting, and back pain are also observed in SMA patients with later onset (summarized in https:// www.drugs.com/sfx/nusinersen-side-efects.html). 

In SMA patients with significant scoliosis or patients who had received surgical spinal fusion, the intrathecal application of Nusinersen is challenging. It usually requires the use of computer tomography guidance, video for angiography, ultrasound, or alternative administration techniques such as subcutaneous intrathecal catheters [199, 283, 314]. 

However, such new devices for the Nusinersen administration have not been approved so far by the relevant regulatory authorities. For unknown reasons, some patients respond better to the ASO than others [54]. 

A problematic issue with Nusinersen/Spinraza™ is the lack of systemic availability and the potential lack of efficacy to counteract the long-term adverse effects of low SMN levels in peripheral tissues. Nusinersen restores SMN expression only in the central nervous system. Preclinical data indicate that restoration of SMN protein levels might also be important for peripheral tissues such as the liver, kidney, muscle, and heart [112, 127]. 

The small molecule and splicing modifier Risdiplam/ Evrysdi™ Another option to restore SMN protein levels through increasing exon 7 inclusion in SMN2 transcripts is via small molecules. Such small molecules appear of advantage especially when they can cross the BBB. 

When administered systemically, they then could act on the processing of the SMN2 gene transcript in peripheral organs. Such small molecules have also been shown to modulate SMN2 splicing. They are bioavailable after oral administration and distributed systemically, thus targeting not only the central nervous system but also the peripheral nervous system and non-neuronal organs and tissues [217, 242, 243]. 

A potential disadvantage of the small splice modifiers in comparison to ASO-based drugs is the higher propensity for off-target effects [28]. To bypass such unspecific effects, a high throughput screening for SMN2 splicing modifiers was performed to receive optimal candidates such as RO073406/RG7916 (Risdiplam) [217, 237, 242]. Risdiplam increases SMN protein levels not only in CNS but also in peripheral tissues in two mouse models of SMA [237]. 

This effect is achieved by stabilizing the U1:5's duplex at the 5's of SMN2 exon 7 [39, 227, 276]. Nevertheless, Risdiplam still produces of target effects on the splicing of exons of several other transcripts such as those coding for STRN3, FOXM1, APLP2, MADD, and SLC25A17 [242, 276]. Administration at 1 mg/kg of body weight produces a robust enhancement in SMN levels in the brain and quadriceps muscle in an SMA mouse model. 

It counteracts NMJ pathology and reduces motoneuron loss [242, 243, 276]. Higher levels of Risdiplam (10 mg/kg body weight) improve life expectancy in SMA mouse models to the same level as for healthy littermates [217]. 

On the clinical level, the evaluation of safety, tolerability, and efficacy of this drug was tested in SMA patients in the FIREFISH trial (SMA type 1 patient, NCT02913482) and the SUNFISH trial (SMA type 2 and 3 patients, NCT02908685) [223]. The FIREFISH trial was designed for infantile-onset SMA as a two-part non-randomized open-label study in which 41 patients (1–7  months) were enrolled and studied for one year. 

All patients had a homozygous deletion of the SMN1 gene and two copies of SMN2. 29% of patients were able to sit independently for at least 5 s after 12 months of treatment, reaching relevant motor milestones, and 42% could live without permanent ventilation [55]. 

Treatment with Risdiplam caused an increase in SMN protein levels in the blood [19]. SUNFISH is a two-part trial with later-onset SMA patients (2 to 25 years), randomized and placebo-controlled. 

The first part with 51 participants is a dose-finding and safety tolerability study whereas part 2 with 180 SMA patients focuses on efficacy and safety [223]. The motor function skills of the Risdiplam-treated patients significantly surpassed those of the untreated patients after 24 months of treatment. 

No treatment-related adverse effects leading to withdrawal or treatment discontinuation during the 24-month trial period have been reported (Dr. Elizabeth Kichula CureSMA Meeting 2021; SUNFISH Part 2: Later-Onset SMA). 

The JEWELFISH study (NCT030321725) was designed as a subsequent multicenter, open-label study primarily evaluating the safety and tolerability of once-daily oral administration of Risdiplam in SMA patients aged 6 months to 60 years who have previously enrolled in other studies including those with RG7800 (NCT02240355), Nusinersen, Olesoxime and Onasemnogene abeparvovoec [239].

 The JEWELFISH population is heterogeneous with a broad spectrum of motor impairment at baseline. 174 SMA type 2 and 3 patients with 3 or 4 SMN2 copies have been enrolled, including non-sitters but also walkers, some of them with scoliosis and hip subluxation or dislocation. 

No serious adverse events related to the drug were reported. 

No ophthalmological findings attributable to Risdiplam exposure were reported [270] as in preclinical studies with cynomolgus monkeys. Retinal toxicity was observed in these monkeys consisting of photoreceptor degeneration and microcystic macular degeneration (MMD) in the central retina after 5–6  months of daily treatment [242]. On August 7, 2020, the FDA approved Risdiplam (Evrysdi™) under the fast-track designation and rare pediatric disease priority review process [223, 276]. 

Data across SUNFISH, FIREFISH, and JEWELFISH suggest that Risdiplam has a favorable safety profile. To this safety profile, the RAINBOWFISH trial (NCT03779334) focusing on pre-symptomatic SMA patients has been started but the enrollment of the patients is still ongoing. 

It is a multicenter open-label study to analyze the efficacy, safety, and pharmacokinetics/dynamics of Risdiplam in infants aged from birth to 6  weeks. Risdiplam is orally administered once daily for 2  years followed by an open-label extension (OLE) phase of at least 3  years. 

A follow-up of at least 5 years for each participant enrolled will finalize the RAINBOWFISH study. In general, the most frequently observed adverse effects include fever, diarrhea, and rash. Especially in SMA infants, respiratory tract infections, pneumonia, bronchiolitis, hypotonia, constipation, and vomiting have been observed (listed in https://www. drugs.com/sfx/risdiplam-side-efects.html).

Another small molecule termed Branaplam is still under investigation. Branaplam (previously known as LMI070) is a pyridazine derivative that interacts with SMN2 pre-mRNA and enhances exon 7 inclusion to increase the level of functional SMN protein [227, 279]. 

Like Risdiplam, Branaplam can be orally administrated. Branaplam was originally expected to be tested in SMA type 1 infants in an open-label, two-part phase 1/2 study (NCT02268552). However, this study has not been initiated yet.

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