SBIR-STTR Award

This is an SBIR Phase I re-submission to fund proof of concept studies for the development of induced pluripotent stem (iPS) cells from a population of HIV/NeuroAIDS patients who abuse alcohol and/or other substances (i.e. cocaine, opium, etc). It has been accepted that alcohol and drugs of abuse are significant cofactors in the progression of human immunodeficiency virus (HIV)-induced disease. HIV infection, alcohol and drugs of abuse significantly affect the immune system as well as the central nervous system (CNS). In patients with HIV, abnormalities intersect to lead to a constellation of symptoms known as NeuroAIDS. The term ""NeuroAIDS"" includes a myriad of novel neurologic disorders which are a primary consequence of damage to the central and peripheral nervous system by HIV. The medical conditions include sensory neuropathy, myelopathy, HIV dementia, and cognitive/motor disorder abnormalities. In minority groups HIV infection and NeuroAIDS progression occur at a disproportionate rate. The existence of biological differences within an ethnic group which might exacerbate the rate of conversion to NeuroAIDS is unknown. More definitive research has to be performed to understand the underlying mechanisms of alcohol and drug abuse on NeuroAIDS, specifically examining neuroimmunity, latent CNS reservoirs, neurons and glial cells. We are proposing to create iPS cell from fibroblast samples collected from minority HIV patients who abuse alcohol and/or drugs. Like human embryonic stem cells (hESCs), iPS cells can self-renew indefinitely and can be differentiated into most cells of the human body, including the CNS. Furthermore, iPS cells can either be modified by targeted gene disruption or created from patients as disease specific cell lines. We have successfully differentiated iPS cells and hESCs into neuronal lineages to study the neurodegenerative effect of various drugs and known toxins such as alcohol. We have successfully identified genes that are differentially regulated by alcohol during neurogenesis. We believe iPS cells to be a powerful tool in gaining insight into which biomarkers are essential for the progression to NeuroAIDS in populations infected with HIV while abusing substances. Obtaining primary cells from a patient's brain would only exacerbate their current neurological problem. The success of this proposal will create the first cell line that is designed to look at biomarkers of NeuroAIDS. Published reports for drugs entering human clinical trials estimate costs to vary from $500 million to $2 billion depending on the therapy. The success rate for all new drugs entering phase I trials and the successful completion of product licensing for human use is approximately 9%, meanwhile, the success rate for CNS drug candidates to become marketed therapeutic is projected at 3%. Several drugs have been tested in phase I and II clinical trials for HIV-associated dementia (HAD), which is commonly associated with HIV/NeuroAIDS and unfortunately none of the studies were able to improve health conditions. There is clearly a need to increase productivity and decrease the cost of drug development using strategies that also encourage innovation while ensuring drug safety and efficacy. HIV/NeuroAIDS patient-derived iPS cells represent a model to study CNS development;function and disease and are a useful tool to complement in vivo experimentation. We propose that the current inefficiencies, high attrition rates, protracted R&D cycles and elevated cost associated with drug development can be reduced by the advent of HIV/NeuroAIDS patient derived iPS cells which are relatively inexpensive and can be used as a model for high- throughput in vitro analysis in first phase drug discovery and preclinical product development in the biotechnology and pharmaceutical industry. The Specific Aims of this Phase I application are: Specific Aim #1: To create iPS cells from fibroblast cells taken from substance abusing minorities and non-minorities with HIV/NeuroAIDS. Specific Aim #2: Differentiate iPS cells into neuronal and glial cell lineages. Successful completion of this work will support a Phase II application, with the goals of including a larger cohort for iPS cell development, toxicology screening and the product leading to FDA 510(k) approval.

Public Health Relevance:
There is clearly a need to increase productivity and decrease the cost of drug development to treat HIV/NeuroAIDS using strategies that also encourage innovation while ensuring drug safety and efficacy. We propose that the current inefficiencies, high attrition rates, protracted R&D cycles and elevated cost associated with drug development can be reduced by the advent of HIV/NeuroAIDS patient derived iPS cells which are relatively inexpensive and can be used as a model for high-throughput in vitro analysis in first phase drug discovery and preclinical product development in the biotechnology and pharmaceutical industry.

