Advancing Gene Targeted Therapies For Central Nervous System Disorders

On April 23 and 24, 2019 the Forum on Neuroscience and Nervous System Disorders convened a workshop titled "Advancing Gene-Targeted Therapies for Central Nervous System Disorders" in Washington, DC. This public workshop brought together experts and key stakeholders from academia, government, industry, philanthropic foundations, and disease/patient-focused nonprofit organizations to explore approaches for advancing the development of gene-targeted therapies for central nervous system (CNS) disorders, and implications of developing these therapies. Participants explored lessons learned from both successful and unsuccessful clinical development programs; new knowledge about the genetic underpinnings of brain disorders; the current status and future potential of gene-targeted therapies for CNS disorders; challenges and potential solutions for translating preclinical findings to approved therapies; and patient and caregiver perspectives. They also discussed what will be needed to develop these therapies for common disorders such as Alzheimer's and Parkinson's disease, as well as neuropsychiatric and neurodevelopmental disorders such as schizophrenia and autism. The workshop included approaches that target both DNA and RNA, as well as gene products using viral vectors, antisense oligonucleotides, and RNA interference. This publication summarizes the presentations and discussion of the workshop.

Handbook of Innovations in CNS Regenerative Medicine provides a comprehensive overview of the CNS regenerative medicine field. The book describes the basic biology and anatomy of the CNS and how injury and disease affect its balance and the limitations of the present therapies used in the clinics. It also introduces recent trends in different fields of CNS regenerative medicine, including cell transplantation, bio and neuro-engineering, molecular/pharmacotherapy therapies and enabling technologies. Finally, the book presents successful cases of translation of basic research to first-in-human trials and the steps needed to follow this path. Areas such as cell transplantation approaches, bio and neuro-engineering, molecular/pharmacotherapy therapies and enabling technologies are key in regenerative medicine are covered in the book, along with regulatory and ethical issues. Describes the basic biology and anatomy of the CNS and how injury and disease affect its balance Discusses the limitations of present therapies used in the clinics Introduces the recent trends in different fields of CNS regenerative medicine, including cell transplantation, bio and neuro-engineering, molecular/pharmacotherapy therapies, and enabling technologies Presents successful cases of translation of basic research to first-in-human trials, along with the steps needed to follow this path

Compared with other disease areas, central nervous system (CNS) disorders have had the highest failure rate for new compounds in advanced clinical trials. Most CNS drugs fail because of efficacy, and the core issue underlying these problems is a poor understanding of disease biology. Concern about the poor productivity in neuroscience drug development has gained intensity over the past decade, amplified by a retraction in investment from the pharmaceutical industry. This retreat by industry has been fueled by the high failure rate of compounds in advanced clinical trials for nervous system disorders. In response to the de-emphasis of CNS disorders in therapeutic development relative to other disease areas such as cancer, metabolism, and autoimmunity, the National Academies of Sciences, Engineering, and Medicine initiated a series of workshops in 2012 to address the challenges that have slowed drug development for nervous system disorders. Motivated by the notion that advances in genetics and other new technologies are beginning to bring forth new molecular targets and identify new biomarkers, the Academies hosted the third workshop in this series in September 2016. Participants discussed opportunities to accelerate early stages of drug development for nervous system disorders in the absence of animal models that reflect disease and predict efficacy. This publication summarizes the presentations and discussions from the workshop.

Neuroinflammation is a burgeoning area of interest in academia and biopharma, with a broadly acknowledged role in many central nervous system (CNS) disorders. However, there is little agreement on the pathophysiological mechanisms that underlie the manifestations of neuroinflammation in the CNS compartment and how neuroinflammation operates as a driver and also as a consequence of disease in the brain. Moreover, another unclear area is how to translate increased understanding of the mechanisms that underlie neuroinflammation and its manifestations in the CNS to therapeutics. To address these gaps in understanding mechanisms and how to translate that understanding into therapeutics, the Forum on Neuroscience and Nervous System Disorders of the National Academies of Sciences, Engineering, and Medicine convened a workshop on March 20-21, 2017, bringing together key leaders in the field from industry, academia, and governmental agencies to explore the role and mechanisms of neuroinflammation in a variety of CNS diseases. The workshop also considered strategies to advance the identification and validation of biomarkers of neuroinflammation that could accelerate development of therapies, bringing much-needed treatments to patients with disorders ranging from neuroinflammatory diseases such as multiple sclerosis (MS) to neuropsychiatric disorders such as depression. This publication summarizes the presentations and discussions from the workshop.

