Toward a Cure for ALS

Written by Margaret Anne Rockwood | Last updated May 6th, 2026
Medically reviewed by Jennifer Morganroth, MD, MBA and Doreen Ho, MD

Therapies that aim to target both genetic and cellular pathways in amyotrophic lateral sclerosis (ALS) are gradually emerging. Despite a median survival rate of 3-5 years from onset, some people living with ALS are defying the odds and surviving many years after diagnosis. With new means of proactive management helping slow progression, the hope is that providers may soon be able to offer these and future patients immunotherapies, genetic targeted and modifying therapies, and new delivery systems that are now at their inception or in a clinical trial.

Most current treatments target the effects of ALS, not its origins, which remain elusive. Some companies are pioneering a new wave of ALS research, combining targeted with innovative biomarker discovery to address the disease at its core. Target ALS is a leader in the shift to this cutting-edge research through collaborative consortia that identify and target the origins of the disease.

Stem Cell–Based Approaches

Working at the cutting edge of the most promising approaches to cure a broad spectrum of diseases, researchers are finding methods to accelerate drug testing. Other research is yielding encouraging outcomes in preclinical and early-phase human trials.

• A team of researchers reprogrammed the skin and blood cells from patients with both familial and sporadic ALS into induced pluripotent stem-cell derived motor neurons. This approach enables screening of thousands of FDA-approved drugs and drug-like molecules to find ones that might be effective against multiple forms of ALS.
• The NurOwn trial involved the infusion of ALS patients’ own bone marrow-derived stem cells, which were then induced in the laboratory to secrete high levels of neurotrophic factors (growth-supporting proteins) before being delivered intrathecally into the spinal fluid. While the Phase 3 trial did not meet its primary efficacy endpoint, a pre-specified subgroup analysis suggested that participants with less severe disease may have retained more function compared to placebo, prompting continued interest in refining this approach.
• Clive Svendsen, PhD, led a trial focusing on generating glial cell line-derived neurotrophic factor (GDNF) from stem cells as a potent growth factor that protects motor neurons.  His team delivered human neural progenitor cells engineered to release GDNF directly into the lumbar spinal cord via surgical transplantation. Supporting the durability of this approach, research on postmortem spinal tissue from 13 participants revealed that the transplanted stem cells survived and produced GDNF in the spine for approximately 3.5 years.

Gene Modifying and Gene Therapy Advances

Delivery of therapeutic cargos to their targets is a challenge in neurodegenerative disease and  beyond. Improvements are underway in various gene delivery vehicles, including AAV, nanoparticles, liposomes, and protein carriers, with goals of transport efficiency and precise delivery of RNAi agents, CRISPR-Cas9 agents and neurotrophic factors. 

An antisense oligonucleotide (ASO) is a short, synthetic strand of nucleic acid that binds to a specific RNA and modifies how a gene is expressed and administered intrathecally in ALS. Multiple ASOs are currently in trials for ALS, including tofersen for SOD1 (already commercially available) and others for C9orf72, FUS, etc.)  These include nL-TARD-001, a personalized ASO being delivered in trials through the Silence ALS Program.

OTHER NOTABLE UPDATES:

Splice-Switching ASOs: Beyond direct silencing, companies are developing ASOs to rescue “cryptic” UNC13A splicing (a downstream effect of TDP-43 loss) to restore synaptic health.

CRISPR-Cas9 gene editing: While there are no clinical applications of CRISPR technologies in ALS to date, CRISPR-Cas9 shows considerable potential for familial ALS. Borrowing from successes in sickle cell anemia, researchers are exploring the use of CRISPR-Cas9 to alter the C9orf72 gene. The C9orf72 hexanucleotide repeat expansion is the most common genetic cause of both ALS and FTD.. In preclinical trials, they found that excising certain genetic repeats can reverse ALS and FTD phenotypes in patient-derived iPSC motor neurons and mouse models.

SYP Gene Suppression: A research group found that SYF2 gene suppression rescued the survival in patient-derived iPSC motor neurons representing C9ORF72, TARDBP, and sporadic forms of ALS. In mouse models, SYF2 suppression improved symptoms and pathology related to the protein TDP-43.

