Jason Holt

Point of accountability for the development and delivery of a comprehensive preclinical safety strategy for programs within their designated therapeutic area. Manager of Translational Medicine In Vivo team primarily responsible for rodent DRF and IND enabling studies. Matrix leadership to ensure Translational Medicine resources are effectively deployed to support programs within their designated therapeutic area, management/resolution of safety issues Ensure delivery of Translational Medicine components of stage gate documentation for health regulatory agencies, Nonclinical Overviews and Investigator Brochures. Address and resolve efficacy and/or toxicological issues arising in drug development programs, and adequately assess the relevance of these findings to human safety Review and endorse regulatory responses and participates in Regulatory Agency interactions, as required by program.

Point of accountability for the development and delivery of a comprehensive preclinical safety strategy for programs within their designated therapeutic area Matrix leadership to ensure Translational Medicine resources are effectively deployed to support programs within their designated therapeutic area, management/resolution of safety issues Ensure delivery of Translational Medicine components of stage gate documentation, Nonclinical Overviews and Investigator Brochures.

Responsible for development of translational biomarkers for both efficacy and toxicity from in vivo models, as well as provide oversight and expertise in evaluation of preclinical in vivo models relevant to specific gene therapy targets. Nonclinical representative in the successful completion of multiple IND filings. Work with external CROs to progress cell therapy and gene editing programs to IND filing.

Responsible for development of translational biomarkers for both efficacy and toxicity from in vivo models, as well as provide oversight and expertise in evaluation of preclinical in vivo models relevant to specific gene therapy targets. Nonclinical representative in the successful completion of multiple IND filings. Work with external CROs to progress cell therapy and gene editing programs to IND filing.

Director responsible for progressing drug candidates into the clinic, by leading project teams responsible for design and implementation of pre-clinical in vivo pharmacology studies, pharmacokinetic studies, safety and toxicity studies, and Investigational New Drug (IND) enabling activities, while maintaining the budget for all program activities and delivering key milestones.

Project leader on pre-clinical drug discovery program focused on oncology and neuropathy indications.

Biologist working on lead optimization drug discovery programs for cancer, kidney disease, and other indications.

Project leader for clinical trial supply chain programs to ensure proper regulatory labeling, distribution, and maintenance of clinical supplies at clinical trial sites. Customers include large international pharmaceutical companies, biotechnology companies, and academic institutions.

• Leader of a matrix team of biologists, chemists, and clinicians in a lead optimization project to investigate the effect of a small molecule inhibitor on the regeneration of skeletal muscle and skeletal muscle pathologies such as Duchenne Muscular Dystrophy. • Leader of a team of cell biologists, in vivo pharmacologists, chemists, and biochemists to understand the effects of a secreted protein on skeletal muscle regeneration.

• Co-Project leader of Myokine discovery effort in collaboration with Biopharm tBDU in Biopharm R&D. • Manager of a direct report to support efforts with the LRH-1 nuclear receptor project, myostatin pathways assay, and Santa Fe pathways effort. • Manager of co-op students and summer intern. • Co-project leader for HTB Lean Sigma efforts. • Member of the Harvard Stem Cell Institute team to investigate therapeutic opportunities of skeletal muscle stem cells and skeletal muscle regeneration and repair. • Developed and ran a cell based screen of new chemical entities in a skeletal muscle stem cell population to be utilized in treatment of skeletal muscle damage and regeneration. • Isolation of mouse stem cells for use in research studies. • Worked closely with respiratory scientists to develop a primary human skeletal muscle cell assay to determine the effect of anti-inflammatory Glucocorticoid receptor compounds in vitro on muscle wasting. • Developed hypothesis for orphan receptor target validation linking RevErbA Alpha and autism. Collaborated with Dr. Rita Cantor at UCLA Medical School to determine if there is a genetic link between RevErbA Alpha and autism. • Developed Glucocorticoid receptor antagonist assay in primary human skeletal muscle cells for validation of anti-cachexia hypothesis as well as to validate antagonist compounds. • Developed amino acid depletion assay in skeletal muscle cells to be run as a medium throughput screen to find novel compounds that will cause increased muscle protein synthesis to be developed as a treatment for sarcopenia. • Ran secondary cell based assays to support the Myostatin Pathways screen to help identify mechanism of action of small molecules found in primary screen.

• Developed cell based models for target validation of the Mineralocorticoid receptor for the treatment of cardiac fibrosis. • Using in vitro cell based assays determined the mechanism of action by which prostaglandin compounds activate NGFIB Beta transcriptional activity. • Determined the mechanism of action of the growth factor FGF19 in bile acid regulation via differential gene expression and protein biochemistry. • Developed cell based assays in both muscle and liver cells to measure activity of RORa compounds and used siRNA to validate effects of compounds.

• Worked with team members to clone all full length human nuclear receptors and subclone into mammalian expression vectors. • Developed Mammalian-Two-Hybrid cell based assay for the Dynamic Stabilization of nuclear receptors, which can be used to screen against compounds to find novel drugs for nuclear receptors. • Generation of reagents for antibody production to Human PNR. • Developed full length NGFIB Beta (NOT1) transient transfection assay. • Developed Gal4 chimera NGFIB Beta (NOT1) transient transfection. • Developed cell based assays to measure activity of RORa compounds. • Worked on Liver X Receptor (LXR) project to help validate hypothesis that transcript profiling can be used to predict effects in phenotypic assays.

Responsibilities: • Upkeep of lab DNA construct book. • Maintenance of radioactivity records. • Maintain and order stock supplies for the lab. • Supervise both work study students and summer interns. • Mating, genotyping, and general maintenance of several knockout mouse colonies. Projects: • Involved in characterizing the internalization, desensitization, recycling, and resensitization of several G-protein coupled receptors. • Helped to characterize functional properties of beta-arrestins interactions with G-protein coupled receptors. • Involved in elucidating the mechanism of clathrin mediated endocytosis. • Generated several Green Fluorescent Protein (GFP) DNA constructs to be used in confocal microscope assays. • Attempted to detect the presence of dopamine transporter mRNA in both the intestines and blood of mice using Northern Blot Analysis and RT-PCR respectively. • Characterized several properties of the dopamine D1 receptor. • Helped generate transgenic mice to re-establish functional losses due to genetic knockout of the VMAT2 gene.