Thesaurus Terms:
1,3,7-Trimethylxanthine;1h-Imidazole-5-Carboxylic Acid, 1-(1-Phenylethyl)-, Ethyl Ester, (R)-;2,6-Bis(1-Methylethyl)Phenol;2,6-Diisopropylphenol;3,7-Dihydro-1,3,7-Trimethyl-1h-Purine-2,6-Dione;8-Azabicyclo(3.2.1)Octane-2-Carboxylic Acid, 3-(Benzoyloxy)-8-Methyl-, Methyl Ester, (1r-(Exo,Exo))-;Ach Receptors;Aids;Aids Virus;Aids Neuropathy;Acetylcholine Receptors;Acquired Immune Deficiency;Acquired Immune Deficiency Syndrome;Acquired Immune Deficiency Syndrome Virus;Acquired Immuno-Deficiency Syndrome;Acquired Immunodeficiency Syndrome;Acquired Immunodeficiency Syndrome Virus;Acquired Immunologic Deficiency Syndrome;Affect;Alcohol Chemical Class;Alcohol Abuse;Alcohols;Amentia;Anesthestic Drugs;Anesthetic Agents;Anesthetic Drugs;Anesthetics;Assay;Bioassay;Biologic Assays;Biological;Biological Assay;Biotechnology;Brain;Brain Diseases;Brain Disorders;Brain Nervous System;Cns Diseases;Cns Nervous System;Cns Agent;Cns Disorder;Caffeine;Cell Culture Techniques;Cell Death;Cell Line;Cell Lineage;Cell Survival;Cell Viability;Cellline;Cells;Central Nervous System;Central Nervous System Agents;Central Nervous System Diseases;Central Nervous System Disorders;Central Nervous System Drugs;Cholinergic Receptors;Cholinoceptive Sites;Cholinoceptors;Clinical Trials;Cocaine;Cognitive;Communicable Diseases;Complement;Complement Proteins;Customized Drugs;Data;Degenerative Neurologic Diseases;Degenerative Neurologic Disorders;Dementia;Designer Drugs;Development;Development And Research;Device Approval;Device Approval Process;Diagnosis;Diprivan;Disease;Disoprofol;Disorder;Doctor Of Medicine;Doctor Of Philosophy;Drug Industry;Drug Abuse;Drug Toxicity;Drugs;Early-Stage Clinical Trials;Encephalon;Encephalon Diseases;Ensure;Epidemiology;Ethnic And Racial Minorities;Ethnic Group;Ethomidate;Etomidate;Extracellular Signal-Regulated Kinase Gene;Fibroblasts;Food And Drug Administration;Funding;Future;Gfac;Gene Targeting;Genes;Glia;Glial Cells;Goals;Growth Agents;Growth Factor;Growth Substances;Hiv;Htlv-Iii;Health;Hospitals;Human;Human Figure;Human Immunodeficiency Viruses;Human T-Cell Leukemia Virus Type Iii;Human T-Cell Lymphotropic Virus Type Iii;Human T-Lymphotropic Virus Type Iii;Human Body;Immune;Immune System;In Vitro;Individual;Infectious Disease Pathway;Infectious Diseases;Infectious Diseases And Manifestations;Infectious Disorder;Intracranial Cns Disorders;Intracranial Central Nervous System Disorders;Kolliker's Reticulum;Lav-Htlv-Iii;Lead;Legal Patent;Licensing;Lymphadenopathy-Associated Virus;M.D.;Map Kinase Gene;Mapk;Man (Taxonomy);Marihuana;Marketing;Medical;Medical Device;Medication;Michigan;Minority;Minority Groups;Mitogen-Activated Protein Kinase Gene;Modeling;Modern Man;Nerve Cells;Nerve Degeneration;Nerve Unit;Nervous System Degenerative Diseases;Nervous System Diseases;Nervous System Injuries;Nervous System Trauma;Nervous System Damage;Neural Cell;Neural Development;Neuraxis;Neurocyte;Neurodegenerative Diseases;Neurodegenerative Disorders;Neuroglia;Neuroglial Cells;Neurologic;Neurologic Degenerative Conditions;Neurologic Disorders;Neurological;Neurological Damage;Neurological Disorders;Neurological Injury;Neurological Trauma;Neuron Degeneration;Neurons;Nicotine;Non-Neuronal Cell;Opium;Patents;Patients;Pb Element;Peripheral Nervous System;Peripheral Sensory Neuropathy;Ph.D.;Phd;Pharmaceutic Industry;Pharmaceutic Preparations;Pharmaceutical Industry;Pharmaceutical Preparations;Phase;Phase 1 Clinical Trials;Phase I Clinical Trials;Phase I Study;Phosphorylation;Pluripotent Stem Cells;Population;Productivity;Propofol;Propofol/Diprivan;Protein Phosphorylation;Proteins Growth Factors;Publishing;Pyridine, 3-(1-Methyl-2-Pyrrolidinyl)-, (S)-;R &D;R&D;Reporting;Research;Research Resources;Resources;Sbir;Sbirs (R43/44);Safety;Sampling;Screening Procedure;Small Business Innovation Research;Small Business Innovation Research Grant;Source;Spinal Cord Diseases;Spinal Cord Disorders;Stem Cell Development;Strains Cell Lines;Symptoms;Technology;Testing;Therapeutic;Toxicology;Toxin;Usfda;United States Food And Drug Administration;Universities;Viral Diseases;Viral Gene Products;Viral Gene Proteins;Viral Proteins;Virus Diseases;Virus-Hiv;Work;Abuse Of Drugs;Abused Drugs;Abuses Drugs;Alcohol Abuse Therapy;Alcohol Abuse Treatment;Alcohol Problem;Alcohol Treatment;Allergic/Immunologic Body System;Allergic/Immunologic Organ System;Base;Biomarker;Cell Culture;Centrally Acting Drug;Clinical Investigation;Cofactor;Cohort;Commercialization;Comparative;Cost;Cultured Cell Line;Design;Designing;Developmental;Disease/Disorder;Drug Candidate;Drug Development;Drug Discovery;Drug Of Abuse;Drug/Agent;Drugs Abused;Drugs Of Abuse;Epidemiologic;Epidemiological;Ethanol Abuse;Hesc;Hazardous Alcohol Use;Heavy Metal Pb;Heavy Metal Lead;High Throughput Technology;Human Es Cell;Human Esc;Human Embryonic Stem Cell;Ips;Improved;In Vitro Model;In Vivo;Induced Pluripotent Stem Cell;Innovate;Innovation;Innovative;Insight;Marijuana;Meetings;Motor Disease;Motor Disorder;Myelopathy;Necrocytosis;Nerve Cement;Nervous System Development;Nervous System Disorder;Neural;Neural Degeneration;Neuroaids;Neurodegeneration;Neurodegenerative;Neurodegenerative Illness;Neurodevelopment;Neurogenesis;Neurological Disease;Neuronal;Neuronal Degeneration;Novel;Phase 1 Study;Phase 1 Trial;Phase I Protocol;Phase I Trial;Pluripotency;Pre-Clinical;Preclinical;Problem Alcohol Use;Problem Drinking;Product Development;Relating To Nervous System;Research And Development;Response;Screening;Screenings;Self-Renew;Self-Renewal;Sensory Neuropathy;Stem;Stem Cell Technology;Success;Tool;Viral Infection;Virus Infection;Virus Protein;Virus-Induced Disease

