SBIR-STTR Award

Oligodendrocytes (OLs) are the myelinating cells of the central nervous system and play a critical role in white matter formation and white matter stability. Serious clinical disorders affect central nervous system white matter during early development and in adulthood. These conditions include periventricular white matter injury (PWMI), which affects up to 20% of very low birthweight premature infants, and diabetes mellitus and multiple sclerosis, which affect both children and adults. Presently, we are unaware of pharmacological approaches that specifically target OLs and/or OL precursor cells that can be applied to stimulate white matter formation either during development or in demyelination conditions. Because white matter injury is now the leading cause of nervous system injury in premature infants, developing new treatments for PWMI will have a major beneficial impact on the lives of children. Recently, we have developed strategies to facilitate high-throughput drug screening aimed at discovering compounds that stimulate OL cell division and activity. In collaboration with the Yale Center for Proteomics and Genomics, we have established a large compound library that targets a wide array of cell surface receptors, ion channels, and intracellular effect systems. We have established new approaches that allow us to assess effects of compounds on OL division and differentiation. We also have in vivo models of PWMI. Based on these observations, we hypothesize that it is possible to develop new pharmacological approaches to treat white matter disorders. To achieve this goal we propose to: (1) Use high-throughput screening to identify compounds (}hits}) that stimulate PreOL proliferation. (2) Perform dose-response studies of }hits}. (3) Assess toxicity of }hits}. (4) Assess influences on OL gene expression The primary objective of the experiments outlined in this Phase I SBIR proposal is to identify compounds that stimulate OL proliferation and myelination. The long-term goal of this work is to develop novel therapeutic agent for the treatment of white matter injuries in premature infants, children and adults. If this Phase I SBIR proposal meets our goals, Phase II studies are envisioned in which extensive in vivo testing will be performed in rodent models of white matter injury. Ultimately, research such as this will lead to important discoveries with significant public health benefit and commercial value. We also anticipate that these studies will lead to the development of novel approaches for treating and preventing white matter injury. PUBIC HEALTH RELEVANCE The primary objective of the experiments outlined in this Phase I SBIR proposal is to identify compounds that stimulate OL proliferation and myelination. The long-term goal of this work is to develop novel therapeutic agent for the treatment of white matter injuries in premature infants, children and adults.

Public Health Relevance:
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Oligodendrocytes (OLs) are the myelinating cells of the central nervous system and play a critical role in white matter formation. Serious clinical disorders affect central nervous system white matter during early development. These conditions include periventricular white matter injury (PWMI), which affects up to 20% of very low birth weight premature infants. PWMI is due to loss of Pre- oligodendrocytes (PreOLs), which are proliferative cells that develop into myelinating OLs. Presently, we are unaware of pharmacological approaches that specifically target PreOLs, resulting in increased proliferation of these cells. Because white matter injury is the leading cause of nervous system injury in premature infants, developing new treatments for PWMI will have a major clinical impact. Under Phase 1 of this SBIR, we proposed to use high-throughput screening to identify compounds ("hits") that would stimulate PreOL proliferation. These studies proved to be highly successful, as we identified diazoxide as a stimulator of PreOL proliferation, and we observed that this compound promotes myelination in a murine model of PWMI. Diazoxide acts by activating KATP channels, and we were able to demonstrate KATP channel component expression in PreOLs. We also found that other KATP activators stimulate PreOL proliferation. Thus, we achieved the major goal of our Phase 1 proposal. In Phase II studies, we propose to extend our study of diazoxide in preclinical, proof-of-concept studies involving cell culture and animal studies. We will: (1) Define OL-stage specific responses to diazoxide. (2) Evaluate protection against PWMI in animal models. (3) Assess long-term effects of neonatal diazoxide therapy. The long-term goal of this work is to develop novel therapeutic agents for the treatment of white matter injuries in premature infants. Support from the NIH through the SBIR program will serve to strengthen the productive academic/industrial collaboration established between scientists at Yale University (Dr. Rivkees) and JS Genetics (New Haven, CT) to discover novel drugs. Ultimately, research such as this will lead to important discoveries with significant public health benefit and commercial value. We also anticipate that these studies will lead to the development of novel approaches for treating and preventing white matter injury in the tens of thousands of premature infants born and hospitalized each year.

