SBIR-STTR Award

This Phase I SBIR Program will develop genetic diagnostic products to improve the safety of atypical antipsychotics (e.g. olanzapine) for treating psychiatric disorders, including schizophrenia. Atypical antipsychotics are prescribed as long-term treatments for an increasing number of indications even to adolescent's patients. In up to 50% of patients, these highly effective drugs induce metabolic syndrome. Genomas and the Institute of Living (IOL) at Hartford bring together the power of genomics and expert psychiatric care to discover genetic markers of susceptibility to drug-induced metabolic syndrome for clinical management of psychiatric disorders. These novel and highly predictive markers are termed "physiotypes" and result from combinations of various contributory genes and baseline characteristics. From patients being first treated with olanzapine as part of best medical practices at IOL, 250 will be asked to participate in this study and requested to consent for genetic analysis. Patients will be followed for 6 months. Clinical assessment, including weight, waist size, lipids, fasting blood glucose and blood pressure will be ascertained at baseline, and 2 and 6 months after initiation of olanzapine treatment. Genomas will haplotype 200 genes in each patient with highly multiplexed genotyping assays. Candidate genes are drawn from CNS, metabolic, cell biological, and genetic studies and represent antipsychotic pharmacology (dopamine, serotonin, histamine), appetite control (leptin, neuropeptide Y), energy regulation (uncoupling proteins), endocrinology (insulin) and cholesterol homeostasis (apolipoproteins). Based on review of medical records, the study has been powered to detect common haplotypes of even modest individual predictive power (odds ratio of 1.7). When combined into physiotypes, the markers have specificity and sensitivity of 80% or more. Genomas will construct physiotypes of drug-induced metabolic syndrome and apply statistical validation techniques to the discoveries. The physiotype generates new knowledge about antipsychotic pharmacology and pathophysiology of metabolic syndrome and becomes intellectual property for development of multigene diagnostic products. The physiotype will have utility for personalized therapy, drug monitoring, and medical prophylaxis. This novel approach utilizing multple physiological pathways, haplotyping, covariate analysis and standardized clinical practice will result in personalized "double-preventive" diagnostics of natural and drug-induced disease.

Thesaurus Terms:
antipsychotic agent, drug adverse effect, genetic marker, genetic screening, genetic susceptibility, metabolic syndrome, schizophrenia, serotonin inhibitor, technology /technique development appetite, blood glucose, blood lipoprotein, blood pressure, cardiovascular disorder risk, computational biology, diabetes risk, genetic polymorphism, insulin sensitivity /resistance, obesity, psychopharmacology, weight gain biotechnology, clinical research, human subject, patient oriented research

Atypical antipsychotic drugs (AAPs) are indicated in the treatment for schizophrenia, bipolar disorder, psychotic depression and other psychiatric disorders. Their drawback is drug-induced metabolic derangements including weight gain, hyperlipidemia, and diabetic risks. These diabetic metabolic symptoms (DiMS) vary widely between drugs and from patient to patient. We propose to develop a novel product termed "Physiotype" to deliver personalized information for each patient on the drug- specific risks among aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone. The Physiotype consists of a multi-gene ensemble of single nucleotide polymorphisms (SNPs) that, interpreted with a biomathematical algorithm, may explain most of the inter-individual differences in DiMS among the 5 AAPs The proprietary physiogenomics technology and state-of-the-art genotyping laboratories of Genomas will be integrated with the clinical resources of the Institute of Living (Hartford CT) and of the University of Kentucky (Lexington KY), through subcontracts, respectively, to Dr. John Goethe and Dr. Jose de Leon. Our goal in Phase II is to discover SNPs predictive of differences in DiMS side effects between these 5 AAPs and to develop them into predictive diagnostic products for psychiatrists in their practice. We will recruit 200 patients treated by each of the 5 AAPs, characterize their weight and lipid profiles, and obtain their DNA for creation of a clinical registry and DNA repository. We will determine each patient's genotype at 100,000 SNPs covering all ~30,000 genes and also evolutionary conserved regions for a comprehensive, hypothesis-free search for genetic markers of DiMS. In Phase I, the collaborators have already accumulated a registry and DNA repository of 374 AAP-treated patients and their DNA. We have genotyped DNA from olanzapine- and risperidone-treated patients in the repository for an array of 384 SNPs in 222 cardiovascular, metabolic and psychiatric candidate genes and performed physiogenomic predictive modeling. We have discovered novel drug-specific DiMS markers for olanzapine and risperidone including the apolipoprotein E and leptin receptor genes, respectively. We have developed a prototype Physiotype and tested it in an independent psychiatric population. The Physiotype predicted that ~20% of patients have the most weight associated with risperidone and ~80% with olanzapine, which is consistent with known olanzapine average effects, and also pinpoints the greater risperidone-specific risk for many individuals. In Phase III, a prospective randomized trial of all 5 AAPs is planned as part of FDA review of a Physiotype device. The Physiotype will assist psychiatrists to avoid side effects by guiding drug selection for each patient according to innate characteristics unraveled and interpreted directly from the person's own DNA. The proposed program will develop DNA diagnostic products to enhance safety of atypical antipsychotic drugs (AAPs) and improve the medical management of schizophrenia and related disorders leading to better outcomes. As of now, the development of AAP side effects is unpredictable, potentially disabling to the patient, and discourages patient compliance. The products will enable DNA- guided medicine: the determination of which AAP is most suitable and the implementation of clinical safeguards, individualized to each patient, using his/her personal genome.

Thesaurus Terms:
antipsychotic agent, diabetes risk, diagnosis design /evaluation, drug adverse effect, drug related diabetes mellitus, genetic susceptibility, hyperlipidemia, mental disorder chemotherapy, metabolism disorder diagnosis, patient safety /medical error, pharmacogenetics, single nucleotide polymorphism clinical trial, endocrine pharmacology, genetic registry /resource /referral center, genotype, patient /disease registry, piperazine, risperidone, serotonin inhibitor, thiazole clinical research, genetic marker, health services research tag, human genetic material tag, human subject, interview, patient oriented research