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Anton R.F.,Medical University of South Carolina | Litten R.Z.,NIAAA | Falk D.E.,NIAAA | Palumbo J.M.,Johnson and Johnson Pharmaceutical Research and Development LLC | And 8 more authors.
Neuropsychopharmacology | Year: 2012

Although progress has been made in the treatment of alcohol use disorders, more effective treatments are needed. In the last 15 years, several medications have been approved for use in alcohol dependence but have only limited effectiveness and clinical acceptance. While academics have developed some standards for the performance of clinical trials for alcohol dependence, they vary considerably, in the type of populations to be studied, the length of trials, salient outcome measures, and data analyses to be used (especially in the treatment of missing data). This variability impedes the commercial development of medications to treat alcohol dependence. Using a model similar to that used to develop an expert consensus for medications to improve cognitive aspects of schizophrenia (MATRICS) and in the treatment of pain (IMMPACT), a workgroup has been formed under the auspices of ACNP, known as the ACTIVE (Alcohol Clinical Trials Initiative) group, to evaluate data from completed clinical trials to develop a consensus on key issues in the conduct of clinical trials in alcohol dependence. ACTIVE consists of academic experts, industry representatives, and staff from the Food and Drug Administration, the National Institute on Alcohol Abuse and Alcoholism, and the National Institute on Drug Abuse. This paper describes the rationale behind the effort, its history and organization, and initial key questions that have been identified as the primary focus of the workgroup. Future papers will focus on knowledge gained from the re-analysis of completed trials and provide consensus opinions regarding the performance of clinical trials that might be undertaken in the future. © 2012 American College of Neuropsychopharmacology. All rights reserved. Source

Bartus R.T.,Ceregene | Bartus R.T.,RTBioconsultants Inc. | Weinberg M.S.,University of North Carolina at Chapel Hill | Samulski R.J.,University of North Carolina at Chapel Hill
Molecular Therapy | Year: 2014

Over the past decade, nine gene therapy clinical trials for Parkinson's disease (PD) have been initiated and completed. Starting with considerable optimism at the initiation of each trial, none of the programs has yet borne sufficiently robust clinical efficacy or found a clear path toward regulatory approval. Despite the immediately disappointing nature of the efficacy outcomes in these trials, the clinical data garnered from the individual studies nonetheless represent tangible and significant progress for the gene therapy field. Collectively, the clinical trials demonstrate that we have overcome the major safety hurdles previously suppressing central nervous system (CNS) gene therapy, for none produced any evidence of untoward risk or harm after administration of various vector-delivery systems. More importantly, these studies also demonstrated controlled, highly persistent generation of biologically active proteins targeted to structures deep in the human brain. Therefore, a renewed, focused emphasis must be placed on advancing clinical efficacy by improving clinical trial design, patient selection and outcome measures, developing more predictive animal models to support clinical testing, carefully performing retrospective analyses, and most importantly moving forward - beyond our past limits. © The American Society of Gene & Cell Therapy. Source

Kordower J.H.,Rush University Medical Center | Olanow C.W.,Mount Sinai School of Medicine | Dodiya H.B.,Rush University Medical Center | Chu Y.,Rush University Medical Center | And 4 more authors.
Brain | Year: 2013

The pace of nigrostriatal degeneration, both with regards to striatal denervation and loss of melanin and tyrosine hydroxylase-positive neurons, is poorly understood especially early in the Parkinson's disease process. This study investigated the extent of nigrostriatal degeneration in patients with Parkinson's disease at different disease durations from time of diagnosis. Brains of patients with Parkinson's disease (n = 28) with post-diagnostic intervals of 1-27 years and normal elderly control subjects (n = 9) were examined. Sections of the post-commissural putamen and substantia nigra pars compacta were processed for tyrosine hydroxylase and dopamine transporter immunohistochemistry. The post-commissural putamen was selected due to tissue availability and the fact that dopamine loss in this region is associated with motor disability in Parkinson's disease. Quantitative assessments of putaminal dopaminergic fibre density and stereological estimates of the number of melanin-containing and tyrosine hydroxylase-immunoreactive neurons in the substantia nigra pars compacta (both in total and in subregions) were performed by blinded investigators in cases where suitable material was available (n = 17). Dopaminergic markers in the dorsal putamen showed a modest loss at 1 year after diagnosis in the single case available for study. There was variable (moderate to marked) loss, at 3 years. At 4 years post-diagnosis and thereafter, there was virtually complete loss of staining in the dorsal putamen with only an occasional abnormal dopaminergic fibre detected. In the substantia nigra pars compacta, there was a 50-90% loss of tyrosine hydroxylase-positive neurons from the earliest time points studied with only marginal additional loss thereafter. There was only a ~10% loss of melanized neurons in the one case evaluated 1 year post-diagnosis, and variable (30 to 60%) loss during the first several years post-diagnosis with more gradual and subtle loss in the second decade. At all time points, there were more melanin-containing than tyrosine hydroxylase-positive cells. Loss of dopaminergic markers in the dorsal putamen occurs rapidly and is virtually complete by 4 years post-diagnosis. Loss of melanized nigral neurons lags behind the loss of dopamine markers. These findings have important implications for understanding the nature of Parkinson's disease neurodegeneration and for studies of putative neuroprotective/ restorative therapies. © The Author (2013). Source

A specific clinical protocol for use toward therapy of defective, diseased and damaged neurons in the mammalian brain, of particular usefulness for treatment of neurodegenerative conditions such as Parkinsons disease. The protocol is practiced by directly delivering a definite concentration of a nerve growth factor via delivery of the protein, an expression vector operably encoding the nerve growth factor, or grafting a donor cell containing such an expression vector into the substantia nigra and preferably also the striatum. The method stimulates growth of targeted neurons, and reversal of functional deficits associated with the neurodegenerative disease being treated.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 99.75K | Year: 2002

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common form of dementia occurring in mid- to late-life. The prevalence of AD and associated health-care costs are expected to increase in the future, due to shifts in life-expectancy and demographics. Gene therapy may provide a treatment for AD. It has been demonstrated that ex vivo nerve growth factor (NGF) gene transfer can prevent neuronal death and reverse decline of cholinergic neurons associated with aging. These findings have led to the first clinical trial of gene therapy to treat an age-related neurodegenerative disorder. However, ex vivo gene delivery may not be practical for wide-scale commercial application. In vivo gene therapy, where vectors are directly injected into the brain, is a more feasible approach. This project will determine whether regulatable in vivo gene transfer can deliver therapeutic molecules to the brain in a safe and effective manner. In addition, the efficacy of regulatable in vivo NGF delivery to reduce neuronal degeneration and ameliorate cognitive decline will be tested in rodent models relevant to AD. Results from this project will support an IND application for regulatable in vivo gene therapy for AD. Hopefully, successful results will lead to eventual commercialization of this process as a therapeutic for AD.

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