Spinal muscular atrophy (SMA) is one of the biggest challenges in today's medicine. This disease affects 1 in every 6,000–10,000 live births [1]. The carrier frequency varies (1:38–1:50), with Caucasian and Asian populations having the highest [2]. It is a neuro-degenerative disease of the spinal cord that causes progressive muscle wasting, weakness, respiratory distress, and paralysis [1, 2]. Furthermore, due to its severity, it has been demonstrated that it is the most common genetic cause of childhood death [3]. SMA is a neuromuscular disorder that is caused by a homozygous deletion or point mutation in the Survival of Motor Neuron 1 (
SMN1- survival of motor neuron; SMN2- survival of motor neuron 2
The disease is characterized by symmetrical muscle weakness, which can cause movement problems and severe physical disability. SMA is classified into four clinical types based on the age of symptom onset and the severity of the disease. According to some sources, SMA type 0 is the most severe form of muscular atrophy, and symptoms appear during prenatal development [10]. SMA type I (also known as Werdnig-Hoffmann disease) manifests itself in the first weeks or months of a child's life as muscle weakness and an apparent lack of movement progress. Children's health rapidly deteriorates, and mechanical airway ventilation may be required. Children with SMA type II (also known as Dubowitz disease) can develop normally up to the age of six months and learn to sit without assistance, but as they get older, they develop symmetrical muscle weakness, swallowing difficulties, and respiratory problems [11]. Symptoms of SMA type III (also known as Kugelberg-Welander disease) appear when children are able to walk. However, the disease causes walking difficulties or difficulties climbing stairs. SMA type IV can occur in adults, but it is extremely rare. Symptoms do not manifest themselves until the age of 20 or 30. They include walking problems, difficulty rising from a squatting position, walking upstairs, and frequent falls. Patients in this group have significantly reduced mobility, but they can move around independently for many years [12].
Some medications are currently available to alleviate the symptoms of this disease, but they are prohibitively expensive. The first, nusinersen, marketed as Spinraza by Biogen (Cambridge, MA, USA), was approved by the FDA in December 2016 and the European Medicines Agency (EMA) in June 2017. The first year's cost ranged from $516,896 to $907,665, and the second year's cost ranged from $258,448 to $457,889. The price differs between the United States and Europe, and it fluctuated over a three-year period between 2017 and 2020. The second medication, onasemnogene abeparvovec, marketed by Novartis (Basel, Switzerland) as Zolgensma, was approved by the FDA in May 2019 and by the EMA in August 2020. It is known as the most expensive medication in the world, with its price of $2.1 million in the USA for a single injection. A third drug is risdiplam, marketed as Evrysdi by Roche, which was approved by the FDA in August 2020 and by EMA in March 2021 [3]. Although the FDA has approved these three drugs for use, clinical trials are still ongoing. Current SMA treatment methods are expensive and frequently insufficient. Because of the limited window, treatment time is a critical component for successful therapy. There is currently no fully successful SMA cure, and more solutions should be developed. This review describes various types of drugs, treatment-related issues, and ongoing research.
There was no efficient method of SMA therapy for a very long time. One of the most promising methods today is a treatment based on SMN protein level restoration. One of the ideas is to use oligonucleotides to modify the splicing of
Nusinersen is an orphan drug (antisense oligonucleotide) that disrupts the function of ISS-N1 in intron 7 of the
Chemical structural formulas of
Autopsy of the three individuals showed that nusinersen after intrathecal injection was transported from cerebrospinal fluid (CFS) to motor neurons, including vascular endothelial cells and glial cells via the central nervous system. The quantity of nusinersen in cerebrospinal fluid (CSF) was still detectable 168 days after dosing, which means that the exposure to this treatment was long-lasting. The maximum plasma concentration was observed between 1.7 and 6.0 h after drug administration, depending on the dosage. Nusinersen was also detected in peripheral tissues, such as kidneys, liver, and skeletal muscle, which supports the observation of its migration from the CSF. Nusinersen is metabolized by an exonuclease 3′- or 5′-mediated hydrolysis, and its terminal elimination half-life is assessed as 135–177 and 63–87 days, respectively. Finally, it is secreted by the urinary tract [17].
