Notice Number: NOT-NS-10-005
Key Dates
Release Date: December 9, 2009
Response Due By: January 29, 2010
Issued by
National Institute of Neurological Disorders and Stroke (NINDS) http://www.ninds.nih.gov
Purpose
This is a time-sensitive Request for Information (RFI) issued by the National Institute of Neurological Disorders and Stroke. The purpose of this RFI is to solicit recommendations on the best practices for animal studies on Huntington’s disease that could advance knowledge and validation of therapeutic targets for disease treatment. The Institute envisions that standardization of animal studies through identification of common protocols, outcome measures and breeding practices will enable comparison of results across studies and targets. Best practice guidelines should be inclusive of in vivo target manipulation through either genetic or pharmacological interventions. The responses to the RFI will be collected and evaluated by a group of Institute staff to assess how best to meet the needs of researchers in the field. Results of that evaluation will be made available to the public and will be part of a larger effort by NINDS to develop best practice guidelines for target discovery and validation for neurological diseases.
Background
Huntington’s disease is a rare neurodegenerative disorder, which like many neurodegenerative diseases, currently has no treatment options to modify disease progression. The gene for Huntington’s disease was discovered in 1993, and genetic testing can now identify individuals carrying the pathological expansion of the CAG repeat in exon1 of the gene, prior to the onset of motor symptoms. Knowledge of the genetic basis for the disease enabled the development of numerous animal models for Huntington’s disease and the discovery of multiple cellular pathways associated with disease pathogenesis. The field currently faces the challenge of determining effective criteria to identify the best targets for therapy development, taking into consideration the number of potential targets, the expense associated with preclinical drug development, and the limited patient population available for clinical trials.
This RFI is meant to solicit input from the extramural research community, scientific and medical organizations, Federal Agencies, and other interested parties well-versed in Huntington’s disease and the challenges facing therapeutic target identification and validation for this disease. Responses to this RFI will be reviewed by NINDS staff and will help inform and complement their assessment of best practice guidelines that will be utilized in the development of initiatives and review criteria involving standardized animal studies for Huntington’s disease therapeutic target validation. Following publication of the results of this RFI, and through ongoing interactions with the Huntington’s disease research community, it is anticipated that development of these guidelines will help to advance and transform the field overall. Best practice guidelines are not meant to limit the number of outcome measures studied, but rather to standardize a core set of outcome measures that can be applied to all studies focused on therapeutic target validation for Huntington’s disease. This RFI is for planning purposes only, and should not be construed as a solicitation for applications or proposals and/or as an obligation in any way on the part of the United States Federal Government.
Information Requested
The mission of NIH is to support biomedical discoveries that will improve health and save lives. To further the development of therapeutic target validation for Huntington’s disease, the NINDS would like input on the following questions:
Best Practice GuidelinesAnimal Models
- Are there animal models of Huntington’s disease that best represent the disease phenotype seen in clinical practice? If so, please describe the model including genetic background, length of time to onset of disease, and the behavior and disease pathology relevant to human Huntington’s disease.
- In reporting results, what information should be required regarding the Huntington’s disease animal model used? (For example, reporting of commercial source or reference to original paper describing model, catalog number, strain background, average life expectancy, range of CAG repeat length across generations, differences in disease phenotype between males and females)
- Can breeding procedures and husbandry be standardized across studies, investigators and institutes? (For example, use of enriched cage environment, maintenance of HD mouse models through breeding with specific background strains). If breeding recommendations exist for specific Huntington’s disease models, please provide details.
- In the experimental design, should a Power analysis be a requirement in the determination of group sizes for each experiment? Should the assumptions made in the Power analysis be included when reporting data and conclusions from the study?
- Should studies be conducted in a blinded fashion, so that the person administering the tests and/or drugs is blinded to the genotypes and/or compounds administered? (Blinding to genotype is feasible at the beginning of a study prior to symptom onset).
- When pharmacologically manipulating a target, what calculations should the study design include? (For example, determination of plasma and target tissue exposure, determination of maximum tolerated dose (MTD) for each genotyped studied, verifying compound activity at the target (e.g. pharmacodynamic data), etc)
Outcome measures
- What common outcome measures could be applied to target validation studies regardless of HD rodent model chosen? (For example, measurement of weight, rotarod performance, change in regional (e.g. striatal) brain volume, life expectancy, etc.)
- What common drug characteristics/properties should be reported when pharmacological manipulation of the target is used? (For example, MTD, target tissue exposure, route of administration, formulation details for the compound, pharmacodynamic data (on target activity),timing of intervention, etc)
Standardized protocols
- Can a standardized protocol for measurement of CAG repeat length be applied to all studies? If so please provide protocol(s).
- Can a standardized protocol for measurement of motor function (such as rotarod, open field or grip strength) be applied to all studies? If so, please provide protocol(s), and any known variation in background strain response.
- Can a standardized protocol for measurement of regional (e.g. striatal) brain volume be applied to all studies? If so please provide protocol.
- Can a standardized protocol for measurement of medium spiny neuron loss be applied to all studies (applicable to Huntington’s disease models demonstrating neuronal loss)? Is so please provide protocol.
- Can a standardized protocol for measurement of huntingtin protein aggregates be applied to all studies? If so please provide protocol.
- Can a standardized protocol for measurement of soluble huntingtin protein levels be applied to all studies? If so please provide the protocol.
- Should other standardized protocols be considered? If so, please provide protocol.
- Please identify the nature of your interest in the area of databases and repositories (i.e. are you a biomedical or clinical researcher, a member of an advocacy or community group, or other?).
- If you are a member of a particular advocacy or professional organization, please indicate the name of the organization.
- Please indicate your main area of research interest.
- Your name.
- Your email address.
Responses
Responses must be submitted electronically using the web-based format (http://www.ninds.nih.gov/funding/areas/neurodegeneration/RFI-for-Hungtington-Disease.htm), and will be accepted through January 29, 2010. Replies to individual questions are optional, and the site will permit anonymous responses. The information provided will be analyzed and may appear in various reports.
Inquiries
Specific questions about this RFI should be directed to the contact listed below:
Margaret Sutherland, PhD
Program Director, Neurodegeneration
NINDS / NIH
6001 Executive Blvd., Rm 2222
Bethesda, MD 20892
Phone: 301-496-5680
Fax: 301-480-1080
E-mail: sutherlandm@ninds.nih.gov
and Human Services (HHS)