Public Health Relevance:
The goal of this work is to assess the utility of diazoxide as a therapeutic agent for the treatment of white matter injuries in premature infants. We anticipate that these studies will lead to the development of novel approaches for treating and preventing white matter injury in the tens of thousands of premature infants born and hospitalized each year.

Thesaurus Terms:
0-11 Years Old; 2h-1,2,4-Benzothiadiazine, 7-Chloro-3-Methyl-, 1,1-Dioxide; Acquired Brain Injury; Acute; Adverse Experience; Adverse Event; Affect; Anatomic; Anatomical Sciences; Anatomy; Animal Model; Animal Models And Related Studies; Animals; Arts; Brain; Brain Injuries; Caring; Causality; Cell Culture Techniques; Cell Growth In Number; Cell Multiplication; Cell Proliferation; Cells; Cellular Proliferation; Central Nervous System; Cerebral Palsy; Child; Child Youth; Children (0-21); Clinical; Collaborations; Development; Diazoxide; Diffuse; Disease; Disorder; Drugs; Drugs, Nonproprietary; Effects, Longterm; Encephalon; Encephalons; Etiology; Fda; Food And Drug Administration; Food And Drug Administration (U.S.); Generic Drugs; Genetic; Goals; Health Benefit; High Throughput Assay; Human, Child; Hyperinsulinemia; Hyperinsulinism; Impairment; Individual; Infant; Infant, Premature; Infant, Very Low Birth Weight; Intellectual Property; Lead; Legal Patent; Long-Term Effects; Low Birth Weight Infant; Mammals, Mice; Medication; Mice; Modeling; Morbidity; Morbidity - Disease Rate; Murine; Mus; Nih; National Institutes Of Health; National Institutes Of Health (U.S.); Necrosis; Necrotic; Neonatal; Nervous System Injuries; Nervous System Trauma; Nervous System Damage; Nervous System, Brain; Nervous System, Cns; Neuraxis; Neurological Damage; Neurological Injury; Neurological Trauma; Oligodendrocytes; Oligodendrocytus; Oligodendroglia; Oligodendroglia Cell; Patents; Pb Element; Periventricular White Matter Injury; Pharmaceutic Preparations; Pharmaceutical Preparations; Phase; Play; Premature Infant; Prevention; Programs (Pt); Programs [publication Type]; Public Health; Reporting; Research; Risk; Role; Sbir; Sbirs (R43/44); Science Of Anatomy; Scientist; Secure; Small Business Innovation Research; Small Business Innovation Research Grant; Staging; Structure; Therapeutic Agents; Time; Trauma, Nervous System; Usfda; United States; United States Food And Drug Administration; United States National Institutes Of Health; Universities; Vlbw (Human); Very Low Birth Weight Infant; White Matter Disease; Work; Anatomy; Behavior Test; Behavioral Test; Brain Damage; Brain Lesion (From Injury); Children; Clinical Applicability; Clinical Application; Cost; Disease Causation; Disease Etiology; Disease/Disorder; Disease/Disorder Etiology; Disorder Etiology; Drug Development; Drug/Agent; Generic; Heavy Metal Pb; Heavy Metal Lead; High Throughput Screening; Hypertension Treatment; Low Birth Weight Infant Human; Low Birthweight; Model Organism; Myelination; New Approaches; New Therapeutics; Next Generation Therapeutics; Novel; Novel Approaches; Novel Strategies; Novel Strategy; Novel Therapeutics; Phase 2 Study; Pre-Clinical; Preclinical; Premature Baby; Premature Infant Human; Preterm Baby; Preterm Infant; Preterm Infant Human; Preterm Neonate; Prevent; Preventing; Programs; Public Health Medicine (Field); Public Health Relevance; Response; Social Role; Substantia Alba; Very Low Birth Weight Infant Human; White Matter; White Matter Injury; Youngster