Study Purpose:This research study is being performed to better understand a specific form of Amyotrophic Lateral Sclerosis (ALS) caused by a mutation (or abnormality) of the C9ORF72 gene. This mutation is the most common genetic cause of ALS, and is present in 40% of ALS patients with a family history of ALS and 5-10% of ALS patients without a family history of ALS.
C9ORF72 Amyotrophic Lateral Sclerosis (ALS)
Type of Intervention:
Study Chair(s)/Principal Investigator(s):
Timothy M Miller, MD, PhD, Washington University School of Medicine
Coordinating Center Contact Information
Washington University School of Medicine
660 S. Euclid Ave.
St. Louis, Missouri, 63110 United States
Full Study Summary:
- Enroll a total of 120 C9ORF72 ALS participants with known mutation at the time of enrollment.
- Determine the C9ORF72 hexanucleotide repeat expansion size in all subjects
- Define ALS disease course
- Determine to what degree the disease course correlates with expansion size
- Collect biomarker samples (blood, DNA and CSF)
- Adults over age 18 with known C9ORF72 ALS status
Participants will have up to 9 in-person visits (this includes two Optional visits for lumbar puncture procedures) and 5 telephone interviews over 3 years. Each in-person visit may be tied to a regular clinic visit if subject is local (except for the optional lumbar puncture visits) or if the subject is from out of town one initial visit can be set up with all other visits performed via a telephone call and medical records review.
At each in town visit, subjects will undergo a blood draw (optional lumbar puncture) and two questionnaires (ALS Functional Rating Scale - revised ALSFRS-R) which measures motor function and the ALS-Cognitive Behavioral Screen (ALS-CBS) which will detect signs of Frontal Temporal Dementia and a breathing test to determine Slow Vital Capacity (SVC) measurements.
For out of town subjects - blood draws can be scheduled locally and sent to the study site for analysis. The ALSFRS-R can be performed over the phone along with other study related questions.
The C9ORF72 mutation is called a "dominant" mutation, which means that their children have a 50% chance of inheriting the gene. Most people who inherit the C9ORF72 mutation will develop either ALS or the related disease called fronto-temporal dementia. However, it may be possible for someone to test positive for the C9ORF72 gene mutation and never develop symptoms. Furthermore, in addition to C9ORF72, there are many other gene mutations that can cause ALS. This study will not test these other genes, and therefore a negative test result for the C9ORF72 mutation will not exclude the possibility that you have a heritable form of ALS.
In order to understand the natural history of C9ORF72 related ALS in terms of measures of rate of progression, the investigators need to understand how the size of the hexanucleotide repeat expansion influences disease parameters. A C9ORF72-focused clinical trial defining an accurate historical control population, will be critical since there may not be enough subjects for a placebo controlled trial. To be ready for upcoming therapeutic trials, the investigators need to start the detailed characterization of the C9ORF72 patients immediately.
Washington University School of Medicine
18 months — 3 years Given changes that may occur with a participants regular clinic visit appointments, the study visit timing of all bio-specimen collections (IDT testing, PBMCs, safety labs, Serum and Southern Blots) may be modified and/or may be scheduled to take place at a local hospital or doctor™s office for the participant's convenience. Each of these blood draws will take approximately 20 minutes. Remote Study Visits (via phone calls placed to participant's home) may take up to 1 hour .The screening visit will last 1 -2 hours Study visit 2 and 4 - each visit will last approximately 2 to 3 hours if an LP is performed. Study visit 3, 5, 6 and 7 - each visit will last approx. 1 -2 hours In order for the project to gather important biomarker, natural history, and disease progression data throughout the course of the project, a modified Study Visit package of information will be re-collected approximately every three months (depending on health status) for a period of 18 months to 3 years
Estimated Study Start Date:
02 / 01 / 2015
Estimated Study Completion Date:
10 / 02 / 2018
Posting Last Modified Date:
07 / 08 / 2021
Date Study Added to neals.org:
02 / 19 / 2016
A series of in-person study visits will occur every 3-4 months for up to 3 years and include two, optional lumbar puncture visits for the collection of cerebral spinal fluid. For participants living in the local vicinity of one of our research centers, the in-person visits may be tied to a regular clinic visit. For out-of-town participants wishing to travel to a research center, please contact the center to determine if an initial, in-person visit may be scheduled and subsequent study visits performed via a telephone call and medical records review.
During the initial study visit, participants will be asked questions about their general health history and medical history/events; family history of diseases; medications being taken. In addition, the following will be performed: brief neurological and physical examination; completion of measures of disease progression including the revised ALS Functional Rating Scale (ALSFRS-R); Current breathing capacity (SVC/FVC); Brief Cognitive Behavioral Screen and Caregiver Behavioral Questionnaire (ALS-CBS); and blood sample donation for biomarker analysis.
Subsequent study visits, where similar information will be re-collected, will occur approximately every 3 months and can be scheduled around your regular clinic visit.
For out of town subjects who are enrolled into the project, serial blood collections may be scheduled locally and sent to the study site for analysis. In addition, the ALSFRS-R may be performed over the phone along with other study related questions about current medication, physical health and medical history/events that may have occurred since the previous study visit.
Background and Rationale for Study: The C9ORF72 mutation is called a "dominant" mutation, which means that their children have a 50% chance of inheriting the gene. Most people who inherit the C9ORF72 mutation will develop either ALS or the related disease called fronto-temporal dementia. However, it may be possible for someone to test positive for the C9ORF72 gene mutation and never develop symptoms. Furthermore, in addition to C9ORF72, there are many other gene mutations that can cause ALS. This study will not test these other genes, and therefore a negative test result for the C9ORF72 mutation will not exclude the possibility that you have a heritable form of ALS.
C9ORF72 repeat expansions were recently identified as a surprisingly common cause of ALS (30% of familial and 5-10% of sporadic ALS). Data collected to date suggest a toxic gain-of-function mechanism for the cause of neuronal loss, either by creating RNA-foci that sequester important RNA binding proteins or by translation of the repeat expansion into aggregation-prone dipeptides. This fact makes antisense oligonucleotide knock-down of C9ORF72 repeat RNA an attractive therapeutic strategy, which is already under development by several groups. Given a recently completed Phase I trial using antisense oligos (ASOs) targeted to SOD1, it is highly likely that a similar strategy will emerge for C9ORF72 in the near future. However, our understanding of clinical characteristics and effect of the hexanucleotide repeat expansion size for C9ORF72 are not yet ready for such a clinical trial. Our collaborative effort proposed here will generate these important phenotype/genotype correlations.
By determining the natural history of disease progression and the effect of the expansion size in patients with C9ORF72 expansions, we will be able to answer important questions regarding clinical trial design such as how many patients will be needed to see an effect on disease progression, whether there are geographic clusters of patients, and will establish an important historical control set that may be used in early clinical trials to determine whether there might be an effect on disease progression.
Can participants use Riluzole?
1. Males or females of any race aged 18 or older
2. Known positive C9ORF72 ALS status via CLIA-certified lab results.
3. Capable of providing informed consent and following study procedures. In the event that an individual lacks the ability to provide informed consent, informed consent may be sought from the individual's legal, surrogate representative.
4. Geographically accessible to the site.
1. Geographically inaccessible to the site
2. C9ORF72 ALS negative via CLIA-certified lab results
Cedars Sinai Medical Center
Los Angeles, California
University of Massachusetts
Massachusetts General Hospital
Washington University in St. Louis
Saint Louis, Missouri
Columbia University Medical Center
New York, New York
Sentara Health Care / Sentara Neurology Specialists
Virginia Beach, Virginia