Translating Antisense Technology into a Treatment for Huntington's Disease.

Advances in molecular biology and genetics have been used to elucidate the fundamental genetic mechanisms underlying central nervous system (CNS) diseases, yet disease-modifying therapies are currently unavailable for most CNS conditions. Antisense oligonucleotides (ASOs) are synthetic single stranded chains of nucleic acids that bind to a specific sequence on ribonucleic acid (RNA) and regulate posttranscriptional gene expression. Decreased gene expression with ASOs might be able to reduce production of the disease-causing protein underlying dominantly inherited neurodegenerative disorders. Huntington's disease (HD), which is caused by a CAG repeat expansion in exon 1 of the huntingtin (HTT) gene and leads to the pathogenic expansion of a polyglutamine (PolyQ ) tract in the N terminus of the huntingtin protein (Htt), is a prime candidate for ASO therapy.State-of-the art translational science techniques can be applied to the development of an ASO targeting HTT RNA, allowing for a data-driven, stepwise progression through the drug development process. A deep and wide-ranging understanding of the basic, preclinical, clinical, and epidemiologic components of drug development will improve the likelihood of success. This includes characterizing the natural history of the disease, including evolution of biomarkers indexing the underlying pathology; using predictive preclinical models to assess the putative gain-of-function of mutant Htt protein and any loss-of-function of the wild-type protein; characterizing toxicokinetic and pharmacodynamic effects of ASOs in predictive animal models; developing sensitive and reliable biomarkers to monitor target engagement and effects on pathology that translate from animal models to patients with HD; establishing a drug delivery method that ensures reliable distribution to relevant CNS tissue; and designing clinical trials that move expeditiously from proof of concept to proof of efficacy. This review focuses on the translational science techniques that allow for efficient and informed development of an ASO for the treatment of HD.

Neurological signs in relation to type of cerebrovascular disease in vascular dementia.

BACKGROUND AND PURPOSE: The aim of this study was to describe the prevalence of a number of neurological signs in a large population of patients with vascular dementia (VaD) and to compare the relative frequency of specific neurological signs dependent on type of cerebrovascular disease. METHODS: Seven hundred six patients with VaD (NINDS-AIREN) were included from a large multicenter clinical trial (registration number NCT00099216). At baseline neurological examination, the presence of 16 neurological signs was assessed. Based on MRI, patients were classified as having large vessel VaD (18%; large territorial or strategical infarcts on MRI), small vessel VaD (74%; white matter hyperintensities [WMH], multiple lacunes, bilateral thalamic lesions on MRI), or a combination of both (8%). RESULTS: A median number of 4.5 signs per patient was presented (maximum 16). Reflex asymmetry was the most prevalent symptom (49%), hemianopia was most seldom presented (10%). Measures of small vessel disease were associated with an increased prevalence of dysarthria, dysphagia, parkinsonian gait disorder, rigidity, and hypokinesia and as well to hemimotor dysfunction. By contrast, in the presence of a cerebral infarct, aphasia, hemianopia, hemimotor dysfunction, hemisensory dysfunction, reflex asymmetry, and hemiplegic gait disorder were more often observed. CONCLUSIONS: The specific neurological signs demonstrated by patients with VaD differ according to type of imaged cerebrovascular disease. Even in people who meet restrictive VaD criteria, small vessel disease is often seen with more subtle signs, including extrapyramidal signs, whereas large vessel disease is more often related to lateralized sensorimotor changes and aphasia.

A placebo-controlled study of sertraline in the treatment of outpatients with seasonal affective disorder.

RATIONALE: Seasonal affective disorder (SAD) is a relatively common cyclical depressive illness characterized by seasonal depressions during winter. The disorder is commonly responsive to light therapy, but antidepressant drug efficacy has not been definitely established. Serotonin selective re-uptake inhibitors are potentially efficacious treatments for SAD. OBJECTIVES: The objective of this study was to evaluate the efficacy, tolerability and safety of sertraline treatment for SAD. METHODS: One hundred and eighty seven outpatients with seasonal pattern recurrent winter depression (DSM-III-R defined) and a minimum 29-item Hamilton depression scale (SIGH-SAD version) score of 22 were randomized to 8 weeks treatment with either sertraline or placebo in a double-blind, multi-country, multi-center, parallel-group, flexible dose (50-200 mg once daily) study. Efficacy was investigated using physician and patient-rated scales measuring depression, anxiety and symptoms characteristic of seasonal affective disorder. RESULTS: Sertraline produced a significantly greater response than placebo at endpoint as measured by changes in the 29-item and 21-item Hamilton depression scales, the clinical global impression (CGI) severity scale, the Hamilton anxiety scale, and the hospital anxiety and depression scale. The proportion of sertraline-treated subjects achieving a response on the CGI improvement rating (ratings of 1 or 2) at endpoint (last observation carried forward) was significantly greater than that of the placebo group. Overall sertraline was well tolerated with the most frequent placebo adjusted adverse events, being nausea, diarrhea, insomnia and dry mouth. Adverse events were mostly mild to moderate and transient. CONCLUSIONS: Sertraline pharmacotherapy has been demonstrated to be an effective and well-tolerated therapy for out patients with SAD. As such, sertraline offers an important pharmacological option in the clinical management of this condition.