PIKFYVE Inhibition: Using genetic and RNA-based approaches, researchers have demonstrated, in a preclinical model, that the drug apilimod (and ASO derivatives) inhibits the PIKFYVE kinase. In doing so, motor neurons are stimulated to clear toxic proteins through exocytosis, reducing neurodegeneration, improving motor function, and lengthening survival.

TARDBP (TDP-43)–Targeted Therapies

Because TARDBP mutations are extremely rare, they are primarily being addressed through personalized ASO programs. Advancements include:

• Creating a validated pTDP-43 antibody (now available) to visualize TDP-43 aggregates in human cells, mouse models, and postmortem human tissue. 
• Silence ALS Program, which develops customized ASOs for individual patients, including N-of-1 approaches for TARDBP-related ALS.
• nL-TARD-001: This is a personalized ASO specifically for individuals with TARDBP variants. As of late 2024 and throughout 2025, patients have begun receiving this intrathecal treatment under “N-of-1” clinical protocols.
• Splice-Switching ASOs: Beyond direct silencing, these are under development to rescue UNC13A splicing (a downstream effect of TDP-43 loss), aiming to fix the functional damage caused by TDP-43 aggregation

Emerging Molecular Targets

Research is underway exploring avenues for understanding and treating the disease. Some of these targets include:

• The role of autophagy and metabolism in cellular breakdown
• Correcting RNA splicing errors on the UNC13A gene
• Targeting the RNA granule protein OTUD4 as a therapeutic pathway
• Analyzing Neural-Derived Exosomes (NDEs) to detect HERV-K and LINE1 RNA as a biomarker of ALS pathology and elucidate their correlation with TDP-43 protein mislocalization
• Creating bioinformatic tools identifying gRNAs that could enable CRISPR editing for many people living with C9 ALS and achieving brain penetrance of Cas9.
• Using a nonviral, protein-based delivery system via a transferrin receptor (TfR) platform, enabling the crossing of the blood-brain barrier, where CRISPR then performs its editing and disappears. Current challenges are how to distribute it more broadly across the brain.
• Using RNA interference (RNAi)-based ALS therapies, which also hold promise for future clinical applications.

Drug Development and Clinical Trials

HEALEY ALS Platform Trial

The HEALEY ALS Platform Trial employs an adaptive, multi-arm design to evaluate multiple investigational therapies simultaneously. Since the trial began in 2020, seven regimens (A–G) have been evaluated.

• Early regimens included Zilucoplan, Verdiperstat, CNM-Au8, Pridopidine, and Trehalose.
• Certain regimens graduated into later phase testing.
• The platform remains active and continues to rapidly and efficiently evaluate new candidates with reduced cost and a shared placebo, allowing for fewer patients in the placebo arm.

NP001 (Sodium Chlorite)

A small molecule designed to rebalance the innate immune system by reprogramming inflammatory macrophages from a toxic (M1) to a non-inflammatory, “wound-healing” (M2) state.

• Clinical Evidence: The Phase 2B trial did not meet its primary endpoint (ALSFRS-R change). However, in a post-hoc subgroup analyses  NP001 was associated with a significant slowing of vital capacity decline and a survival benefit, particularly in a pre-specified subgroup of patients with baseline systemic inflammation (elevated C-reactive protein) and patients between the ages of 40-65. These subgroup findings are hypothesis-generating and require confirmation.
• 2026 Update: Following a successful Type C meeting with the FDA, Phase 3 clinical testing is slated for 2026. The pivotal trial will use vital capacity as its primary efficacy measure to confirm the survival signals seen in earlier studies.

CNM-Au8 (Gold Nanocrystals)

A proprietary oral suspension of gold nanocrystals with catalytic properties designed to support cellular energy (ATP) production and reduce oxidative stress by enhancing the NAD+ pathway.

• Clinical Evidence: While the primary endpoint in the HEALEY Trial (ALSFRS-R) was not met by the collective cohort, long-term follow-up and independent analyses have shown statistically significant reductions in Neurofilament Light Chain (NfL)—a key biomarker of nerve damage.
• Survival Signal: In 2026, new data presented to the FDA demonstrated a 73–77% reduction in mortality risk at one year for patients treated with the 30mg dose compared to concurrently randomized controls.
• Regulatory Status: As of early 2026, the manufacturer is pursuing an Accelerated Approval pathway with the FDA based on these NfL biomarker reductions and linked survival benefits.

Key ALS Trials to Watch in 2026