In the first phase, the doses 1, 3, 6, and 9 mg of nusinersen were administrated intrathecally to 28 children aged 2–14. Briefly, in patients treated with 1 and 3 mg, no difference was observed, but in those treated with 6 and 9 mg of nusinersen, there was twice the quantity of SMN protein 9–14 months after injection compared to the baseline. The visible symptomatic effect of this treatment was shown, however, only in patients treated with 9 mg of nusinersen 85 days after injection. The improvement was examined by Hammersmith Functional Motor Scale-Expanded score [15]. Also, the mortality was much lower – 16 of 20 patients lived longer than 18 months, while previously the average survival in a patient with SMA type I was 10 months. What is more, 10 of 16 patients did not need respiratory support [18].
Success in the first phase has led to the second phase performed on 20 participants, aged 3 weeks to 7 months, who obtained doses of 6 or 12 mg of nusinersen. In this phase, patients had homozygous gene deletion or mutations or compound heterozygous mutation of
In the ENDEAR study (NCT02865109), 121 participants aged <7 months were examined after obtaining a dose equivalent to 12 mg of nusinersen in a 2-year-old child. A year after the first dose, there was a significant amelioration in achieving the motor-milestone response in comparison to the control group. In addition, the risk of death was reduced by 63% compared with the control group, as was mortality, which was reduced by 23%. CHOP-INTEND and HFMSE scores were also much higher [21].
Side effects were very similar in every phase. The most common were procedural headache (21.4% of participants), and back pain (17.9% of participants). Other side effects were procedural nausea, puncture syndrome, post-lumbar pain, nausea, headache, fluid leakage, vomiting, and cerebrospinal leakage. There was no significant difference in side effects between the control group and group treated with nusinersen. An immunogenic response to nusinersen was not detectable 9–14 months after a single intrathecal dose of nusinersen [15, 19, 21].
On May 24, 2019, FDA approved onasemnogene abeparvovec (Zolgensma) for treating pediatric patients younger than 2 years suffering from spinal muscular atrophy with bi-allelic mutations in the
Mechanisms of SMA treatment using different types of therapy.
AAV9 vector technology can cross the blood-brain barrier and target central nervous system neurons at all regions of the spinal cord. AAV9 virus vector contains a hybrid cytomegalovirus enhancer-chicken beta-actin promoter which permits long-lasting production of SMN [22, 24]. Onasemnogene abeparvovec is a one-dose intravenous infusion which is a hopeful alternative to more commonly used chronic treatment with nusinersen. The dosage is determined by patients' body weight. According to the FDA the recommended dose for pediatric patients is 1.1 × 1014 vector genomes per kilogram (vg/kg) [22, 25].
Studies of saliva, urine, and stool were taken at different amounts of time after the infusion of oasemnogene abeparvovec. This shows a higher concentration of vector in stool than in either saliva or urine – after 1 day, the level of AAV9 vector in saliva and urine was low; in saliva, the concentration was undetectable within 3 weeks and in urine within 1 to 2 weeks. In stool, the amount of vector was significantly higher after 1 and 2 weeks than in saliva and urine and also was undetectable in 1 to 2 months after the infusion. The autopsy of two patients who died after the infusion of nasemnogene abeparvovec shows the highest level of this therapeutic in the liver, but vector was also detected in the spleen, heart, pancreas, inguinal lymph node, skeletal muscles, peripheral nerves, kidney, lung, intestines, spinal cord, brain, and thymus. The immunostaining experiments of SMN protein show expression in spinal motor neurons, neuronal and glial cells of the brain, but also in the heart, liver, and skeletal muscles [22].
