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Bartus R.T.,Ceregene | Herzog C.D.,Ceregene | Chu Y.,Rush University Medical Center | Wilson A.,Ceregene | And 5 more authors.
Movement Disorders | Year: 2011

Background: AAV2-neurturin (CERE-120) is designed to deliver the neurotrophic-factor, neurturin, to the striatum to restore and protect degenerating nigrostriatal neurons in Parkinson's disease (PD). A common hypothesis is that following expression in the striatum, neurotrophic-factors like neurturin (NRTN) will be transported from degenerating terminals to their cell bodies in the substantia nigra pars compacta (SNc). Methods: We tested this concept using immunohistochemistry, comparing the bioactivity of AAV2-neurturin in brains of PD patients versus those of nonhuman primates similarly treated. Results: NRTN-immunostaining in the targeted striatum was seen in all PD cases (mean putaminal coverage: ∼15% by volume); comparable expression was observed in young, aged, and parkinsonian monkeys. In the SNc cell bodies, however, only rare evidence of neurturin was seen in PD, while ample evidence of intense nigral-NRTN was observed in all monkeys. NRTN-expression was associated with occasional, sparse TH-induction in the striatum of PD, but nothing apparent in the SNc. In primates, NRTN produced robust TH-induction throughout the nigrostriatal neurons. Discussion: These data provide the first evidence that gene therapy can increase expression of a neurotrophic-factor deep in the PD brain and that clear but modest enhancement of degenerating neurons can be induced. They also provide important insight regarding deficiencies in the status of nigrostriatal neurons in advanced PD, suggesting that serious axon-transport deficits reduced the bioactivity of AAV2-NRTN by limiting the protein exposed to the cell body. Thus, future efforts using neurotrophic-factors to treat neurodegenerative diseases will need to target both the terminal fields and the cell bodies of degenerating neurons to assure maximal benefit is achieved. © 2010 Movement Disorder Society.


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.


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).


