The ANA Q&A: Amyotrophic Lateral Sclerosis

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"We are currently undergoing a significant shift in the way in which we conduct clinical trials for the ALS population. Increasing recognition of cohort enrichment, where a more homogeneous treatment group is identified, is more evident today and greatly increases our ability to find effective treatments."

~ Jeffrey Rosenfeld PhD, MD, FAAN, FANA, Professor and Associate Chairman, Department of Neurology, the Director for the Center for Restorative Neurology at Loma Linda, and the Director for Neuromuscular/ALS Programs at Loma Linda University Health Systems

In recognition of ALS Awareness Month (May), we spoke with ANA member and Professor of Neurology, Dr. Jeffrey Rosenfeld.

What does the public need to understand about ALS that it often doesn’t?

There are two main concepts that are most frequently not understood or not known among the ALS patient population:  

1. ALS, and the associated motor neuron diseases are treatable diseases. If you are aggressive and proactive, we already have very effective ways of modifying disease progression. Even though we do not yet have a means to remove or cure the disease, effectively modifying the disease progression is a very realistic goal through a combination of pharmacologic and allied health therapies. The fear associated with an initial diagnosis can unfortunately become more devastating than the symptoms that led to that diagnosis. The impact of our currently available therapies is often not appreciated as a means to offset the feared progression of the disease.  

2. ALS is not likely one disease. The spectrum of ALS presentation and disease course is very broad under the single diagnostic label. Lumping patients under the same ALS disease label for diagnosis or clinical trial can be very counter-productive, especially if the drug being tested might be more effective at treatment of one subtype and not another.

For example, a person may present with predominantly, or sometimes exclusively, bulbar symptoms (speech, swallowing, or possibly breathing problems) and their extremities may remain quite strong throughout the disease.  Conversely, we might see exclusive extremity involvement with complete bulbar sparing.  Similarly, the disease course can be very indolent, while in other cases very rapid.  To date, we have considered all these patients to have the same condition

I believe we need to pay much closer attention to the diversity of presentations and better recognize that these might in fact be, or are likely, separate diseases with selected treatments that may be more relevant to one type but not the other.

How are treatment options for ALS different today from 10 years ago?

There are now two disease-modifying medications approved by the FDA to treat ALS patients and numerous on- and off-label therapies for the effective treatment of many of the problematic symptoms in the disease. These therapies highlight, even more so, the necessity to recognize the disease early and to treat aggressively in order to have the largest impact. What we have today that we did not have 10 years ago is a lot of different types of drugs that are being considered as potential therapies.

Further, the number of genetic markers associated with or potentially causing the disease has markedly increased over the past 10 years. 

Eventually, a better understanding of any one of the many gene products (protein) identified in the pathophysiology of ALS will be important in identifying new drug targets and in directing therapy.  

Lastly, the advent of both RNA and DNA therapies as well as stem cell approaches are experimental treatment options that were not available just 10 years ago.   

What promising research is poised to change the standard of treatment for ALS? 

As we understand more about the individual subtypes of the clinical spectrum of ALS, the opportunity to discover targeted therapies will become a reality. A personalized medicine approach, whereby a patient’s specific biomarker(s) could determine the optimal therapeutic approach is perhaps the most impactful and fundamental advance that might be realized in the near future

We are currently undergoing a significant shift in the way in which we conduct clinical trials for the ALS population. Increasing recognition of cohort enrichment, where a more homogeneous treatment group is identified, is more evident today and greatly increases our ability to find effective treatments. Similarly, the efforts to test multiple drugs simultaneously in the same clinic trial introduces an efficiency we have not seen before.

There is also now a much greater awareness of the immune system as a therapeutic target in ALS than in the past. Whether causing or propagating the disease, modifying the deleterious effects of the immune system on motor neuron viability will likely have an important role in upcoming therapies.

What work is your lab undertaking to move understanding or treatment for ALS forward?

For many years, my research efforts have been directed to a better understanding of the disease heterogeneity and the notion that we are likely categorizing disparate diseases under the diagnostic label of ALS.  

We have developed a simple classification scheme where any patient with a motor neuron disease can be categorized on four diagnostic axes based on the extent of upper motor neuron signs, lower motor neuron signs, bulbar signs and frontotemporal cognitive changes. This diagnostic scheme allows us to separate and stratify the ALS population for the study of individual groups. In collaboration with small biotech companies, we have identified promising biomarkers specific to individual clinical groups that can be used for diagnosis and targeted therapy.   

In addition, we have been involved in the development of induced pluripotent stem cells (iPSCs) and motor neuron cell lines from the disparate clinical groups identified in our diagnostic scheme. Having such in vitro tools will allow us to hopefully identify unique features of specific groups, affording a better opportunity to understand what might be driving the pathology in individual subsets of ALS patients  

How has the ANA supported your career and/or work in this area? 

The ANA has enabled me an opportunity to enrich my professional association with many colleagues for collaboration and networking. During my tenure as Co-Chair of the E-mentoring Program, I was able to meet and interact with a diverse group of colleagues at varied stages of their career. Beyond that, the ANA has provided me an organizational network to enhance my professional development since I became a member.