Our group completed the natural history study of premanifest Huntington disease (HD) entitled Predict-HD which evaluated over 1400 research volunteers who were healthy but had undergone the predictive test for the gene that causes HD. Findings revealed that signs and symptoms of HD were evident up to 15 years before the traditional diagnosis of HD was given in the clinic. From these data we were able to develop models of prognosis, disease progression and prediction of HD onset. Disease-modifying clinical trials are currently underway to slow the progression, or delay the onset, of HD. More recently, a collaborative group published an assay to measure the amount of mutant huntingtin protein in the cerebral spinal fluid of HD participants. Questions of central importance to the success of this measure for clinical trials require investigation: (1) how reliable is the measure in the same person when repeated (intra-subject test-retest reliability); (2) how reliable is the measure in the same person when analyzed by two different labs (inter-lab reliability); (3) does the measure reflect disease symptoms (content validity); (4) does the measure predict meaningful disease outcomes (prognostic validity); (5) does the measure track disease progression or severity; and (6) how many (and what stage of HD) research subjects do we need to know with confidence that an intervention is working (i.e., delaying onset/slowing progression)? The proposed research study will address all of these limitations to more effectively test new experimental interventions such as gene therapies and new drugs. Findings will immediately inform how the field should best design preventive clinical trials for HD.
This project addresses key challenges to the design of clinical trials to prevent the onset of Huntington's disease (HD). The project will provide necessary psychometric data for a measure of mutant huntingtin protein in the cerebral spinal fluid to address questions of central importance to the success of this measure for premanifest clinical trials such as: (1) How reliable the measure is in the same person when repeated over time; (2) how reliable the measure is in the same person when analyzed by two different labs/sites; (3) how well the measure reflects disease symptoms; (4) how well the measure predicts meaningful disease outcomes; (5) how well the measure tracks disease progression or severity; and (6) how many research subjects are required to test that an intervention is delaying/slowing the onset of HD? Answers to these questions will better position the field to more effectively test new interventions to prevent HD such as gene therapies and new drugs.