News Article | November 30, 2016
Site: globenewswire.com

SAN DIEGO, Nov. 30, 2016 (GLOBE NEWSWIRE) -- Otonomy, Inc. (NASDAQ:OTIC), a biopharmaceutical company focused on the development and commercialization of innovative therapeutics for diseases and disorders of the ear, today announced the appointment of Kathie M. Bishop, Ph.D., as chief scientific officer. Dr. Bishop is a neuroscientist with more than fifteen years of pharmaceutical development experience. At Ionis Pharmaceuticals, she led translational research and development of programs in the neurology franchise including SPINRAZAä (nusinersen), a treatment for patients with spinal muscular atrophy that is awaiting regulatory approval. "Kathie is a great fit to lead our development efforts given her neuroscience background and successful track record managing significant development programs from inception through to registration," said David A. Weber, Ph.D., president and CEO of Otonomy. "Furthermore, her extensive experience with local drug delivery in the nusinersen as well as other programs is highly relevant to our focus in developing locally administered therapeutics for otic disorders." Dr. Bishop succeeds Carl LeBel, Ph.D., who had previously announced his retirement. She joins Otonomy from Tioga Pharmaceuticals where she served as chief scientific officer since 2015. Previously, she served in product development management roles at Ionis Pharmaceuticals including vice president, clinical development. At Ionis, she led translational research and development of a portfolio of programs in the neurology franchise which included clinical-stage products for the treatment of spinal muscular atrophy, myotonic dystrophy, and amytrophic lateral sclerosis and preclinical programs targeting various disorders including retinal degeneration. Prior to Ionis, she served in research and development leadership roles at Ceregene, a company focused on the development of gene therapy products for the treatment of neurodegenerative disorders and retinal diseases. Before joining Ceregene, she worked as a post-doctoral fellow in the Molecular Neurobiology Lab at the Salk Institute in La Jolla. Dr. Bishop obtained her Ph.D. in Neuroscience from the University of Alberta, a B.A. in Psychology from Simon Fraser University and a B.Sc. in Cell Biology and Genetics from the University of British Columbia. Otonomy is a biopharmaceutical company focused on the development and commercialization of innovative therapeutics for diseases and disorders of the ear. OTIPRIO® (ciprofloxacin otic suspension) is approved in the United States for use during tympanostomy tube placement surgery in pediatric patients, and commercial launch commenced in March 2016. OTO-104 is a steroid in development for the treatment of Ménière's disease and other severe balance and hearing disorders. Two Phase 3 trials in Ménière's disease patients are underway, with results expected during the second half of 2017. OTO-311 is an NMDA receptor antagonist for the treatment of tinnitus that is in a Phase 1 clinical safety trial. Otonomy’s proprietary formulation technology utilizes a thermosensitive gel and drug microparticles to enable single dose treatment by a physician. For additional information please visit www.otonomy.com. This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements generally relate to future events or future financial or operating performance of Otonomy. Forward-looking statements in this press release include, but are not limited to, the timing of results for the two OTO-104 Phase 3 clinical trials in Ménière's disease. Otonomy's expectations regarding these matters may not materialize, and actual results in future periods are subject to risks and uncertainties. Actual results may differ materially from those indicated by these forward-looking statements as a result of these risks and uncertainties, including but not limited to: Otonomy's limited operating history and its expectation that it will incur significant losses for the foreseeable future; Otonomy's ability to obtain additional financing; Otonomy's dependence on the commercial success of OTIPRIO and the regulatory success and advancement of additional product candidates, such as OTO-104 and OTO-311, and label expansion indications for OTIPRIO; the uncertainties inherent in the clinical drug development process, including, without limitation, Otonomy's ability to adequately demonstrate the safety and efficacy of its product candidates, the preclinical and clinical results for its product candidates, which may not support further development, and challenges related to patient enrollment in clinical trials; Otonomy's ability to obtain regulatory approval for its product candidates; side effects or adverse events associated with Otonomy's product candidates; competition in the biopharmaceutical industry; Otonomy's dependence on third parties to conduct preclinical studies and clinical trials; the timing and outcome of hospital pharmacy and therapeutics reviews and other facility reviews; the impact of coverage and reimbursement decisions by third-party payors on the pricing and market acceptance of OTIPRIO; Otonomy's dependence on third parties for the manufacture of OTIPRIO and product candidates; Otonomy's dependence on a small number of suppliers for raw materials; Otonomy's ability to protect its intellectual property related to OTIPRIO and its product candidates in the United States and throughout the world; expectations regarding potential market size, opportunity and growth; Otonomy's ability to manage operating expenses; implementation of Otonomy's business model and strategic plans for its business, products and technology; and other risks. Information regarding the foregoing and additional risks may be found in the section entitled "Risk Factors" in Otonomy's Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (the "SEC") on November 3, 2016, and Otonomy's future reports to be filed with the SEC. The forward-looking statements in this press release are based on information available to Otonomy as of the date hereof. Otonomy disclaims any obligation to update any forward-looking statements, except as required by law.


News Article | December 1, 2016
Site: www.newsmaker.com.au

There are different kinds of growth factors present in the human body. Some of the major growth factors include insulin-like growth factors, platelet-derived growth factors, epidermal growth factors, and nerve growth factor. Moreover, some cytokines, such as small proteins secreted by one cell to regulate the function of another cell, also act as growth factors. Growth factors are mainly used in the treatment of chronic diseases, such as anemia, renal disorders, cancer, etc. For instance, erythropoietin, which stimulates the growth of Red Blood Cells (RBCs), is used to treat anemia. Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) and Granulocyte Colony-Stimulating Factor (G-CSF) are involved in the stimulation of White Blood Cells (WBCs) in cancer patients. However, abnormal production of growth factors causes several diseases. For instance, vascular endothelial growth factor provokes endothelial cells to penetrate tumor in blood capillaries. The global growth factors market covers various blood growth factors and tissue growth factors. Blood growth factors include colony stimulating factors, erythropoietins, interferons, and interleukins. In terms of geography, North America dominates the global growth factors market. This is due to improved health care infrastructure and increasing prevalence of chronic diseases in the region. In addition, growing demand for recombinant growth factors has also propelled the growth of the market in North America. The U.S. represents the largest market for growth factors in North America, followed by Canada. In Europe, Germany, France, and the U.K. account for the major share of the growth factors market. The growth factors market in Asia is also expected to expand at a higher rate in the next five years. This is due to the rising awareness about therapeutic applications of growth factors in the treatment of chronic diseases in the region. In addition, increasing prevalence of chronic diseases and growing aging population are driving the expansion of the growth factors market in the region. Growing demographics and economies in developing countries, such as India and China, are expected to lead to the rise in the growth factors market in Asia. Moreover, India, China, and Japan, are expected to be the fastest growing markets for growth factors in the region. Increasing prevalence of chronic diseases and rising awareness about therapeutic applications of growth factors in treatment of various diseases are among the major driving factors for the global growth factors market. Also, increasing research in the field of synthetic blood growth factor has propelled the growth of the global growth factors market. Risk and complications associated with synthetic growth factors in treatment of diseases is a key restraint for the global growth factors market. In addition, the imposition of stringent regulations for the approval of synthetic growth factors inhibits the growth of the market. Rapid product launches and increasing number of mergers and acquisitions between growth factors manufacturing companies are some of the major trends observed in the market. The major companies operating in this market are Wockhardt Ltd., F. Hoffmann-La Roche AG, Alseres Pharmaceuticals, Inc., Bayer HealthCare Pharmaceuticals Inc., Amgen Inc., BioMimetic Therapeutics Inc., Ceregene, Inc., FibroGen, Inc., Novo Nordisk A/S, Johnson & Johnson Limited, Merck Serono International S.A., PeproTech Inc., NsGene A/S, Insmed Inc., Reliance GeneMedix Plc., and Lonza Group. Key geographies evaluated in this report are:


