precision medicine for systemic sclerosis through pharmacologic profiling
TRANSCRIPT
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Precision medicine for systemic sclerosis through pharmacologic
profiling
Rick Neubig – Pharmacology/ToxicologyMichigan State University
VPRGS Precision Medicine – Oct 29, 2015
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Scleroderma/Systemic Sclerosis• Excessive deposition of collagen and other
extracellular matrix components – Skin, Lungs, Kidney, etc.
• Unknown cause – Relatively young onset (ages of 25 to 55)– Women>men (4:1)
• Most current therapies – target inflammation – have shown limited efficacy
• Identifying ways to disrupt the fibrosis mechanism itself could provide new and more effective therapies for SSc.
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Multiple pro-fibrotic signals cause myofibroblast activation in fibrosis
CCG-203971
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Fibrosis: SclerodermaHuman skin fibroblasts: Gene expression @ 24 hours
CCG-203971 (uM)
CCG-209371 (uM)
Andrew Haak
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Fibrosis: Scleroderma
Andrew Haak
Normal skin fibroblasts: aSMA protein @ 72 hours
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Fibrosis: Scleroderma
Andrew Haak
SSc patient skin fibroblasts: aSMA protein @ 72 hours
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Hypothesis• Different SSc patients will have distinct
mechanisms of myofibroblast activation in vitro
• Genomic subtyping has only marginally helped identify specific therapies for SSc
• Identifying known clinical drugs (repurposing) that differentially affect myofibroblasts in vitro could define precision SSc therapies
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• Drug Repurposing Screen in Assay Development and Drug Repurposing Core
• Primary human SSc fibroblasts (18 patients)• 384-well plate aSMA immunohistochemistry• ~5,000 compounds
– Preswick Clinical Collection – 1,280– Microsource Spectrum – 2,400– LOPAC – 1,280– GSK Kinase Inhibitor Collection - 563
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Acknowledgements• Neubig Lab
– Andrew Haak– Erika Lisabeth– Tom Dexheimer
• Scott Larsen– Jessica Bell– Kim Hutchings
• Dinesh Khanna - UM
• Funding– Rye Family– MSU CTSI