Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease impacting nerve cells in the brain and spinal cord. These affected cells, known as motor neurons, control voluntary movements like walking and talking. As motor neurons deteriorate and die, they stop sending signals to the muscles, leading to a loss of muscle control.
Gene therapy is a medical approach that treats diseases by modifying a person’s genetic information. This can involve replacing a faulty gene with a healthy copy, inactivating a mutated gene, or introducing a new gene to help fight a disease. The primary principle is to address the root genetic cause of a condition.
The Genetic Roots of ALS
While most ALS cases are sporadic with an unknown cause, about 5% to 10% of all cases are familial (fALS), resulting from inherited genetic mutations. This genetic link provides a clear target for therapeutic intervention.
The most common genes in familial ALS are SOD1 (superoxide dismutase 1) and C9orf72. SOD1 mutations, among the first linked to ALS, account for about 12% of fALS cases, while C9orf72 mutations account for approximately 40%. Scientists have identified over 25 different genes associated with the disease.
The SOD1 gene normally provides instructions for an antioxidant enzyme. When mutated, it produces a misfolded, toxic protein that damages motor neurons. The C9orf72 gene’s function is less understood, but its mutations involve a large repetition of a DNA sequence, leading to the loss of normal protein function and the creation of toxic products.
Mechanisms of Gene Therapy in ALS
A primary strategy for addressing faulty genes in ALS uses antisense oligonucleotides (ASOs). ASOs are short, synthetic strands of DNA or RNA designed to be chemically complementary to a specific segment of messenger RNA (mRNA). The mRNA carries genetic instructions from a gene to the cell’s protein-making machinery.
By binding to the target mRNA, an ASO intercepts the genetic message before it becomes a protein, a process known as gene silencing. For ALS caused by SOD1 or C9orf72 mutations, the ASO stops the cell from making the toxic proteins believed to drive motor neuron death.
Another approach uses viral vectors, like adeno-associated viruses (AAVs), which are modified to be non-pathogenic. AAVs can deliver genetic material directly into motor neurons for gene replacement or to deliver microRNAs that silence harmful genes. These AAV-based therapies are currently in earlier stages of development for ALS.
Current Gene-Targeted Treatments
The first gene-targeted therapy approved by the FDA for a form of ALS is tofersen (Qalsody). This treatment is specifically for patients with a confirmed SOD1 gene mutation and is administered directly into the cerebrospinal fluid via an intrathecal injection.
Tofersen is an ASO that targets the mRNA produced from the mutated SOD1 gene. This action reduces the production of the toxic SOD1 protein within motor neurons. By lowering levels of this harmful protein, the therapy aims to mitigate cellular damage and slow neurodegeneration.
Clinical trials for tofersen measured its impact on biomarkers. Treatment led to a reduction in neurofilament light chain, a marker of nerve cell damage. While initial studies showed a trend toward slowed functional decline, longer-term follow-up suggested better clinical outcomes with earlier treatment. Therapies targeting the C9orf72 gene are now in late-stage clinical trials.
Expanding Therapeutic Approaches
Research is underway to develop gene therapies for other genetic mutations linked to ALS. Genes such as FUS and TARDBP also cause some forms of the disease, and therapies targeting these specific genetic errors are in various stages of preclinical and clinical development.
A major challenge is developing treatments for sporadic ALS, which accounts for most cases and lacks a single, identifiable genetic cause. The mechanisms of sporadic ALS are complex, likely involving a combination of genetic predispositions and environmental factors, making it difficult to identify one target for gene therapy.
Researchers are investigating methods to target downstream cellular pathways disrupted in most forms of ALS, regardless of the initial cause. These pathways include processes like neuroinflammation, oxidative stress, and protein quality control. Therapies that modulate these common processes could benefit a broader population of patients, including those with sporadic ALS.