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ALS is a rare neurological disease that currently has no cure. Several failed clinical trials have caused researchers to turn to more innovative methods of treating the disease such as antisense oligonucleotide, gene therapy, stem cell therapy and others.

Amyotrophic lateral sclerosis (ALS) is a rare neurological disease that is characterized by the deterioration of motor neurons, nerve cells that control voluntary muscle movement.

Currently, only two drugs have been approved for the treatment of ALS: riluzole (Rilutek) and edaravone (Radicava). However, while these drugs prolong survival, they are not a cure for the disease.

Unfortunately, over the last decade, several other drugs that have gone to clinical trials have not been successful, causing researchers to look for different ways to treat the disease.

1. Antisense oligonucleotides (ASOs)

Patients with familial ALS often have a mutation in the gene SOD1, which leads to the production of mutated SOD1 proteins. ASOs are drugs that bind to the RNA transcript of a gene (the intermediary product between gene and protein), which triggers the destruction of the RNA transcript before it ever becomes a protein.

IONIS-SOD1Rx (BIIB067) is an ASO that is currently under investigation. It is being developed in a collaboration between Ionis Pharmaceuticals and Biogen. The drug is designed to reduce levels of the SOD1 mutated protein that is toxic to patients, which will hopefully slow down disease progression. This drug was developed based on studies in a mouse model of ALS where the ASO was also able to significantly lower SOD1 protein levels and improve survival.

Biogen and WAVE Life Sciences are concurrently developing ASOs to target C9ORF72, another mutation in patients with ALS. These ASOs are expected to enter clinical trials soon.

2. Gene Therapy

Development of gene therapies for neurological diseases has really taken off since a viral vector (a delivery vehicle for genes) known as the adeno-associated virus 9 (AAV9), was found to cross the blood-brain barrier, which was an issue in prior attempts at gene therapy.

AVXS-301 is a gene therapy being developed by Novartis that is composed of AAV9 with SOD1 targeting short hairpin RNAs (which reduce levels of whatever they are targeted towards). Mouse models have shown that AVXS-301 improves life expectancy and improves motor function. Currently, the drug is in preclinical safety testing.

3. Stem Cell Therapy

Another strategy to target ALS is through injecting a beneficial population of cells in the patient rather than changing gene expression (as is the case with ASOs or gene therapy).

ALS patients have been shown to have high levels of inflammation, which is toxic to nerve cells. One particular cell therapy consists of inserting cells that have been matured from patients’ own bone marrow-derived mesenchymal stem cells (MSCs). These MSCs impart protective factors and immune system regulating molecules that both help maintain motor neuron function and reduce inflammation.

Currently, there is a phase 3 trial that will enroll 200 patients who will receive three injections of MSCs in the spine every two months. Results are expected in 2020.

NSI-566, another stem cell therapy, is under development by Neuralstem for treatment of ALS. It is composed of neural stem cells derived from the human spinal cord. These stem cells can help protect and repair the patients’ remaining motor neurons.

CNS10-NPC-GDNF is another stem-cell based therapy being developed by Cedars-Sinai hospital for the treatment of ALS. It is composed of neural progenitor cells that are genetically engineered to produce glial cell line-derived neurotrophic factor, which has a protective effect on neurons.

4. Therapies to target the immune system

While not a typical autoimmune disease, there are several factors that suggest that the immune system plays a major role in the progression of ALS. In particular, inflammation (an immune response mounted by the immune system) has been shown to be present at high levels in patients with ALS, which can be detrimental. There are several drugs being developed to regulate the immune system in patients.

H.P. Acthar Gel is currently under investigation by Mallinckrodt Pharmaceuticals for treatment for ALS. The gel contains a hormone known as the adrenocorticotropic hormone (ACTH), which has been shown, in animal studies, to regulate the immune system by reducing inflammation in the brain (neuroinflammation).

MN-166 (ibudilast) is being investigated by MediciNova for treatment of ALS. It is a small molecule that has been shown in animal and clinical studies to have anti-inflammatory properties.

AMX0035, a combination of two chemicals (sodium phenylbutyrate and tauroursodeoxycholic acid), is being developed by Amylyx to help reduce nerve cell loss and inflammation of the brain by blocking signaling pathways that contribute to cell death and inflammation.

Fingolimod (Gilenya), an already approved treatment for multiple sclerosis, is being investigated for ALS as a treatment for reducing inflammation.

NP001 is an investigational therapy under development by Neuraltus to slow down or stop the progression of ALS. NP001 can reduce neuroinflammation by inactivating a type of pro-inflammatory immune cell.

Masitinib is being developed by AB Science to treat ALS by targeting immune cells that block signaling proteins that increase inflammation.

5. Other investigation therapies

  • BHV-0223 is a new formulation of riluzole, the first medication approved by the FDA to treat ALS. This drug, which dissolves orally, is designed to address the issues that are associated with the solid oral dosage form as patients have difficulty swallowing.
  • GM604 is being designed by Genervon and is thought to prolong motor neuron survival in ALS patients.
  • Arimoclomol (Orph-001), an investigational therapy under development by Orphazyme and the University of Miami. This therapy is designed to increase the production of heat-shock proteins that bind and remove the toxic SOD1 protein.
  • AT-1501, an investigational drug being developed by Anelixis Therapeutics. This drug is an antibody that binds and blocks CD40 ligand (a protein) which has been shown to be overactive in ALS patients.
  • VM202, an investigational DNA-based therapy, is being developed by VM Biopharma for the treatment of ALS. VM202 contains the genetic information necessary to produce a protein called hepatocyte growth factor (HGF). This factor is proved to improve the survival and growth of nerve cells.
  • Reldesemtiv is an experimental therapy under development by Cytokinetics that improves muscle strength in ALS.
  • Mexiletine, which has been approved by the FDA to irregular heartbeat, is under investigation to treat muscle cramps in ALS patients.

  • Mazzini, Letizia, et al. "Stem cell therapy in amyotrophic lateral sclerosis: a methodological approach in humans." Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders 4.3 (2003): 158-161.
  • Aebischer, P., et al. "Gene therapy for amyotrophic lateral sclerosis (ALS) using a polymer encapsulated xenogenic cell line engineered to secrete hCNTF." Human gene therapy 7.7 (1996): 851-860.
  • Calvo, Andrea, et al. "Involvement of immune response in the pathogenesis of amyotrophic lateral sclerosis: a therapeutic opportunity?." CNS & Neurological Disorders-Drug Targets (Formerly Current Drug Targets-CNS & Neurological Disorders) 9.3 (2010): 325-330.
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