"Antisense Technology in the Central Nervous System describes the promises and the pitfalls of this approach, and compares it to other approaches. The practical experience of leading researchers is combined with a thorough description of the theoretical foundation of the technique, making the book ideal for researchers and clinicians alike."--BOOK JACKET.

Antisense oligonucleotide (ASO) therapies for central nervous system (CNS) indications have advanced significantly within the past three years, including FDA approval for an ASO therapy for spinal muscular atrophy and clinical trials for several other neurological disorders. ASOs are ~6-8 kDa, single-stranded DNA or RNA oligomers and are attractive therapeutic candidates for diseases caused by known genetic abnormalities because they are disease-modifying therapeutics that can interact with target RNA to modify protein production. ASOs are unable to cross the blood-brain barrier on their own, so they are administered centrally, typically achieved by intrathecal administration. Despite the clinical use of CSF-administered ASOs, there is a paucity of knowledge concerning CSF-to-brain transport mechanisms and the resulting CNS biodistribution. Here, we investigated ASO transport and distribution in the CNS following intrathecal administration, focusing on the effects of different ASO chemistries and two transport mechanisms: diffusion in the extracellular spaces and convection/dispersion in perivascular spaces (PVS) surrounding the cerebral vasculature. We have demonstrated that intrathecal administration of fluorescently-labeled ASOs in rats leads to limited diffusion at CSF-brain and CSF-spinal cord interfaces and rapid distribution within the PVS. ASOs distributed to the PVS surrounding vessels of all type and caliber. We have also demonstrated that the extent to which perivascular distribution occurs differs in a sequence- and chemical modification-specific manner, a finding not yet reported in the literature. Furthermore, we have found that ASOs with a nucleotide sequence that allowed a random coil conformation had a significantly smaller hydrodynamic size compared to ASOs that formed secondary structures and that smaller hydrodynamic size correlated with more extensive diffusion and perivascular access. The difference in perivascular signal between the PS-ASO and the 2'MOE-ASO was significant when quantified and was particularly apparent in the dorsal cortex as well as in subcortical brain regions such as the striatum and hippocampus. Biodistribution and transport studies such as those conducted in the present work may provide an improved framework for understanding ASO delivery to brain and spinal cord targets. It is our hope that this framework may assist in developing ASO therapies for optimal CNS distribution to improve treatment results for devastating neurological conditions.

Antisense technology is the ability to manipulate gene expression within mammalian cells providing powerful experimental approaches for the study of gene function and gene regulation. For example, methods which inhibit gene expression permit studies probing the normal function of a specific product within a cell. Such methodology can be used in many disciplines such as pharmacology, oncology, genetics, cell biology, developmental biology, molecular biology, biochemistry, and neurosciences. This volume will be a truly important tool in biomedically-oriented research. The critically acclaimed laboratory standard for more than forty years, Methods in Enzymology is one of the most highly respected publications in the field of biochemistry. Since 1955, each volume has been eagerly awaited, frequently consulted, and praised by researchers and reviewers alike. Now with more than 300 volumes (all of them still in print), the series contains much material still relevant today-truly an essential publication for researchers in all fields of life sciences.

This book provides a cutting-edge review of polyglutamine disorders. It primarily focuses on two main aspects: (1) the mechanisms underlying the pathologies’ development and progression, and (2) the therapeutic strategies that are currently being explored to stop or delay disease progression. Polyglutamine (polyQ) disorders are a group of inherited neurodegenerative diseases with a fatal outcome that are caused by an abnormal expansion of a coding trinucleotide repeat (CAG), which is then translated in an abnormal protein with an elongated glutamine tract (Q). To date, nine polyQ disorders have been identified and described: dentatorubral-pallidoluysian atrophy (DRPLA); Huntington’s disease (HD); spinal–bulbar muscular atrophy (SBMA); and six spinocerebellar ataxias (SCA 1, 2, 3, 6, 7, and 17). The genetic basis of polyQ disorders is well established and described, and despite important advances that have opened up the possibility of generating genetic models of the disease, the mechanisms that cause neuronal degeneration are still largely unknown and there is currently no treatment available for these disorders. Further, it is believed that the different polyQ may share some mechanisms and pathways contributing to neurodegeneration and disease progression.

Annotation Dr. Agrawal's newest book is of significant importance since oligonucleotide-based drugs have the advantage of retaining their recognition for the target RNA, and provide the tools needed to modulate the expression of specific genes, making Antisense Therapeutics an essential resource for all antisense researchers.

This state-of-the-art reference provides comprehensive coverage of the development of antisense oligonucleotides to inhibit cancer cells as well as those involved in infectious, inflammatory, and immune-mediated diseases-highlighting new tools and technologies in medicinal chemistry, RNA biochemistry, and molecular and cellular biology to produce new therapeutic compounds. Presents previously unpublished data on the use of antisense technology to dissect pharmacological processes and confirm the roles of various genes! Showcasing the benefits of antisense drug use, including reduced toxicity and earlier disease detection, Antisense Drug Technology discusses novel formulations of antisense drugs practical methods to design effective isotype selective inhibitors molecular mechanisms of antisense drugs mRNA as a current biological template modern postreceptor binding mechanisms and more! With contributions by over 60 seasoned experts in the field and containing more than 3000 helpful references, tables, drawings, and photographs, Antisense Drug Technology is an illuminating source for organic, medicinal, and pharmaceutical chemists; biochemists; geneticists; hematologists; oncologists; molecular and cell biologists; virologists; immunologists; and medical school and graduate students in these disciplines.

Antisense technology is the ability to manipulate gene expression within mammalian cells providing powerful experimental approaches for the study of gene function and gene regulation. For example, methods that inhibit gene expression permit studies which probe the normal function of a specific product within a cell. Such methodology can be used in many disciplines such as pharmacology, oncology, genetics, cell biology, developmental biology, molecular biology, biochemistry, and neurosciences. This volume will be a truly important tool in biomedical-oriented research. The critically acclaimed laboratory standard for more than forty years, Methods in Enzymology is one of the most highly respected publications in the field of biochemistry. Since 1955, each volume has been eagerly awaited, frequently consulted, and praised by researchers and reviewers alike. Now with more than 300 volumes (all of them still in print), the series contains much material still relevant today--truly an essential publication for researchers in all fields of life sciences.