Beyond Improved Survival: Entering the Era of Multi-Target Therapies for Spinal Muscular Atrophy with Motor Function Reconstruction
Background
Spinal muscular atrophy (SMA) is a rare genetic disorder characterized by the loss of motor neurons, leading to muscle atrophy throughout the body. First reported in 1891, this disease has long lacked effective treatments, but the discovery of the causative gene, survival motor neuron 1 (SMN1), in 1995 opened the door to potential therapies. Scientists focused on modulating the splicing process of a similar gene, SMN2, to increase protein production.
The U.S. Food and Drug Administration (FDA) approved nusinersen, an antisense oligonucleotide (ASO) drug, in 2016. This was followed by the approval of onasemnogene abeparvovec, a gene replacement therapy, in 2019, and risdiplam, an oral small-molecule compound, in 2020. These three drugs have been shown to improve survival rates and motor development indicators in patients diagnosed early through newborn screening.
However, existing treatments leave significant gaps. Even after drug administration, the damage to already degenerated nerve cells or muscle tissue is irreversible. Adult patients diagnosed later or those with advanced disease show minimal therapeutic effects.
Key Findings
Recently, the scientific community has been conducting precise comparative analyses of the three existing treatments and accelerating the introduction of biomarkers to maximize therapeutic efficacy. Clinical studies have shown that nusinersen is administered via intrathecal injection, directly acting on the central nervous system, while onasemnogene abeparvovec uses an adeno-associated virus 9 (AAV9) vector to deliver the gene with a single intravenous injection. Risdiplam, an orally administered drug that crosses the blood-brain barrier, exhibits systemic effects. Based on the individual characteristics of these drugs, a trend is emerging to establish criteria for switching treatments based on the patient's age and the stage of disease progression.
To quantitatively evaluate therapeutic effects, neurofilament light chain (NfL) and compound muscle action potential (CMAP) analysis are actively utilized. NfL is a protein released into the blood or cerebrospinal fluid when axonal damage occurs, and a lower level indicates that neurodegeneration is being suppressed. CMAP measures muscle response induced by electrical stimulation, assessing the function of motor nerves. By combining these two biomarkers, a method has been proposed to assess the patient's degree of nerve damage in real-time and design an optimal treatment plan.
In an effort to overcome the limitations of the existing SMN protein increase approach, various non-SMN target substances have been discovered. These include inhibiting PTEN, a protein that interferes with the survival and growth of nerve cells, or controlling the activity of plastin 3 and neurocalcin delta, which regulate calcium concentration and assist in intracellular substance transport. In addition, therapies that inhibit the activity of myostatin, which blocks muscle growth, to prevent muscle atrophy and alleviate neuroinflammation are being studied in various ways.
Significance and Prospects
Moving beyond the era of single-target therapies, the paradigm shift towards multi-target and combination therapies is expected to be a new milestone in SMA treatment. A method of administering existing drugs to smoothly induce SMN protein secretion while simultaneously administering muscle protectants or neuroprotectants is considered an alternative to prevent further degeneration of nerve cells and partially restore muscle function. In clinical practice, research on personalized precision medicine combining non-SMN treatments has already begun, targeting patient groups with complex genetic variations.
However, there are many challenges to be solved before combination therapies can be widely used in clinical practice. There is still insufficient information on the safety of potential toxicity and drug interactions that may occur when drugs with different mechanisms of action are administered in combination. The enormous treatment costs associated with combining expensive gene therapies with existing drugs and the burden on national health insurance are also areas that require social coordination.
In the future, with the introduction of next-generation splicing regulators and precise gene editing technologies, it is expected that we will be able to approach a fundamental treatment that prevents permanent loss of motor function. The combination of newborn screening, which begins at the pre-disease stage, and biomarker-based precision diagnostics is expected to lead to a fundamental change in the patient's quality of life.
Spinal muscular atrophy (SMA) is a devastating autosomal recessive neuromuscular disorder characterized by progressive degeneration of lower motor neurons, leading to muscle weakness and atrophy predominantly manifesting in childhood. The disease is caused by homozygous deletion or loss-of-function mutations in the survival motor neuron 1 (SMN1) gene, with the nearly identical SMN2 gene acting as a critical modifier of disease severity. Since the initial clinical descriptions in 1891 and the identification of the causative gene in 1995, the field has witnessed transformative therapeutic progress. The FDA approval of nusinersen, an antisense oligonucleotide targeting SMN2 splicing, in 2016 marked the first disease-modifying therapy, followed by the gene replacement therapy onasemnogene abeparvovec in 2019 and the orally administered small-molecule splicing modifier risdiplam in 2020. These SMN-targeted therapies have substantially improved survival and motor outcomes, particularly when administered presymptomatically as enabled by increasingly widespread newborn screening programs. However, a significant proportion of patients, especially those with later-onset disease and adults, show limited responses, and existing therapies cannot reverse established neurodegeneration or muscle pathology. In this review, we trace the history of SMA research and therapy development, critically compare the three approved treatments, and discuss key unresolved challenges including treatment-switching criteria, management of late-diagnosed patients, and the emerging role of biomarkers such as neurofilament light chain and compound muscle action potential. We further explore non-SMN therapeutic strategies targeting PTEN, plastin 3, neurocalcin delta, myostatin, and neuroinflammation, and examine the rationale for combination approaches that integrate SMN restoration with muscle- and neuro-protective agents. Finally, we address future directions encompassing precision medicine, next-gen
This research provides practical guidance for establishing patient-specific combination therapy strategies in clinical practice. Clinicians will be able to design scenarios in which they confirm NfL levels through blood analysis to diagnose subtle damage to nerve cells and adjust the dosage of existing SMN-targeted drugs in real-time. From the pharmaceutical industry perspective, this is likely to be a catalyst for activating joint development and combination clinical trials between companies with non-SMN candidate substances, such as myostatin inhibitors, and existing gene therapy manufacturers. Ultimately, it is expected to lead to the combination of newborn screening and personalized genomic screening, accelerating the commercialization of precision genetic medicine by administering the optimal drug combination immediately upon diagnosis.