Challenges and lessons learned from clinical pharmacogenetic implementation of multiple gene-drug pairs across ambulatory care settings.

PURPOSE: Incorporating a patient's genotype into the clinical decision-making process is one approach to precision medicine. The University of Florida (UF) Health Precision Medicine Program is a pharmacist-led multidisciplinary effort that has led the clinical implementation of six gene-drug(s) pairs to date. This study focuses on the challenges encountered and lessons learned with implementing pharmacogenetic testing for three of these: CYP2D6-opioids, CYP2D6/CYP2C19-selective serotonin reuptake inhibitors, and CYP2C19-proton pump inhibitors within six pragmatic clinical trials at UF Health and partners. METHODS: We compared common measures collected within each of the pharmacogenetic implementations as well as solicited feedback from stakeholders to identify challenges, successes, and lessons learned. RESULTS: We identified several challenges related to trial design and implementation, and learned valuable lessons. Most notably, case discussions are effective for prescriber education, prescribers need clear concise guidance on genotype-based actions, having genotype results available at the time of the patient-prescriber encounter helps optimize the ability to act on them, children prefer noninvasive sample collection, and study participants are willing to answer patient-reported outcomes questionnaires if they are not overly burdensome, among others. CONCLUSION: The lessons learned from implementing three gene-drug pairs in ambulatory care settings will help shape future pharmacogenetic clinical trials and clinical implementations.

Inside OCD: Perspectives on the Value of Storytelling with Individuals with OCD and Family Members.

The Center for Arts in Medicine at the University of Florida (UF) partnered with the UF Center for OCD, Anxiety, and Related Disorders to develop a storytelling program for individuals with obsessive compulsive disorder (OCD) and their families. Over ten weeks, participants shared stories regarding their experiences with OCD and engaged in theater and storytelling exercises. In collaboration with each other and the facilitators, participants workshopped and transformed their stories into a cohesive theatrical performance. Participants performed in front of a live audience and engaged in a post-show discussion with the audience, which focused on the diagnosis of OCD, stigma regarding the illness, and the benefits of the program. Program members participated in a post-program focus group and completed a qualitative and quantitative online survey. Participants reported improved understanding of their OCD, more acceptance from family and friends, less shame and guilt related to their OCD, and more confidence about sharing their OCD stories. Although the program was not designed to be therapeutic, participants also reported therapeutic value. Preliminary findings of this study suggest storytelling programs can lead to a reduction in both self-stigma and community stigma; improvement of understanding of the lived experience of OCD by families, loved ones, and clinicians; and facilitation of interpersonal connections.

Acceptability, Feasibility, and Utility of Integrating Pharmacogenetic Testing into a Child Psychiatry Clinic.

Pharmacogenetic (PGx) testing is a tool to identify patients at a higher risk of adverse events or treatment failure. The concern for unwanted side effects can limit medication adherence, particularly in children and adolescents. We conducted a pragmatic study to evaluate the acceptability and feasibility and gather pilot data on the utility of PGx testing in a child and adolescent psychiatry clinic. Both physicians and families participated in the study and answered pre-survey and post-survey questionnaires to examine their attitudes toward PGx testing. Patients were randomized into implementation (N = 25) and control groups (N = 24) and underwent PGx testing at the beginning or end of the study, respectively. Clinical consult notes with genotype-guided recommendations were provided to physicians for their consideration in clinical decisions. Patient-reported symptom severity and antidepressant-related side effects were assessed at baseline and for 12 weeks. Both participating physicians and families agreed that PGx testing is a useful tool to improve medication selection. The time from sample collection to having PGx test results was ~ 10 days and 15 days to having consult notes available, which may have impaired test utility in clinical decision making. There were no differences in any clinical end point between the implementation and control arms; however, there were higher antidepressant side effect scores for CYP2D6 poor and intermediate metabolizers after the eighth week of treatment. Our findings revealed benefits and pitfalls with the use of PGx testing in the real-world clinical setting, which may inform the methodology of a larger trial focused on outcomes.

Novel neuroprotective function of apical-basal polarity gene crumbs in amyloid beta 42 (aß42) mediated neurodegeneration.

Alzheimer's disease (AD, OMIM: 104300), a progressive neurodegenerative disorder with no cure to date, is caused by the generation of amyloid-beta-42 (Aß42) aggregates that trigger neuronal cell death by unknown mechanism(s). We have developed a transgenic Drosophila eye model where misexpression of human Aß42 results in AD-like neuropathology in the neural retina. We have identified an apical-basal polarity gene crumbs (crb) as a genetic modifier of Aß42-mediated-neuropathology. Misexpression of Aß42 caused upregulation of Crb expression, whereas downregulation of Crb either by RNAi or null allele approach rescued the Aß42-mediated-neurodegeneration. Co-expression of full length Crb with Aß42 increased severity of Aß42-mediated-neurodegeneration, due to three fold induction of cell death in comparison to the wild type. Higher Crb levels affect axonal targeting from the retina to the brain. The structure function analysis identified intracellular domain of Crb to be required for Aß42-mediated-neurodegeneration. We demonstrate a novel neuroprotective role of Crb in Aß42-mediated-neurodegeneration.

Activation of JNK signaling mediates amyloid-ß-dependent cell death.

BACKGROUND: Alzheimer's disease (AD) is an age related progressive neurodegenerative disorder. One of the reasons for Alzheimer's neuropathology is the generation of large aggregates of Aß42 that are toxic in nature and induce oxidative stress, aberrant signaling and many other cellular alterations that trigger neuronal cell death. However, the exact mechanisms leading to cell death are not clearly understood. METHODOLOGY/PRINCIPAL FINDINGS: We employed a Drosophila eye model of AD to study how Aß42 causes cell death. Misexpression of higher levels of Aß42 in the differentiating photoreceptors of fly retina rapidly induced aberrant cellular phenotypes and cell death. We found that blocking caspase-dependent cell death initially blocked cell death but did not lead to a significant rescue in the adult eye. However, blocking the levels of c-Jun NH(2)-terminal kinase (JNK) signaling pathway significantly rescued the neurodegeneration phenotype of Aß42 misexpression both in eye imaginal disc as well as the adult eye. Misexpression of Aß42 induced transcriptional upregulation of puckered (puc), a downstream target and functional read out of JNK signaling. Moreover, a three-fold increase in phospho-Jun (activated Jun) protein levels was seen in Aß42 retina as compared to the wild-type retina. When we blocked both caspases and JNK signaling simultaneously in the fly retina, the rescue of the neurodegenerative phenotype is comparable to that caused by blocking JNK signaling pathway alone. CONCLUSIONS/SIGNIFICANCE: Our data suggests that (i) accumulation of Aß42 plaques induces JNK signaling in neurons and (ii) induction of JNK contributes to Aß42 mediated cell death. Therefore, inappropriate JNK activation may indeed be relevant to the AD neuropathology, thus making JNK a key target for AD therapies.