In the NCT02122952 clinical trial, Mendell et al. studied functional replacement of the mutated gene
The cost-effectiveness of onasemnogene abeparvovec in comparison to the chronic treatment for SMA type I with nusinersen was also studied by Malone et al. They created a Markov model which simulates the experience of pediatric patients diagnosed with SMA I and two copies of
The infusion of onasemnogene abeparvovec can provide aminotransferase elevations like the significantly higher level of rate of aminotransferase (AST) and alanine aminotransferase (ALT). Moreover, one patient in the clinical trial had a serious liver injury – prior to the infusion this patient had increased AST and ALT (unknown reason). Due to that, patients are receiving an oral corticosteroid therapy before and after the infusion. Besides aminotransferase elevations, treating with onasemnogene abeparvovec can thrombocytopenia, increased troponin-I level, vomiting, and thrombotic microangiopathy [22]. In the NCT02122952 clinical study, 14 patients (14/15) had respiratory illnesses, which can be very dangerous for children suffering from SMA type I and can result in death or tracheostomy [24].
Risdiplam (Evrysdi) is a
Pharmacokinetics has been studied in healthy adult individuals and patients with SMA. Doses of risdiplam reached levels between 0.6 and 18 mg in a single-ascending-dose study in healthy adults and between 0.02 and 0.25 mg/kg once daily in a multiple-ascending-dose study in patients suffering from SMA [27]. After taking risdiplam orally the maximum concentration of this therapeutic in plasma (Tmax) was achieved between 1 and 4 hours. Risdiplam can bind to serum albumin, but there was no binding to alpha-1 acid glycoprotein. Risdiplam has an elimination half-life from healthy adults of 50 hours, and this drug is primarily metabolized by flavin monooxygenase 1 and 3 (FMO1, FMO3) and also by cytochromes 450 (CYPs) [27].
Currently, there are four still-open clinical trials investigating Risdiplam. The first trial is named FIREFISH (NCT02913482) and this is a two-part open-label study of infants aged 1–7 months with SMA type I and two
The aim for the second part was to investigate the efficacy of risdiplam at the dose selected in the first part of the trial. Effectiveness here means the proportion of infants sitting without support for 5 seconds after 12 months of treatment (based on the Gross Motor Scales of Infant and Toddler Development, third edition [BSID-III]). The study met its primary endpoint [26, 29].
Another two-part trial is SUNFISH (NCT02908685) which is a double-blind, placebo-controlled study of patients aged 2–25 years with SMA types II or III. Part 1 of this study was focused on dose escalation and in the second part the efficacy of the risdiplam dose selected in the first part was compared with placebo patients [26, 30]. The analysis of the results after 2 years showed an improvement of motor function compared to natural history data. The results were measured using the Motor Function Measure scale (MFM) which is a validated scale used to calculate motor function, and the change from a baseline was higher than in the historical cohort [26].
JEWELFISH (NCT03032172) is a clinical trial which finished recruitment and is focusing on people aged between 6–60 years who had been treated with other SMA-directed therapies in the past. The analysis of safety data showed no drug-related safety finding [26, 31].
RAINBOWFISH (NCT03779334) is a single-arm, multicenter study which is currently in phase 2 and is focused on analyzing the efficacy, safety, pharmacokinetics, and pharmacodynamics in babies who are not yet presenting any symptoms. No results have yet been published [26].
According to the SUNFISH clinical study the most common side effects observed were fever, cough, vomiting, upper respiratory tract infections, cold and sore throat. However, the most dangerous illness was pneumonia [26]. Impairment of fertility was also studied on rat models – oral administration to rats for 4 or 26 weeks resulted in histopathological changes in the testis (and epididymis at mid/high doses of risdiplam). Retinal abnormalities were observed in a 39-week toxicity study in monkeys – risdiplam taken orally induced functional abnormalities on the electroretinogram in all mid and high-dose animals earliest examination time. On week 22 retinal degeneration was detected by optical coherence tomography [27].
