Biomarkers to Enable the Development of Neuroprotective Therapies for Huntington’s Disease

The ultimate therapeutic goal for Huntington’s disease (HD) is to develop disease-modifying therapies able to (1) delay or prevent clinical illness in those who are at genetic risk; and (2) slow the progression and permit some recovery in those who have manifest clinical illness. Rapidly advancing basic and translational research has identified numerous potential targets for neuroprotection. Some targets may be generically neuroprotective and relevant for a variety of neurological insults, whereas others may be more selective for HD. None yet stand out sufficiently to enable concentrating efforts on just a few of these, with the exception of the huntingtin protein itself, which does not have a conventional pharmacology with which to work. Each potential target for HD is approached by multiple strategies, primarily small molecules but also by RNA interference, antisense, gene therapy, or cellular therapy. These strategies start with families of compounds or biologicals. Medicinal chemistry, pharmacology, and biological assays winnow these families down by ordering them in terms of potency, favorable pharmacological properties, toxicity, teratogenicity, off-target effects, bioavailability, central nervous system (CNS) penetration, and so on. However, as helpful as , , and models are, they provide only an incomplete understanding of target and treatment properties and disease modifying potential. Indeed, for neurological disease, there is much more history with compounds working in cellular and in animal models and subsequently not working in human disease than there is of models successfully predicting effective therapies (e.g., in stroke or amyotrophic lateral sclerosis [ALS]). There may be more hope for HD because of its dominant genetic nature and the greater relevance of the models. In the end, target validation and prioritization, as well as discerning the potential risks and benefits of individual compounds, will have to come from clinical experiments in human subjects, particularly those with premanifest or manifest HD. However, the capacity to conduct clinical trials is not close to keeping up with the numbers of compounds for which there are already some rationale and likelihood of safety and tolerability—and the gap is quickly widening. There are many reasons for this gap, and these mostly come down to limited resources of time, effort, money, investigators, and subjects. At-risk and affected individuals inexorably progressing toward clinical disease or through increasing disability provide an underlying urgency not only to do more testing of potential therapies but also to improve the process. In this context, the development and use of biomarkers in clinical trials for HD will have profound potential to increase the rate and accuracy with which treatments and by implication their targets, can be assessed. Thus, there is a great need for the development of biomarkers for HD which are useful in early- and late-phase clinical trials. Although finding a dose range for a treatment in HD patients and testing for safety and tolerability are straightforward, it can be difficult to find signals that indicate that the desired pharmacological activity is occurring and is optimal, or that compare one agent with another. A further difficulty has been the lack of clinical or other outcome measures able to provide preliminary evidence of efficacy for neuroprotection that would help in the prioritization of compounds for large Phase III studies. Indeed, without such signals it is also very difficult to stop development of a compound short of its failure in a large-scale study. Moreover, in premanifest HD, there may be no clinical measures to provide useful assessment of efficacy. In manifest HD, clinical symptoms progress slowly and are extremely variable, and their modulation does not intrinsically correspond to disease modification. Thus, although modulation of symptoms may point to a symptomatic benefit, improving symptoms does not necessarily predict slowing the disease process. For example, haloperidol can suppress chorea yet hasten death by worsening dysphagia. Biomarkers that can indicate whether a potential disease-modifying therapy interacts with its target or affects disease processes (state) or progression in smaller, shorter early-phase trials are urgently needed to help decision making about therapeutic development, such that not every candidate has to be tested in large futility or Phase III studies Biomarkers able to provide supportive or even primary evidence for efficacy would also facilitate late-phase trials. Indeed, the National Institutes of Health (NIH) Neuroscience Blueprint has made biomarker development for neurodegenerative diseases a high priority (http://neuroscienceblueprint.nih.gov). However, although biomarker research is being embraced, there remains some confusion about biomarkers. This chapter will provide a framework for considering the development, assessment, and use of different types of biomarkers that could facilitate the development of neuroprotective therapies for HD.