Summaries of 2013 HDSA- funded HD Human Biology Projects

 

  • Dr. Tanya Garcia, Assistant Professor, Texas A&M Health Science Center

Title:  Improved Definition and Prediction of Huntington’s disease motor-onset using advanced statistical models.

A vital area of clinical and statistical research that we will address is objectively defining disease-onset, and identifying salient biological markers that can track disease progression and predict when the disease starts.  Such information will help to improve our understanding of HD, evaluate potential therapies, and provide appropriate genetic counseling to patients and their family members.  Ongoing observational studies are finding promising biological markers, but no statistical model exists that comprehensively assesses the relationship between these markers and HD.  To fill this gap, we will develop novel and advanced statistical models.  The models will include (i) personalized motor-sign decline curves, and (ii) patient-specific factors such as genetic features, brain imaging measures, and cognitive performance. Modeling the dynamic worsening of motor-signs provides a new way to determine optimal treatment-intervention time periods, and even predict the likelihood of being diagnosed with HD in future time periods. Using modern statistical techniques, we will assess patient-specific markers so as to discover their usefulness in predicting HD motor-diagnosis. Our models will thus advance the fundamental understanding of HD, and outperform existing models in the clinical literature which only use genetic factors that determine whether, but not when the disease will begin.

 

  • Dr. Jun Hua, Postdoctoral Research Associate, Kennedy Krieger Institute

Title:  Functional and Neurovascular biomarkers for HD using MRI at 7T.

Reliable HD markers for disease progression monitoring and potential treatment assessment in the clinic, especially those present in the early stages of the disease, are of the utmost importance to the HD community. Magnetic resonance imaging (MRI) is a non-invasive, repeatable and versatile imaging technique that is capable of measuring a number of essential physiological parameters in the human brain. We will perform functional and neurovascular measurements using novel MRI techniques at ultrahigh field strength (7T) with enhanced sensitivity in prodromal (pre-symptomatic) and early affected HD patients and age-matched healthy controls. We will evaluate the suitability of the neurovascular readouts as imaging biomarkers in the early stages of HD. These studies will refine our understanding of functional and neurovascular abnormalities in prodromal and early HD populations.  Furthermore, these parameters are expected to be important measures for tracking disease progression and assessing efficacy of huntingtin lowering strategies in the clinic.

 

  • Dr. Robert Boggio, Senior Research Scientist, IRBM Promidis, Pomezia, Italy

Title:  Development of a novel, ultra sensitive bioassay for quantification of full-length mutant huntingtin in patient body fluids and analysis of different forms of huntingtin during disease progression.

The long preclinical and clinical phases of Huntington’s disease provide opportunities of early therapeutic interventions for disease-modifying therapies. A major obstacle to achieving this goal is the lack of quantitative, robust and reliable biomarkers for use in primary diagnosis, monitoring disease progression, patient stratification and evaluating efficacy of therapeutics in the clinic. Promidis is developing novel, sensitive, quantitative and robust immunoassay to enable quantification of mutant huntingtin protein levels in body fluids of patients, in particular cerebral spinal fluid (CSF) and plasma.  The aim of this project is to develop a novel huntingtin immunoassay specifically recognizing “full length mutant huntingtin” and to assess the levels of huntingtin during disease progression in human bio-fluids such as plasma, Peripheral Blood Mononuclear Cells (PBMCs) and CSF in patient samples provided by HDSA Centers of Excellence.

 

The development of ultra-sensitive assays for huntingtin can impact HD drug development on several levels: 1) Characterization of wild-type and mutant huntingtin  in clinically relevant samples will provide a baseline for huntingtin levels at different stages of disease and can support stratification of patient populations for clinical trials. 2) Quantitative detection of huntingtin in the CSF (as a surrogate of brain tissue) may provide evidence of treatment efficacy of huntingtin lowering therapies in the central nervous system. 3) Assays for quantification of wild-type and mutant huntingtin (including its different structural conformations and fragments) can be used to better understand the pathophysiology of HD and may lead to the identification of novel treatment targets.

 

  • Dr. Helen Budworth, Project Scientist, Lawrence Berkeley National Laboratory

Title: Metabolomic and gene expression analysis of fatty acid metabolism biomarkers of Huntington’s disease.

Since HD primarily affects the brain, monitoring the onset of symptoms and progression of the disease are extremely difficult.  Biological markers of disease that are present in the blood of patients would be of great utility in tracking the disease and also in testing how effective prospective therapies are.  Huntington’s disease is known to affect a patient’s metabolism.   For example, patients often experience dramatic weight loss despite increased caloric intake.  Therefore, we will use metabolic markers of disease that are present in the blood, such as fatty acids, to help us better track disease progression and test effectiveness of novel therapies.  This metabolic profile will be integrated with a gene expression profile from the same human HD blood to create a “metabolomic signature” for HD.

 

 

For more information about these fellowships please contact George Yohrling, Ph.D. at gyohrling@hdsa.org