Summary of risdiplam clinical trials Roche. Roche announces 2-year risdiplam data from SUNFISH and new data from JEWELFISH in infants, children and adults with spinal muscular atrophy (SMA) [29, 30, 31, 32, 33] SMN1- survival of motor neuron; SMN2- survival of motor neuron 2; MFM- Motor Function Measure
FIREFISH | NCT02913482 | Two-part, open label study. | Infants aged 1–7 months of age with SMA type I and two SMN2 gene copies. | Part one: dose-escalation study |
The study met its primary endpoint. |
SUNFISH | NCT02908685 | Two-part, double blind, placebo-controlled study. | People between 2–25 years old with SMA type II or III. | Part one: dose-escalation study |
The study met its primary endpoint. |
JEWELFISH | NCT03032172 | Open-label exploratory trial. | People between 6 months – 60 years, previously treated with SMA-directed therapies | Safety and tolerability of daily risdiplam dose in non-naïve patients who have taken nusinersen, olesoxime or onasemnogene abeparvovec-xioi. | The study has completed recruitment. |
RAINBOWFISH | NCT03779334 | Single-arm, multicentre study. | Babies from birth to six weeks of age (at first dose) with genetically diagnosed SMA, without symptoms. | Efficacy, safety, pharmacokinetics and pharmacodynamics. | The study is currently in phase 2. No results were published yet. |
The Food and Drug Administration and the European Medicines Agency have authorized three therapies thus far: Spinraza, Zolgensma, and Evrysdi are all SMN-enhancing medications, although other medicines are being tested in clinical studies as well. Currently, therapies in clinical trials are aimed at treating the disease's symptoms rather than the cause, which in SMA are neuromuscular function, muscle weakness, and muscle fatigue. Reldesemtiv (previously CK-2127107, CK-107) is a fast skeletal muscle troponin activator of the next generation (FSMT). Nerve impulses are diminished in numerous disorders, including SMA, and this adds to muscle weakness. Damage to motor neurons reduces calcium ion release, resulting in less effective muscle activation to produce a movement [34]. The calcium sensitivity of the troponin-tropomyosin complex is increased by reldesemtiv. The rate of calcium release from troponin slows, resulting in an increase in the amount of calcium in the body. The drug is currently in phase II clinical trials for people with SMA types II, III, and IV (NCT02644668) [35].
Scholar Rock's Apitegromab (SRK-015) is a myostatin inhibitor that allows the body's muscle mass to grow. Myostatin (GDF-8, growth differentiation factor 8) is a non-active polypeptide proMyostatin that inhibits muscle cell growth and differentiation. The mature growth factor is released from the precursor in two stages. Proprotein convertases cleave proMyostatin, resulting in the production of inactive, latent myostatin. Second, pre-domains are cleaved by a BMP/Tolloid protease, such as Tolloid-like protein 2 (TLL-2) or bone morphogenetic protein 1 (BMP1), releasing the mature growth factor and allowing it to interact with its receptor [36]. The conformational flexibility of known latency-related structural elements, as well as regions adjacent to the tolloid and furin of the proteolytic cleavage site, is affected by highly specific binding to the arm region in the prodomain of pro/latent myostatin, according to structural studies on the binding of apitegromab to proMyostatin and the latent form of the protein [37]. Positive results from a phase 2 clinical trial (TOPAZ, NCT03921528) contributed to Scholar Rock's announcement of a phase 3 study named SAPPHIRE (NCT05156320), which might be the final step for approval of SRK-015 as an addition therapy to conventional SMN treatment [38].
Many different drugs have been attempted since the genetic basis of the disease was discovered, but the majority of them have failed. For instance, olesoxime (cholest-4-en-3-one, oxime) is a cholesterol-like compound that was first developed by Trophos [39, 40]. The drug was found to be safe and well-tolerated in phase 2 clinical studies in 3- to 25-year-olds with confirmed SMA type II or non-ambulatory SMA type III. However, there was no improvement in motor function when compared to those receiving placebo [41, 42]. The goal of the open-label extension study (OLEOS, NCT02628743) was to examine the safety, tolerability, and efficacy of the drug over a longer period of time. It was discovered that motor function looked to remain steady for 52 weeks, but then began to deteriorate [40, 43]. Roche decided to stop developing olesoxime in May 2018 because of technological challenges and lower-than-expected efficacy.
