Defining Clinical Characteristics in C9ORF72 ALS Patients

Full Study Summary:

Individuals diagnosed with ALS, who are confirmed to carry the Chromosome 9 Open Reading Frame 72 (C9ORF72) gene mutation by CLIA-certified lab results, are eligible for enrollment. Researchers want to understand the natural history of C9ORF72 related ALS in terms of measures of rate of progression as well as understanding how the size of the hexanucleotide repeat expansion influences disease parameters. The investigators hope that the intense study of patients with the C9ORF72 mutation will ultimately help us develop treatments for this common form of ALS.

Objectives:
-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)

• More Information

  Design:
  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.

• Eligibility Criteria

  Gender:

  Female, Male

  Minimum Age:

  18

  Maximum Age:

  N/A

  Time since Symptom Onset:

  N/A

  Time since Diagnosis:

  N/A

  Can participants use Riluzole?

  Yes

  
  

  Inclusion:
  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.
  
  Exclusion:
  1. Geographically inaccessible to the site
  2. C9ORF72 ALS negative via CLIA-certified lab results

• Site Contact Information

  Cedars Sinai Medical Center
  (Ashley) Katherine A. Fetterman / .(JavaScript must be enabled to view this email address) / 127 S. San Vicente Blvd. Advanced Health Sciences Pavilion
  Los Angeles, California 90048
  United States

  Johns Hopkins
  Kristen Riley / .(JavaScript must be enabled to view this email address) / ALS Clinic, Department of Neurology
  Baltimore, Maryland 21287
  United States

  Massachusetts General Hospital
  Tiina Xu / .(JavaScript must be enabled to view this email address) / 617-643-7428
  15 Parkman Street
  Boston, Massachusetts 02114
  United States

  University of Massachusetts
  Diane McKenna-Yasek / .(JavaScript must be enabled to view this email address) / 55 Lake Ave. North
  Amherst, Massachusetts 01003
  United States

  Washington University in St. Louis
  St. Louis, Missouri 63110
  United States

  Columbia University Medical Center
  New York, New York 10032
  United States

  Sentara Health Care / Sentara Neurology Specialists
  Lisa Richardson / .(JavaScript must be enabled to view this email address) / 1950 Glenn Mitchell Dr.
  Virginia Beach, Virginia 23456
  United States

  University Medical Center Utrecht
  Balint de Vries / .(JavaScript must be enabled to view this email address) / Department of Neurology
  Utrecht, 3508
  Netherlands