Project 1

Biomarkers of Disease Activity and Progression in Systemic Sclerosis

PI – Robert Lafyatis, MD

Systemic Sclerosis (SSc) is characterized by heterogeneous disease manifestations and variations in disease presentations. Systemic sclerosis (SSc) presents special problems for developing therapies due to the heterogeneous clinical presentation, the variability of disease progression and the difficulty quantifying the extent of disease. Heterogeneous disease progression makes it impossible with currently available clinical tools to tell whose skin and internal organ disease is going to progress, and whose is going to stabilize or improve spontaneously. We have recently shown that expression of four genes in the skin correlates highly with the modified Rodnan skin score (MRSS), suggesting that markers for disease progression, predicting future changes in the MRSS, might also be identified with the proper clinical/pathological samples.

>The first aim in this project is to identify biomarkers predicting future changes in the Modified Rodnan skin score, utilizing RNA expression analyses and immunohistochemical studies targeting markers of vascular inflammation and injury.

Biomarkers of disease activity might supplement or, in early phase trials, replace clinical outcome measures, such as the MRSS, potentially permitting short (open label) trials where the skin score would not normally be expected to change significantly.

> The second aim in this project is to standardize and validate the performance of this 4-gene biomarker of skin disease, by comparing reproducibility in biopsies repeated in adjacent and contralateral forearm, and by examining the change over short and longer periods of time.

Effective treatments for fibrotic disease in SSc are still lacking. TGFβ is the leading candidate for stimulating fibrosis in SSc. Notably, the potent profibrotic cytokine, transforming growth factor-β (TGFβ) regulates two of the genes in our 4-gene skin biomarker (COMP and THS1).

> For the third aim we will conduct a short-term open label trial of the high affinity pan-anti-TGFβ antibody, GC1008. We will test the hypothesize that this antibody will rapidly inhibit TGFβ signature mRNA expression in the 4-gene biomarker, validating utility of the biomarker and providing preliminary proof-of-concept data for a larger clinical trial using this agent.