This is an SBIR Phase I re-submission to fund proof of concept studies for the development of induced pluripotent stem (iPS) cells from a population of HIV/NeuroAIDS patients who abuse alcohol and/or other substances (i.e. cocaine, opium, etc). It has been accepted that alcohol and drugs of abuse are significant cofactors in the progression of human immunodeficiency virus (HIV)-induced disease. HIV infection, alcohol and drugs of abuse significantly affect the immune system as well as the central nervous system (CNS). In patients with HIV, abnormalities intersect to lead to a constellation of symptoms known as NeuroAIDS. The term"NeuroAIDS"includes a myriad of novel neurologic disorders which are a primary consequence of damage to the central and peripheral nervous system by HIV. The medical conditions include sensory neuropathy, myelopathy, HIV dementia, and cognitive/motor disorder abnormalities. In minority groups HIV infection and NeuroAIDS progression occur at a disproportionate rate. The existence of biological differences within an ethnic group which might exacerbate the rate of conversion to NeuroAIDS is unknown. More definitive research has to be performed to understand the underlying mechanisms of alcohol and drug abuse on NeuroAIDS, specifically examining neuroimmunity, latent CNS reservoirs, neurons and glial cells. We are proposing to create iPS cell from fibroblast samples collected from minority HIV patients who abuse alcohol and/or drugs. Like human embryonic stem cells (hESCs), iPS cells can self-renew indefinitely and can be differentiated into most cells of the human body, including the CNS. Furthermore, iPS cells can either be modified by targeted gene disruption or created from patients as disease specific cell lines. We have successfully differentiated iPS cells and hESCs into neuronal lineages to study the neurodegenerative effect of various drugs and known toxins such as alcohol. We have successfully identified genes that are differentially regulated by alcohol during neurogenesis. We believe iPS cells to be a powerful tool in gaining insight into which biomarkers are essential for the progression to NeuroAIDS in populations infected with HIV while abusing substances. Obtaining primary cells from a patient's brain would only exacerbate their current neurological problem. The success of this proposal will create the first cell line that is designed to look at biomarkers of NeuroAIDS. Published reports for drugs entering human clinical trials estimate costs to vary from $500 million to $2 billion depending on the therapy. The success rate for all new drugs entering phase I trials and the successful completion of product licensing for human use is approximately 9%, meanwhile, the success rate for CNS drug candidates to become marketed therapeutic is projected at 3%. Several drugs have been tested in phase I and II clinical trials for HIV-associated dementia (HAD), which is commonly associated with HIV/NeuroAIDS and unfortunately none of the studies were able to improve health conditions. There is clearly a need to increase productivity and decrease the cost of drug development using strategies that also encourage innovation while ensuring drug safety and efficacy. HIV/NeuroAIDS patient-derived iPS cells represent a model to study CNS development;function and disease and are a useful tool to complement in vivo experimentation. We propose that the current inefficiencies, high attrition rates, protracted R&D cycles and elevated cost associated with drug development can be reduced by the advent of HIV/NeuroAIDS patient derived iPS cells which are relatively inexpensive and can be used as a model for high- throughput in vitro analysis in first phase drug discovery and preclinical product development in the biotechnology and pharmaceutical industry. The Specific Aims of this Phase I application are: Specific Aim #1: To create iPS cells from fibroblast cells taken from substance abusing minorities and non-minorities with HIV/NeuroAIDS. Specific Aim #2: Differentiate iPS cells into neuronal and glial cell lineages. Successful completion of this work will support a Phase II application, with the goals of including a larger cohort for iPS cell development, toxicology screening and the product leading to FDA 510(k) approval.