Steven M. Hersch - US grants

Transcriptional modulation is a promising approach to neuroprotection in Huntington's disease (HD). Our preliminary data indicates that transcriptionally active compounds like histone deacetylase (HDAC) inhibitors and aureolic acid antibiotics including mithramycin are among the most promising potential treatments available for HD. Phenylbutyrate is the HDAC inhibitor most developed for human use and with the best evidence for brain bioavailability. Mithramycin is used to treat Paget's disease, several types of malignancy, and hypercalcemia of malignancy and has the greatest efficacy in HD transgenic mice to date. The safety, tolerability, and efficacy of these agents is completely unknown in HD or other neuro-degenerative disorders. This project will test the feasibility of these medications in HD in large scale trials of efficacy. In aim one, we will examine whether phenylbutyrate is safe and tolerable for use in HD patients and whether it can improve any symptoms or biological markers of HD. A randomized double-blind placebo-controlled long-term safety and tolerability trial of phenylbutyrate in HD patients will be performed. We will assess the impact of phenylbutyrate treatment on: standardized clinical ratings of motor function, cognition, behavior, and functional capacity. We will also examine In vivo markers of neurodegeneration and transcriptional modulation including proton magnetic resonance spectroscopy for lactate and NAA, and peripheral markers of transcriptional modulation, histone acetylation, and phenylbutyrate activity. In aim two, we will examine whether mithramycin is safe and tolerable in long-term use in HD patients and whether it can improve any symptoms or biological markers of HD. Following an open label dose-ranging trial in which a maximally tolerated dose will be determined, subjects will be randomized into a double-blind placebo controlled safety and tolerability trial of mithramycin using intermittent infusion. We will also assess the impact of mithramycin treatment on; standardized clinical ratings of motor function, cognition, behavior, and functional capacity. We will examine In vivo markers of neurodegeneration including proton magnetic resonance spectroscopy of the basal ganglia and cortex, and peripheral markers of mithramycin activity.

Increasing evidence suggests that transcriptional dysregulation in Huntington's disease (HD) perturbs cellular function and compromises protective mechanisms ultimately leading to neuronal death. We have discovered novel interactions between the Huntington's disease protein (huntingtin) and transcriptional regulators and that medications acting on these regulators are highly effective in vitro and in vivo. These compounds have provided by far the largest single drug effects on ameliorating the phenotype of HD transgenic mice to date. This work has arisen from collaborations between our different laboratories and the proposed projects are designed to understand and explore the therapeutic potential in lid of these compounds, conventionally used as chemotherapeutic agents. Project 1 (Dimitri Krainc, PI) will explore the molecular interactions between hunting(in and transcriptional machinery and how these interactions might be affected by medications. Project II (Dr. Rajiv Ratan, PI) will study the downstream mechanisms of neuroprotection exerted by the medications as they relate to oxidative and apoptotic signaling. Project IlI (Dr. Robert Fen'ante, PI) will utilize HD transgenic mice to examine the effects of the chemotherapeutic medications on an in vivo HD phenotype and model Preclinical treatments that can be used in humans. Project IV (Dr. Jang-Ho Cha, PI) will examine the effects of huntingtin and the medications on chromatin remodeling in part utilizing cells and tissues from the other aims. Project V (Dr. Steven Hersch, PI) will perform early phase clinical trials of the medications in HD patients to pave the way for potential large-scale efficacy trials. The Gene Expression Core (Dr. Ruth Luthi-Carter, PI) will provide transcriptional readouts relevant for studies in each of the projects. Our program thus examines new classes of therapeutic agents for HD and encompasses molecular, genetic and cellular mechanisms, therapeutic discovery in transgenic mouse models, and translation to early clinical use in HD patients. The projects are highly integrated, each interacting extensively with all the others to contribute to the overall program. The three institutions involved insure that the program will exist in a highly supportive environment.

Huntington's disease; drug screening /evaluation; pharmacokinetics; creatine; human therapy evaluation; brain disorder chemotherapy; patient oriented research; human subject; clinical research;

