A major challenge to therapy development efforts in the field of ALS is the relatively late stage in the course of the disease at which treatment is initiated. While the reasons for this are complex, one critically important factor is that the disease process almost certainly begins well before the earliest clinical manifestations of disease with significant loss of motor neurons by the time of symptom onset, and even more so by the time of diagnosis (which is typically made about a year after symptom onset). We have long championed the idea that an early therapeutic, or even a preventative, trial would offer much greater likelihood of success and could be undertaken in people at risk for ALS. In contemplating such a trial, however, we recognized that too little was known about the pre-symptomatic phase of ALS, including elements critical to trial design. This prompted us to initiate (in 2007) Pre-fALS (Pre-Symptomatic Familial ALS), a longitudinal natural history and biomarker study of pre-symptomatic individuals who are carriers of an ALS-associated gene mutation; they are currently the only known population at risk for ALS and in whom a study of pre-symptomatic disease may be considered. Over the course of the last 10 years, we have developed and refined methods for screening and enrolling individuals who may be at risk for developing ALS; providing pre-symptomatic genetic counseling and testing; and maintaining longitudinal follow-up with minimal loss to follow-up. In so doing, we have gradually expanded the Pre-fALS cohort to include 113 gene-positive individuals and have accumulated a total of ~447 person- years follow-up; 14 of these individuals have progressed to clinically manifest disease, yielding an estimated average two-year phenoconversion rate of ~10%. With significant preliminary data in hand and the operational infrastructure now in place, we are poised to expand the Pre-fALS cohort, significantly extend cumulative follow-up time and can expect to observe a total of ~45 phenoconversion events by the end of the grant cycle. Employing a multi-modal array of evaluative procedures that includes both ?wet? and ?dry? biomarkers which permit quantification of subclinical signs of disease, we will address two very specific questions that are fundamental to the design of a future disease prevention trial. First, we will determine whether it is possible to identify a subset of people at genetic risk for ALS who are at a sufficiently high-short term risk of developing disease that a reduction in risk could be used to adequately power a disease prevention trial. Second, we will quantify longitudinal trajectories of pre-symptomatic biomarkers to determine whether changes in these biomarkers could be used to quantify the biological impact of an experimental therapeutic in a disease prevention trial. These data and the insights we glean into the pre-symptomatic stage of disease, will enable us to design and implement a disease prevention or early intervention trial in the near future that could utilize whatever therapeutic agent(s) hold the most promise at the time we are ready to initiate a groundbreaking trial of this sort. SOD1 and C9orf72 antisense oligonucleotides are likely early experimental therapeutic candidates.

Public Health Relevance

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Therapeutic development efforts have been hampered by the relatively late stage in the disease at which treatment is initiated. As for other neurodegenerative diseases, there are powerful reasons to believe that therapeutic success is most likely to emerge from early therapeutic intervention or disease prevention efforts. Preparation for such studies requires a detailed knowledge of the pre-symptomatic stage of disease including longitudinal trajectories of biomarkers of pre-symptomatic disease and predictors of high short-term risk of phenoconversion to manifest disease. The Pre-fALS study, which is designed to answer precisely these questions, will lay the essential groundwork for ALS prevention trials, likely first in populations at genetic risk based on SOD1 and C9orf72 genetic mutations.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Gubitz, Amelie
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University of Miami School of Medicine
Schools of Medicine
Coral Gables
United States
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