The Latest in ALS Research: Challenges and Progress
Bill Holt
Bill Holt
Executive Director, Neurosciences, Scientific Affairs

On May 5, 2017, the U.S. FDA approved the first new therapy for amyotrophic lateral sclerosis (ALS) in more than 20 years. With an average of 15 people a day – more than 5,600 people every year – diagnosed with ALS, this is very hopeful news to the more than 300,000 Americans who are estimated to be currently living with the disease.

Also called Lou Gehrig’s disease, ALS is a progressive neurodegenerative disease affecting nerve cells in the brain and spinal cord. As these cells die, patients lose their voluntary muscle control and movement. As the disease progresses, patients face total paralysis.

Here, PRA’s Bill Holt discusses some of the challenges and progress of ALS research.

Recent years have brought a wealth of new scientific understanding regarding the physiology of ALS. Which areas of scientific focus are currently leading the way in advancing ALS research?

No definitively validated target or targets have yet been identified for ALS. Current treatment options include riluzole, a drug with potential hepatotoxicity. Currently, a prodrug of riluzole is being developed with a potentially improved safety profile and improved therapeutic effect. As potential drug targets are being sought, development of several compounds for both symptomatic treatment and disease modifying effects are in trials including drugs to improve muscle contractility, muscle growth, reduction of rogue proteins seen in ALS, reduction of neuroinflammation, neuroprotectants and agents to improve mitochondrial function. A list of ongoing clinical trials can be found at

What are the current gene targets for drug development?

Gene therapy may help if it can deliver a beneficial protein to salvage dying nerve cells. Gene therapy can be simply a means to boost on-site production of a trophic (growth enhancing) factor, at places where nerve cells are in trouble. Researchers can disarm many types of viruses, and put in the genetic instructions to make therapeutic protein. The redesigned viruses are called vectors. They are simply carriers for therapeutic genes. Knowledge of the SOD1 mutations linked to some forms of ALS has produced a vast body of evidence, pointing to a general strategy for the disease that might be successfully implemented through gene therapy.

In ALS, a small percentage of patients have a known defect in a gene. This genetic mistake, in the gene coding for the SOD1 protein, produces disease no different from any other form of ALS, inherited or not. Gene therapy might be designed for a particular SOD1 defect, but that therapy may or may not work for other ALS patients.

What is encouraging is that the knowledge of the SOD1 mutations has produced a vast body of evidence for what does go wrong in other cases of ALS. And that evidence is pointing to a general strategy that might be successfully implemented through gene therapy.

ALS patient and mom reduced size

Can you tell us more on the role of neuroinflammation in ALS?

A decade ago, scientists and doctors working on ALS were beginning to suspect that inflammation was critical to the disease process. It wasn’t a popular idea. But a growing body of evidence is mounting in support of this theory and is leading to the identification of possible immune system biomarkers and even novel treatments.

In 1993, the first genetic cause in ALS was identified, a point mutation in the gene encoding Cu2+/Zn2+ superoxide dismutase (SOD1). The following year, the human cassette containing the G93A mutation of SOD1 (mSOD1) was inserted into a mouse. Surprisingly, these mSOD1 transgenic mice developed a motor neuron disease similar to human ALS. Currently, > 150 genetic mutations and > 20 different genes have been identified that can lead to the same clinical disease of ALS in patients. Thus, multiple mechanisms converge leading to inflammation and selective motor neuron death.

Unfortunately, drugs targeting neuroinflammation such as celecoxib, ceftriaxone, thalidomide, and minocycline that were reported to enhance survival in transgenic mice have been shown to be ineffective in human ALS trials. Several novel strategies are being developed to target the neuroinflammation pathways in attempts to decrease motor neuron demise in ALS.

What is the connection between ALS and frontotemporal dementia (FTD)?

Researchers have begun to recognize an important connection between frontotemporal degeneration (FTD) and ALS. FTD is a syndrome of progressive changes in behavior and language due to loss of function of neurons in the frontal and temporal lobes. Usually, FTD has relatively little effect on the parts of the nervous system that control movement, and so many FTD patients remain physically strong and relatively agile until late in the illness. However, in about 10-15% of patients with FTD, the disease also involves the nerve cells controlling voluntary movement, called motor neurons. When this occurs, the syndrome is called FTD with motor neuron disease (FTD/MND) or FTD with ALS.

Approximately 30% of ALS patients will show signs of frontal lobe decline, which affects organizational function and behavioral comportment.

Patients with FTD/MND may present with the same behavioral and/or language changes seen in other subtypes of FTD. In this syndrome however, these changes are accompanied by a deterioration of motor neurons that manifest as weakness in the muscles with stiffness, difficulty making fine movements, atrophy (shrinkage) of the muscles, and fine muscle twitches and cramps. Muscle changes can affect the arms and/or legs on one or both sides of the body, or the face, tongue and mouth, depending on how the nervous system is affected in that individual. As the disease worsens, more parts of the motor system become involved.

Approximately 30% of ALS patients will show signs of frontal lobe decline, which affects organizational function and behavioral comportment. Patients with FTD/MND may first present with features of either FTD or ALS with the additional symptoms developing as the disease progresses. All patients with FTD/MND will experience a gradual, steady decline in functioning.

Nerve cell reduced size

There are a number of precision medicine programs/partnerships in ALS, what are their common goals?

Precision medicine is an innovative approach that uses emerging biomedical technologies to deliver optimally targeted and timed interventions, customized to the molecular drivers of an individual’s disease. This approach is only just beginning to be considered for treating ALS. These groups strive to bring together the key elements of precision medicine to ALS: phenotypic classification, comprehensive risk assessment, presymptomatic period detection, potential molecular pathways, disease model development, biomarker discovery and molecularly tailored interventions. Together, these would embody a precision medicine approach, which may provide strategies for optimal targeting and timing of efforts to prevent, stop or slow progression of ALS.