DESCRIPTION (provided by applicant): Creatine Safety, Tolerability, and Efficacy in Huntington's Disease: CREST-E Cellular energy depletion and secondary oxidative injury are present early, even presymptomatically in Huntington's disease (HD), and play a significant role in its pathogenesis. Creatine is an inexpensive and well-tolerated nutritional supplement that is converted in the body to phosphocreatine that acts as a high- energy phosphate store for restoring ATP from ADP. We have extensively shown creatine to delay the onset and slow the progression of the pathologic phenotypes in HD transgenic and knockin mice in a dose dependent manner and to correct their ATP deficiencies in brain. In our double-blind placebo-controlled study of 8 grams per day of creatine for 16 weeks in HD patients, we demonstrated that creatine is safe and tolerable, increases serum and brain levels of creatine, and markedly reduces a serum biomarker of oxidative injury to DNA (8OH2'dG) suggesting beneficial effects on a fundamental mechanism of pathogenesis in HD. We subsequently completed an open-label dose escalation study pushing creatine up to 40 grams daily. We found 30 grams daily to be the optimal dose based on serum and brain bioavailability, reduced tolerability at higher doses, dose dependent suppression of 8OH2'dG levels, evidence for slowed cognitive decline, and a sustained reduction in brain atrophy as determined by MRI morphometry. We now propose a multi-center, randomized, double-blind, placebo-controlled trial of 30 grams daily creatine in 650 symptomatic individuals with HD recruited from about 42 Huntington Study Group (HSG) sites, treated for 36 months to test the hypothesis that it will slow the progressive functional decline of HD. Our secondary clinical aims are to assess safety and tolerability by analyzing clinical and laboratory adverse events and to assess the clinical impact of creatine on impressions of global health (CGI), quality of life measures (SF-36), and on motor, cognitive, psychiatric, behavioral, and functional symptoms of HD. We also propose collaborating with a program project on HD biomarkers to provide additional secondary endpoints and to exploit this first opportunity to assess and validate particular biomarkers in a large prospective HD clinical trial. We have conceived a design incorporating interim analyses of safety, futility, and efficacy that would provide early and repeated safety data and also permit early stopping or modification. A companion application is also submitted to support study coordination, data management, and biostatistical support under the auspices of the HSG (Bernard Ravina, principal investigator).

Analysis, Data; Bio-Informatics; Bioinformatics; Biologic Marker; Biological; Biological Markers; Biometrics; Biometry; Biometry and Biostatistics; Biostatistics; Clinical; Communication; Data; Data Analyses; Data Set; Dataset; ENPT; End Point; EndPointCode; Endpoints; Genomics; Grant; Heart; Human Resources; Image; Individual; Informatics; Lead; Manpower; Mining; Minings; Molecular Marker; Multicenter Trials; Pb element; Predictive Value; Problem Solving; Programs (PT); Programs [Publication Type]; Research Resources; Resource Informatics; Resources; Science of Statistics; Severities; Signature Molecule; Statistics; Symptoms; Validation; Validity and Reliability; Work; base; biomarker; data management; data mining; datamining; disease risk; disorder risk; heavy metal Pb; heavy metal lead; imaging; measurement of metabolism; member; metabolomics; personnel; programs; prospective; statistics; statistics/biometry

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Description (provided by applicant): The ultimate goal in Huntington's disease (HD) is to develop disease-modifying therapies that will prevent the onset of clinical symptoms in those individuals who are at risk and slow the progression of symptoms in those individuals already affected with symptoms. Several neuroprotective strategies have been successful in transgenic models and hold potential for use in human studies. However, HD encompasses disordered motor control, cognition and emotion and the clinical heterogeneity and the unpredictable course of disease makes clinical trials in HD challenging. Indeed, it is difficult to find a signal that can be seen as preliminary evidence for activity or efficacy that would help the prioritization of compounds for large phase III studies. Moreover, while symptoms can be modulated pharmacologically, a symptomatic response may not correspond to disease modification or predict slowing of the disease process. Clinical trials testing potential neuroprotective treatments in symptomatic HD are currently based on insensitive and unreliable clinical outcome measures. Slowing of functional decline over time, a relatively insensitive but reliable measure, is the sine qua non of affecting progression and this requires following 100s of subjects for 2 to 5 years to detect a significant change. Markers of disease activity ("state") are urgently needed to facilitate early and late phase clinical trials. The inherent difficulties of performing clinical trials in slowly progressive neurodegenerative diseases are all the more challenging in the genetically at-risk population. Cognitive and emotional symptoms likely start more than a decade prior to the onset of motor dysfunction, and may be the greatest source of morbidity for individuals prior to a clinical diagnosis of HD. Several studies are currently focusing on developing cognitive assessments to detect early changes in this population;however, cognitive measures are highly variable in control populations and assessments of progressive changes in cognitive performance may lack the necessary sensitivity for interventional trials. Phenoconversion, the point at which an individuals presumably transitions from a state of "health" to one of illness is not a single point, but rather, represents that accumulation of multiple biological insults over time. Since HD is fundamentally a progressive neurodegenerative disease, a method for monitoring that neurodegeneration would be ideal. MRI morphometry holds great promise as a surrogate for progressive neurodegeneration as it can be used to prospectively measure brain shrinkage. Most efforts in HD so far have been focused on the striatum because it is so severely affected. However, by the time symptoms are detectable about 50% of the striatum has already atrophied such that there is already a floor effect reducing the sensitivity of the measures. We have found that MRI measures of cortical neurodegeneration are detectable years before symptom onset, are progressive in both presymptomatic and symptomatic HD, and correlate with disabling symptoms. More importantly, we have also found that in symptomatic HD, they appear to be responsive to neuroprotective treatments, and thus may have the potential to provide far greater experimental power than clinical outcomes. The principal goals of Project 1 are to determine the sensitivity, reliability and responsiveness of the MRI measures to treatment. However, we will not only compare MRI measures to clinical symptoms, we will also help examine how metabolomic (Project 2) and genomic (Project 3) biomarkers of HD correlate to our neuroimaging measures.