Novartis's Branaplam (LMI070, NVS-SM1) was in a phase II clinical trial in children with SMA type I (NCT02268552). It is a small molecule that is taken orally once a week. It was discovered during a high-throughput screening of pyridazine 2 and refined using multi-parameter lead optimization (Fig. 2C) [32]. It works by modifying SMN2 exon 7 splicing to increase the amount of functional SMN protein. Branaplam stabilizes the duplex U1:5′ splice site at the 5′ splice site SMN2 exon 7, thereby improving exon 7 inclusion (Fig. 3D). The drug has been shown in studies to improve the survival rate of a mouse model of SMA [33]. Novartis announced in July 2021 that it would no longer pursue branaplam as a treatment for SMA but would instead promote the molecule as a potential treatment for Huntington's disease.
PTC Pharmaceuticals, Roche, and the SMA Foundation collaborated to develop RG7800, a small molecule. An oral small-molecule compound was discovered through chemical screening and optimization to modify the splicing of SMN2 exon 7. A compound from the pyrazolopyrazine subclass has begun clinical trials in adults with SMA type II or type III, and the study is known as MOONFISH [42]. Initial results were promising as SMN protein levels doubled [43]. However, further studies were halted because it was discovered that the drug accumulates in the cornea of the experimental animals and is not removed quickly enough, which could lead to toxicity. The focus was on creating another chemical, RG7916, and participants in the MOONFISH (NCT02240355) research were invited to join in the JEWELFISH clinical trial of risdiplam (NCT03032172) [44].
The quinazoline derivative RG3039 was developed as an oral experimental medication to block a scavenger mRNA decapping enzyme (DcpS) and so enhance protein levels. The medication penetrated the blood-brain barrier into CNS tissues and inhibited the enzyme DcpS, however, SMN levels were low in early tests. DcpS enzyme activity is significantly suppressed in tissues from SMA mice, suggesting that enzyme activity could be used as a pharmacodynamic measure of medication activity in SMA patients' clinical trials [45]. RG3039 has also been proven to extend life and improve SMN protein levels in mice with varied degrees of illness severity [46]. Repligen, which created the drug, has secured a deal with Pfizer to continue developing RG3039. However, the contract was unexpectedly terminated in 2015, and progress on the drug was suspended.
Valproic acid (VPA) is a short-chain carboxylic acid, a drug with anticonvulsant properties and a histone deacetylase (HDAC) inhibitor with a terminal half-life (t1/2) of 8–10 hours in human serum. The function of HDAC is deacetylation, which can alter gene transcription selectively and thus promote chromatin condensation. It was able to conclude that his-tone deacetylase inhibitor drugs increase
Patients had high hopes when research on each of these drugs began; however, none of these drugs have been brought to market for various reasons.
The current treatment for SMA is insufficient. Several children were not cured after receiving nusinersen injections during the ENDEAR clinical study; several still need breathing support, assistance with feeding, and other daily routine tasks. In rare cases, motor development was interrupted, and some individuals died as a result [18]. Furthermore, the medication's intrathecal injection may cause tissue damage, infections, weakness, and malaise [14]. A large number of patients have severe scoliosis, making intrathecal injections extremely difficult, if not impossible [52]. Chronic treatment, on the other hand, can be a major challenge to conquer. Intranasal or oral administration is one technique to tackle this problem, although it is insufficient due to the blood-brain barrier. Because of the preservation of nusinersen in peripheral tissues, which can cause substantial damage, pharmacodynamics and pharmacokinetics must also be investigated [14]. Treatment with nusinersen did not result in significant improvement in adult patients. The compound muscle action potential (CMAP) was measured, and while there was an improvement in terms of higher CMAP amplitudes, there was a decrease in CMAP upon repetitive motor stimulation. Neuromuscular defects persist after treatment, implying that nusinersen treatment is ineffective in adult patients. Furthermore, there was a link between CMAP results and motor function (as measured by the 6-minute walk), fatigue, elbow extension, shoulder abduction, and revised upper limb module. This could imply that this disease is more complex in adults, and that in their case, all disabilities are secondary effects, and that restoring the SMN protein is insufficient. There is also no correlation between CMAP decrement and disease severity, disease duration, or patient age, implying that this disease is unique in each case and that there are individual differences. Examining these differences can lead to the best treatment method for each individual, but it will also be a difficult and time-consuming process. More clinical research is needed to confirm the short- and long-term tolerability, safety, effectiveness, and peripheral administration of all SMA therapies [52].
