The world of ALS patients and their families focuses on the most current research, theories, clinical trials taking place, potential treatment opportunities and symptom relief availability. While a great deal of information is available on this website, current updates with the most recent information can be read here. At times, brief statements are offered as well as links to other websites for in depth explanations. Steve will do his best to keep information current as he combs the internet, visits with researchers, explores bio-medical facilities and meets with patients and their families.
"USING GENETICS TO GUIDE TREATMENT" BY DR. ZACHARY SIMMONS
Dr. Zachary Simmons, Director of the Neuromuscular Program and ALS Center at Penn State Hershey Medical Center, is a highly resourceful, compassionate and intelligent neurologist who we are privileged to know. We are pleased to present his relevant, informative views on the search for both the genetic origins and treatment resolutions to ALS/MND.
Using Genetics to Guide Treatment
Zachary Simmons, MD
Professor of Neurology and Humanities
Director, Neuromuscular Program and ALS Center
Penn State College of Medicine and Penn State Hershey Medical Center
Some of the questions I am asked most frequently by my patients are the "why" questions: Why did I get ALS? Why now, when I've been healthy? Why me, when no one else in my family has had this before? There are also the "what" questions: What causes ALS? What might this have to do with my job, my diet, or the place I live? What might I have done to bring this on? These are very tough questions for which I have very limited answers, particularly in the face of the devastating nature of this diagnosis. But I believe that we are getting much closer to providing better answers to these questions. There are many reasons for this, but today I would like to focus on genetics.
To understand how genetics may guide our understanding and, eventually, our treatment of ALS, it is important to understand the heterogeneity of ALS. ALS is a syndrome, not a single disease. By this, we mean that it has a broadly identifiable clinical presentation, but with considerable variability. These variations include the degree of upper vs. lower motor neuron involvement, bulbar vs. limb involvement, age at onset, and rate of progression. And, there are non-motor manifestations such as the frontotemporal dementia that occurs in about 15% of individuals with ALS. Of course, the final common pathway is motor neuron loss, but many pathways function abnormally in ALS, including mitochondrial dysfunction, oxidative stress, defective axonal transport, protein misfolding, and glutamate toxicity. Based on this, we should not expect ALS to have only a single cause.
Our approach to treatment to date has been to try a single drug in a large group of patients with ALS and compare the outcome to those given a placebo. Not surprisingly, this approach has failed repeatedly, leaving us with a single drug (riluzole) that has demonstrated only modest efficacy in slowing ALS progression. The list of failed drugs is tragically long and horribly disappointing. Most recently, ceftriaxone, olesoxime, lithium, and dexpramipexole joined that list. Why should we expect one drug to work for a disease that likely has so many different causes? Realistically, we should not, and our approach to therapy must change. Keep in mind that it is possible that a drug that has "failed" clinical trials may have been effective in a few patients in those trials, but if it helped only 1 in 100, then the effect on the "average" survival of the group would have been negligible, and the drug would have been classified as a failure. For example, perhaps one drug that was effective in the mouse model (the SOD1 transgenic mouse) might be effective only in those individuals with ALS caused by the specific SOD1 mutation that was in the mouse model. We need a much more targeted and scientifically rigorous approach to ALS therapy.
Genetics can help us untangle the heterogeneity of ALS. Only 5-10% of ALS is classified as "familial ALS" (fALS), usually interpreted as meaning that the affected individual has a first degree relative (parent, sibling, child) or at least 2 more distant relatives affected by the disease. Other cases are classified as "sporadic ALS" (sALS). Depending on the reference you consult, there appear to be at least 9, and possibly 19, genes that can develop mutations that cause ALS, plus several others that modify ALS risk or progression (1,2). Testing an individual with fALS for all known ALS-causing gene mutations will identify such mutations in 60-68% of such individuals. That's not perfect, but very respectable, and represents a huge increase from the figure of less than 20% just 8-10 years ago. Interestingly, these same mutations can be found in about 10% of individuals with sALS.
What does this mean? Quite frankly, we're not sure for those with sALS. If an individual with sALS has an "ALS gene mutation," then we do not know if that gene is causing ALS in that individual or is just an incidental finding. If it is causing ALS, does that mean that it was not present in any family members prior to the affected individual? Or, does it mean that they also had this mutation, but that there are other factors that determine whether an "ALS gene mutation" will cause ALS, such as other gene mutations that must also be present, or perhaps specific environmental factors such as chemicals and other toxins, foods, trauma, vaccinations, viruses, etc.? Certainly genes are not the whole answer, because the identical twin of someone with ALS does not always develop ALS. Similarly, environment is clearly not the only answer, because individuals may live together for many years, yet it is extremely rare for 2 individuals in the same home to both develop ALS.
It is likely that specific gene mutations increase our probability of developing ALS. Such genes may be thought of as the "fuse" to the time bomb we call ALS. But, it appears that some "trigger" is then needed to ignite the fuse that results in ALS. Clearly this means that the separation of ALS into fALS and sALS categories is artificial. We just don't yet know what that really means, which is why we do not recommend testing all patients with sALS for ALS gene mutations. We simply do not know what to do with that information.
How will increasing our knowledge of ALS genetics make us smarter (or at least less ignorant)? A multi-step process likely will be needed:
Step 1 - Identification of genes that appear to cause ALS or to modify ALS risk or progression: We and other centers are collecting DNA samples for whole-exome sequencing. The exome is the portion of the gene that contains the exons, which are the coding portions of the gene. Using this information in collaboration with clinical features of our patients should permit us to identify gene mutations that cause or contribute to ALS.
Step 2 - Use model systems: These gene mutations can then be put into simple experimental models, such as the zebra fish. Defects will occur in the formation of the brain and/or spinal cord. Drugs can be given to determine which ones prevent such malformations. For starters, these could be drugs approved for other diseases by the US Food and Drug Administration (or its equivalent organization in other countries). Such drugs are readily available and would be quick and easy to test. If successful in simple model systems, they could then be tested in more complex models and eventually in patients who have the specific mutation that was present in the model for which the drug was found to be effective. Any drug identified as being helpful would not be a treatment for all ALS, but a very specific treatment for the type of ALS caused by this specific mutation.
Step 3 - Understand mechanisms: While step 2 represents the "fast track" to treatment, genetics could also spur the development of new drugs targeted toward specific ALS mutations. Once such mutations are identified, then identifying the functions of these genes will lead to an understanding of how these gene mutations are involved in causing ALS. Therapies can then be developed that are specifically targeted toward the defective functions of the mutated genes.
Step 4 - Forward into the future: Thus, in the future, it is likely that individuals with ALS will be stratified into specific subtypes, determined by their gene mutations. Rather than simply diagnosing a patient with ALS, the neurologist should be able to tell the patient: "You have ALS type 14B, which is caused by a mutation in genes A and B, and causes defects of axonal transport." The treatment that we have found to be most effective is treatment Y." That is my hope, and I firmly believe that hope can become a reality within a few years.
Renton AE et al. State of play in amyotrophic lateral sclerosis genetics. Nature Neuroscience 2014;17(1):17-23.
Su XW et al. Genetic heterogeneity of ALS: implications for clinical practice and research. Muscle Nerve DOI: 10.1002/mus.24198.