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DESCRIPTION (provided by applicant): Huntington's disease (HD) is caused by the expression of the toxic mutant huntingtin protein (mthtt). Huntingtin is also the most salient molecular target for disease modifying therapy and indeed treatments that target its production, processing, or turnover are under development. Measurement of mthtt has broad potential as a biomarker. Its levels in blood could correlate to disease activity, severity, or stage;changes in its levels could provide a pharmacodynamic marker for therapies directly or indirectly modulating huntingtin. We recently helped develop a bioassay for measuring soluble mutant huntingtin levels utilizing time-resolved Forster Resonance Energy Transfer (trFRET). In preliminary studies applying the assay to blood in HD mice and human HD, it is highly sensitive for soluble mutant huntingtin in tissues and cellular fluids and detects it in blood from premanifest and manifest HD subjects. Through our NIH supported Program Project (P01- NS058792, Biomarkers for Huntington's Disease: accelerating the development of therapies), we are accumulating blood samples from large populations of controls, premanifest HD, manifest HD subjects, and HD subjects participating in therapeutic trials. In this application, we are seeking to optimize and validate this assay, ready it for GLP use, and assess how blood levels of huntingtin change with the development of symptoms, with progression of symptoms, and in response to a potential neuroprotective treatment. This accelerated review PAR is appropriate because it depends on subjects and blood samples from active single and multi-center clinical research studies supported by NIH including REVEAL-HD, PRECREST, PHAROS, and CREST-E observational and therapeutic trials. PUBLIC HEALTH RELEVANCE: Huntington's disease (HD) is caused by a genetic abnormality in the huntingtin protein. Many potential treatments for HD are in development that target huntingtin protein. To help monitor whether such treatments are working and whether they can slow down HD, we have developed the first blood test that measures levels of mutant huntingtin. We propose to optimize this test and to use it to help several large NIH supported studies meet their goals.

? DESCRIPTION (provided by applicant): Huntington's Disease (HD) is an inherited disease that results from expansion of a trinucleotide (CAG, cytosine/adenine/guanine) repeat that encodes a polyglutamine tract in the huntingtin protein. Psychiatric symptoms, including irritability and aggression, are common in HD patients. These are among the most distressing aspects of the disease. They have adverse effects on daily life and often result in institutionalization. Despite the frequent occurrence and severe consequences of irritability and aggression in HD, these symptoms have received little attention to date. Effective treatments are lacking and well-validated scales for measuring changes in these symptoms are not available. Faced with a significant unmet need, neurologists cannot currently determine whether new drug therapies might be useful in treating neuropsychiatric symptoms in HD. The Phase II clinical trial we propose in HD patients (n=108), A randomized, placebo controlled, double blind, multi-center study to assess the tolerability of SRX246 in irritable/aggressive subjects wit Huntington's Disease (HD), will allow us to rigorously evaluate the tolerability of a potential ne drug for the treatment of irritability and aggression. It will also provide additional safety data n the compound and explore various rating scales for the assessment of changes in these symptoms. Thus, we will obtain critical data that can be used to plan future Phase II or III clinicl trials of drugs that might blunt irritability and aggression in HD. The compound that we propose to test is SRX246, a first-in-class vasopressin 1a (V1a) receptor antagonist. SRX246 crosses the blood-brain barrier following oral administration, exhibits high affinity and selectivity for is target receptor, has a strong safety profile, is well-tolerated in healthy volunteers, and has excellent pharmacokinetics. Extensive preclinical pharmacology studies and an experimental medicine fMRI study in healthy volunteers have shown that SRX246 has CNS effects after oral administration and that it modulates brain circuits involved in responses to stimuli that elicit aggression/fear. These findings strongly suggest that SRX246 might have a beneficial effect on the irritability and aggression seen in a sizable proportion of HD patients. The proposed project will generate data needed to plan a future clinical trial that can rigorously test SRX246 for efficacy as a treatment for irritability and aggression.