Bartus R.T.,Ceregene | Baumann T.L.,Ceregene | Siffert J.,Ceregene | Siffert J.,Avanir Pharmaceuticals | And 10 more authors.
Neurology | Year: 2013

Objective: In an effort to account for deficiencies in axonal transport that limit the effectiveness of neurotrophic factors, this study tested the safety and feasibility, in moderately advanced Parkinson disease (PD), of bilaterally administering the gene therapy vector AAV2-neurturin (CERE-120) to the putamen plus substantia nigra (SN, a relatively small structure deep within the midbrain, in proximity to critical neuronal and vascular structures). Methods: After planning and minimizing risks of stereotactically targeting the SN, an open-label, dose-escalation safety trial was initiated in 6 subjects with PD who received bilateral stereotactic injections of CERE-120 into the SN and putamen. Results: Two-year safety data for all subjects suggest the procedures were well-tolerated, with no serious adverse events. All adverse events and complications were expected for patients with PD undergoing stereotactic brain surgery. Conclusions: Bilateral stereotactic administration of CERE-120 to the SN plus putamen in PD is feasible and this evaluation provides initial empirical support that it is safe and well-tolerated. Classification of evidence: This study provides Class IV evidence that bilateral neurturin gene delivery (CERE-120) to the SN plus putamen in patients with moderately advanced PD is feasible and safe. © 2013 American Academy of Neurology.


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.


Bartus R.T.,Ceregene | Baumann T.L.,Ceregene | Brown L.,Ceregene | Kruegel B.R.,Ceregene | And 2 more authors.
Neurobiology of Aging | Year: 2013

Neurotrophic factors have long shown promise as potential therapies for age-related neurodegenerative diseases. However, 20 years of largely disappointing clinical results have underscored the difficulties involved with safely and effectively delivering these proteins to targeted sites within the central nervous system. Recent progress establishes that gene transfer can now likely overcome the delivery issues plaguing the translation of neurotrophic factors. This may be best exemplified by adeno-associated virus serotype-2-neurturin (CERE-120), a viral-vector construct designed to deliver the neurotrophic factor, neurturin to degenerating nigrostriatal neurons in Parkinson's disease. Eighty Parkinson's subjects have been dosed with CERE-120 (some 7+ years ago), with long-term, targeted neurturin expression confirmed and no serious safety issues identified. A double-blind, controlled Phase 2a trial established clinical "proof-of-concept" via 19 of the 24 prescribed efficacy end points favoring CERE-120 at the 12-month protocol-prescribed time point and all but one favoring CERE-120 at the 18-month secondary time point (p = 0.007 and 0.001, respectively). Moreover, clinically meaningful benefit was seen with CERE-120 on several specific protocol-prescribed, pairwise, blinded, motor, and quality-of-life end points at 12 months, and an even greater number of end points at 18 months. Because the trial failed to meet the primary end point (Unified Parkinson's Disease Rating Scale motor-off, measured at 12 months), a revised multicenter Phase 1/2b protocol was designed to enhance the neurotrophic effects of CERE-120, using insight gained from the Phase 2a trial. This review summarizes the development of CERE-120 from its inception through establishing "clinical proof-of-concept" and beyond. The translational obstacles and issues confronted, and the strategies applied, are reviewed. This information should be informative to investigators interested in translational research and development for age-related and other neurodegenerative diseases. © 2013.


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.


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