RFI for Hungtington's Disease

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 Guidelines

Animal Models

1. 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.
2. 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)
3. 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.

Study Design

1. 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?
2. 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).
3. 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

1. 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.)
2. 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

1. Can a standardized protocol for measurement of CAG repeat length be applied to all studies? If so please provide protocol(s).
2. 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.
3. Can a standardized protocol for measurement of regional (e.g. striatal) brain volume be applied to all studies? If so please provide protocol.
4. 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.
5. Can a standardized protocol for measurement of huntingtin protein aggregates be applied to all studies? If so please provide protocol.
6. Can a standardized protocol for measurement of soluble huntingtin protein levels be applied to all studies? If so please provide the protocol.
7. Should other standardized protocols be considered? If so, please provide protocol.

General Information

1. 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?).
2. If you are a member of a particular advocacy or professional organization, please indicate the name of the organization.
3. Please indicate your main area of research interest.
4. Your name:
5. You email address:

Responses must be submitted electronically using this web form, 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.

Specific questions about this RFI should be directed to the contact listed below:

Margaret Sutherland, PhD
Program Director NINDS
Neurodegeneration Cluster
NSC Rm 2203
6001 Executive Blv.
Rockville, MD 20852
Phone (301) 496-5680
Fax (301) 480-1080
E-mail: sutherlandm@ninds.nih.gov

Last updated May 2, 2011