ALS, also known as Lou Gehrig’s disease, is a progressive neurodegenerative disease that affects nerve cells in the brain and spinal cord. It causes loss of muscle control, paralysis, and eventually respiratory failure. There is currently no cure for ALS and treatment focuses on slowing progression and managing symptoms. However, research into new treatments is ongoing and aims to find ways to stop or reverse disease progression.
What causes ALS?
The exact causes of ALS are still unknown. About 10% of cases are inherited or familial ALS, caused by genetic mutations. The remaining 90% of cases, known as sporadic ALS, have no clearly defined risk factors.
Some theories about what triggers sporadic ALS include:
- Glutamate toxicity – Excess glutamate leads to damage and death of motor neurons
- Protein misfolding – Misfolded proteins accumulate and form toxic clumps inside cells
- Mitochondrial dysfunction – Impaired energy production in cells
- Oxidative stress – Cellular damage from reactive oxygen species
- Impaired axonal transport – Disruption of cellular transport systems
- Neuroinflammation – Overactive immune responses
- Abnormal RNA metabolism – Defects in RNA processing
The leading theory is that ALS is caused by a combination of genetic and environmental factors. Advancing understanding of ALS disease mechanisms is key for identifying potential therapeutic targets.
Current ALS treatments
There are only two FDA-approved drugs for ALS:
- Riluzole – Glutamate blocking agent, modestly slows progression
- Edaravone – Antioxidant, slows decline in daily functioning
These drugs have only a small impact on prolonging survival by a few months. Additional medications may be prescribed to manage symptoms like muscle cramps, stiffness, excessive saliva, and emotional changes. Non-invasive ventilation is used to support breathing function as the disease progresses. Overall, current treatments have limited efficacy in halting disease progression or significantly extending lifespan.
Emerging ALS treatments in clinical trials
With increased understanding of ALS disease mechanisms, many potential therapies are currently under investigation in clinical trials.
Gene therapies
Gene therapies aim to silence mutant genes, replace defective genes, or introduce new genes to protect motor neurons:
- Antisense oligonucleotides – Bind to RNA to reduce production of mutant proteins
- Viral vector gene replacement – Deliver normal genes using modified viruses
- Neurotrophic factor delivery – Express proteins that support neuron health and growth
Stem cell therapies
Stem cell transplantation may help replace lost motor neurons or provide neuroprotective effects:
- Neural stem cells – Multipotent cells that can differentiate into neurons
- Mesenchymal stem cells – Derived from bone marrow, secrete protective factors
- Induced pluripotent stem cells – Generated from patient’s own cells, avoid immune rejection
Immunotherapy
Dampening activated immune responses may protect neurons:
- Monoclonal antibodies – Target specific immune signaling proteins
- Regulatory T cells – Suppress overactive immune cells
Neuroprotection
Compounds that protect motor neurons from degeneration:
- Ceftriaxone – Antibiotic with neuroprotective effects
- Pimozide – Neuroleptic agent that blocks TDP-43 aggregation
- TUDCA – Bile acid that reduces ER stress
Other
- CuATSM – Copper-based agent that improves mitochondrial function
- NP001 – Modulates macrophage activity to reduce neuroinflammation
- Masitinib – Tyrosine kinase inhibitor with anti-neuroinflammatory effects
While many avenues are being explored, it will take large clinical trials to determine safety and efficacy. Gene therapies and stem cell-based treatments currently show the most promise.
ALS drug approvals in 2022
Two new milestone ALS drugs were approved by the FDA in 2022:
AMX0035 (Relyvrio)
AMX0035 is a combination of two compounds:
- Sodium phenylbutyrate – Reduces ER stress
- Taurursodiol – Bile acid that stabilizes cellular membranes
In the Phase 2 CENTAUR clinical trial, ALS patients who took AMX0035 had slower functional decline compared to placebo over 24 weeks. Based on these results, the FDA granted approval in September 2022. AMX0035 is now the first approved ALS therapy in many years to demonstrate efficacy for slowing disease progression.
Albrioza (efanesoctocog alfa)
Albrioza is a genetically engineered version of a clotting factor that reduces blood clots. It was approved by the FDA in December 2022.
Up to 20% of ALS patients have concomitant frontotemporal dementia (ALS-FTD). These patients have an increased risk of aspiration, which can lead to pulmonary emboli blood clots in the lungs. By reducing blood clotting, Albrioza improves outcomes and prolongs survival in ALS-FTD patients.
Other emerging ALS therapies
In addition to drugs in active clinical testing, other innovative treatment approaches are being explored at earlier stages of research:
Gene editing
Gene editing tools like CRISPR/Cas9 can directly modify genes to correct mutations that cause familial ALS. This has potential to permanently reverse the disease. Gene editing has so far only been tested in animal models of ALS.
Viral delivery to motor neurons
Injecting viruses that target motor neurons could enable delivery of gene therapies or growth factors directly to affected cells in the spine. Early research is assessing safety and efficacy.
Brain-computer interfaces
Devices that record brain signals could be used to control computers, speech synthesizers, or exoskeletons. This may improve communication and mobility for ALS patients with paralysis. Brain-computer interfaces are currently limited to highly controlled laboratory settings.
Motor neuron replacement
Replacing damaged motor neurons through transplantation or stem cell differentiation remains an aspiration. This will require significant advances in cell-based therapies and nerve regeneration methods.
Challenges in developing new ALS treatments
While progress has been made, there are still major obstacles to developing effective ALS therapies:
- ALS is a heterogenous disease, making it hard to target all subtypes
- The blood-brain barrier limits delivery of drugs to the central nervous system
- ALS progresses rapidly, making it difficult to intervene before irreversible nerve damage
- Animal models imperfectly replicate key features of human ALS
- Clinical trials require large cohorts given ALS’s low prevalence
Overcoming these research barriers will require sizable, sustained investment. Government and non-profit funding for ALS lag far behind other major diseases. International collaboration between academia and industry is also key for running robust clinical trials.
ALS treatment research priorities
To accelerate development of effective therapies, ALS experts recommend focusing on:
- Uncovering more genetic causes of ALS
- Defining molecular subtypes of sporadic ALS
- Identifying reliable ALS biomarkers
- Standardizing clinical trial outcome measures
- Testing combination therapies that target multiple mechanisms
- Advancing gene therapies and regenerative medicine
- Improving drug delivery across the blood-brain barrier
- Increasing recruitment for large-scale clinical trials
With a coordinated effort, researchers are optimistic that meaningful treatments are within reach. Promising early results with AMX0035 and Albrioza provide evidence that ALS clinical trials can deliver new approved therapies.
Conclusion
The past few years have seen major strides in understanding ALS disease mechanisms. This has enabled numerous clinical trials testing novel drug targets and therapeutic approaches like gene therapy. Recent approvals of AMX0035 and Albrioza demonstrate that this research is beginning to pay off. While current treatments still have limitations, the ALS field is gaining momentum. Advances in biomarkers, gene editing methods, drug delivery, and clinical trial design will help accelerate the development of therapies that can dramatically slow or halt disease progression. With continued research, the ultimate goal is to find a cure for ALS.