Despite substantial advances in developing treatments for the serious illnesses that affect people worldwide, there remains a tremendous unmet need in the treatment of complex neurologic diseases, including neuropsychiatric and neurodegenerative disorders. Chief among the challenges that have hindered the development of therapeutics for central nervous system (CNS) disorders is the bloodâ€"brain barrier (BBB). The Forum on Neuroscience and Nervous System Disorders of the National Academies of Sciences, Engineering, and Medicine convened a workshop to explore the challenges associated with the BBB that have thus far stymied development of CNS drugs, examine new technologies that could address these challenges, and highlight potential opportunities for moving the field forward. This publication summarizes the presentations and discussions from the workshop.

Few areas of biomedical research provide greater opportunities to capitalize upon the revolution in genomics and molecular biology than gene therapy. This is particularly true for the brain and nervous system, where gene transfer has become a key technology for basic research and has recently been translated to human therapy in several landmark clinical trials. Gene Therapy in the Brain: From Bench to Bedside represents the definitive volume on this subject. Edited by two pioneers of neurological gene therapy, this volume contains contributions by leaders who helped to create the field as well as those who are expanding the promise of gene therapy for the future of basic and clinical neuroscience. Drawing upon this extensive collective experience, this book provides clear and informative reviews on a variety of subjects which would be of interest to anyone who is currently using or contemplating exploring gene therapy for neurobiological applications. Basic gene transfer technologies are discussed, with particular emphases upon novel vehicles, immunological issues and the role of gene therapy in stem cells. Numerous research applications are reviewed, particularly in complex fields such as behavioral neurobiology. Several preclinical areas are also covered which are likely to translate into clinical studies in the near future, including epilepsy, pain and amyotrophic lateral sclerosis. Among the most exciting advances in recent years has been the use of neurological gene therapy in human clinical trials, including Parkinson's disease, Canavan disease and Batten disease. Finally, readers will find "insider" information on technological and regulatory issues which can often limit effective translation of even the most promising idea into clinical use. This work provides up-to-date information and key insights into those gene therapy issues which are important to both scientists and clinicians focusing upon the brain and central nervous system.

This book provides a comprehensive overview of brain metastases, from the molecular biology aspects to therapeutic management and perspectives. Due to the increasing incidence of these tumors and the urgent need to effectively control brain metastatic diseases in these patients, new therapeutic strategies have emerged in recent years. The volume discusses all these innovative approaches combined with new surgical techniques (fluorescence, functional mapping, integrated navigation), novel radiation therapy techniques (stereotactic radiosurgery) and new systemic treatment approaches such as targeted- and immunotherapy. These combination strategies represent a new therapeutic model in brain metastatic patients in which each medical practitioner (neurosurgeon, neurologist, medical oncologist, radiation oncologist) plays a pivotal role in defining the optimal treatment in a multidisciplinary approach. Written by recognized experts in the field, this book is a valuable tool for neurosurgeons, neuro-oncologists, neuroradiologists, medical oncologists, radiation oncologists, cognitive therapists, basic scientists and students working in the area of brain tumors.

The therapeutic options for the treatment of Multiple Sclerosis (MS) and other neurodegenerative and traumatic diseases such as spinal cord injury, Alzheimer's, Parkinson's disease, etc. have experienced enormous progress over recent years. Despite these encouraging developments, available therapies are only partially effective, and the ultimate goal is still far from being attained. Improved understanding of the cellular and molecular mechanisms of the pathogenesis of neurodegeneration and demyelination has led to a variety of new therapeutic targets and approaches. In addition to modulation of the inflammatory process (MS) and classical neuroprotection (stroke, AD), therapeutic approaches focusing on active remyelinization and neuronal regeneration have become increasingly important. Based on current concepts, this book summarizes new therapeutic approaches.