Another significant limitation is time, which is crucial in the treatment. To begin with, the disease is very aggressive, and the sooner treatment begins, the better the chances of survival and better results. The age of the patient at the start of therapy has a high correlation with treatment success. Early SMA therapy appears to be critical for enhancing therapeutic results. Elevating the SMN protein level in a patient with advanced SMA, who has essentially no motor neurons, is ineffective [18]. Second, the cost of drugs rises in tandem with the weight of the child, which rises rapidly as the child grows. Because of the extremely high cost of this treatment, it may be discontinued. Hopefully, the FDA recently accepted the lower pricing of risdiplam, which may result in other cost reductions [52].
Summary of approved therapeutics and substances under clinical trials for SMA [20, 23, 24, 28, 35, 36, 38]
Spinraza** | Biogen | Survival motor neuron 2 ( |
All ages and types | Administered by intrathecal injection at an equivalent dose of 12 mg (4–5 ml based on age) |
Zolgensma** | Novartis Gene Therapies* | Gene therapy based on using recombinant adeno-associated virus subtype 9 (AAV9) to overexpression |
Less than two years old paediatric patients with spinal muscular atrophy and bi-allelic mutations in the |
One intravenous infusion; dosage based on patient's body weight |
Evrysdi** | Roche, Genetech Inc. | Survival motor neuron 2 ( |
Patients 2 months of age and older suffering from SMA | Administrated orally once a day; dosage is determined by patient age and body weight |
Reldesemtiv | Cytokinetics/Astellas | Muscle drug (non- |
Patients with SMA types 2, 3 and 4 who are age 12 or older | Administrated orally; phase 2 trial completed |
Apitegromab | Scholar Rock | Muscle drug (non- |
Patient between 2 and 21 who have SMA type 2 or 3. | Administrated by intravenous infusion; phase 2 trial ongoing |
previously the name of the company was AveXis Inc.
therapeutics approved by EMA and FDA
It is also critical to reduce the cost of all treatments. Because of the extremely high cost, the treatment is not covered by all insurance companies in the United States. They added some restrictions to the treatment's availability, such as if the disease is caused by biallelic SMN1 mutations. Other restrictions include age, symptom manifestation, and disease stage. Furthermore, the high cost of the drug is not the only financial issue; there are numerous other expenses such as rehabilitation, the purchase of specialized equipment, administration costs, and the inability to work caused by the disease in the case of adult patients or parents who have children with SMA and must care for them full-time [53, 54, 55]. As a result, access to the treatment may be severely restricted.
Despite the fact that there are several approved medicines on the market and compounds in clinical trials, researchers are always looking for new drugs to help SMA sufferers. The future direction in which neuromuscular junction (NMJ) instability can be studied is worth emphasizing. It may be able to increase NMJ protection in adults by using phenotypic modifiers, and it may also be possible to undertake alterations in embryos that result in an improved postnatal phenotype. Mice have been used in such research with great success [56].
The goals of future research will then be to solve all of the previously mentioned problems. Because SMN-based therapies will be sufficient for the majority of SMA patients, it is crucial to enhance SMN restoration to improve motor function and to carefully examine all drug action and metabolism [52].
The discovery of genetic causes of SMA has allowed for the development of disease-treating therapies. Each of these therapies, however, has advantages and disadvantages. Nusinersen has transformed the lives of SMA children and their families. In 51% of patients, the treatment reduces the risk of death while also improving the patients' quality of life [18]. According to the findings of Sansone and colleagues (2020), the use of nusinersen aids in the treatment of respiratory problems by lowering mortality and the need for respiratory support [57]. However, there are some significant obstacles to overcome and better investigate in this treatment. Treating patients with spinal muscular atrophy who have bi-allelic mutations in the