Precision medicine for systemic sclerosis through pharmacologic

profiling

Rick Neubig – Pharmacology/ToxicologyMichigan State University

VPRGS Precision Medicine – Oct 29, 2015

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.

Multiple pro-fibrotic signals cause myofibroblast activation in fibrosis

CCG-203971

Fibrosis: SclerodermaHuman skin fibroblasts: Gene expression @ 24 hours

CCG-203971 (uM)

CCG-209371 (uM)

Andrew Haak

Fibrosis: Scleroderma

Andrew Haak

Normal skin fibroblasts: aSMA protein @ 72 hours

Fibrosis: Scleroderma

Andrew Haak

SSc patient skin fibroblasts: aSMA protein @ 72 hours

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

• 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

Acknowledgements• Neubig Lab

– Andrew Haak– Erika Lisabeth– Tom Dexheimer

• Scott Larsen– Jessica Bell– Kim Hutchings

• Dinesh Khanna - UM

• Funding– Rye Family– MSU CTSI