# Pre-Symptomatic Familial ALS (Pre-fALS) Study - Prelude to a Treatment Trial

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2022 · $549,173

## Abstract

PROJECT SUMMARY
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 p...

## Key facts

- **NIH application ID:** 10469619
- **Project number:** 5R01NS105479-05
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Michael Benatar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $549,173
- **Award type:** 5
- **Project period:** 2018-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10469619

## Citation

> US National Institutes of Health, RePORTER application 10469619, Pre-Symptomatic Familial ALS (Pre-fALS) Study - Prelude to a Treatment Trial (5R01NS105479-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10469619. Licensed CC0.

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