HSP47: a potential target for fibrotic diseases and implications for therapy

ABSTRACT

Introduction: Chronic fibrotic disorders are challenging clinical problems. The major challenge is the identification of specific targets expressed selectively in fibrotic tissues. Collagen accumulation is the hallmark fibrosis. HSP47 is a collagen-specific chaperon with critical role in collagen folding. This review discusses the anti-fibrotic potential of HSP47.

Areas covered: This review compiles data retrieved from the PubMed database with keywords ‘HSP47+fibrosis’ from 01/2005 to 06/2020. We examined 1) collagen biology and its role in fibrotic diseases, 2) HSP47 role in fibrosis, 3) HSP47 inhibition strategies and 4) clinical investigations.

The identification of the HSP47-collagen binding site led to the development of methods to screen HSP47 inhibitors with anti-fibrotic potential. Specificin vivo delivery systems of HSP47 siRNA to fibrotic tissue reduced collagen production/secretion associated with fibrosis inhibition in preclinical models. This strategy is about to be tested in clinical trials.

Expert opinion: As a collagen-specific chaperon, HSP47 is a promising therapeutic target in fibrosis. Preclinical models have shown encouraging anti-fibrotic results. Anti-HSP47 strategies need to be further evaluated in clinical trials. The increase in circulating-HSP47 in lung fibrosis patients highlights the potential of HSP47 as a noninvasive biomarker and may represent an important step toward personalized medicine in fibrotic disorders.

KEYWORDS:

• collagen
• chaperon
• fibrosis
• heat shock protein 47

Article highlights

• HSP47 is an ER-chaperon specific for collagen

• HSP47 deficiency leads to misfolded collagen accumulation in the ER resulting in delays in collagen secretion and reduced extracellular collagen fibrils.

• HSP47 inhibition has been proved successful to reduce fibrosis in preclinical models of fibrosis

• Circulating HSP47 appears as a relevant biomarker of fibrosis severity in patients

• Clinical evaluation of safety/tolerability/efficacy of HSP47 inhibition remains to be investigated

Disclosure statement

Philippe Bonniaud reports personal fees for advisory board work and travel support for meeting attendance from Roche and Novartis, personal fees for advisory board work and reimbursement of meeting registration from Boehringer, personal fees for advisory board work from TEVA and AstraZeneca, travel support for meeting attendance from Chiesi, reimbursement of meeting registration from Stallergene, all outside the submitted work. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

Olivier Burgy is supported by the French ‘Investissements d’Avenir’ programme, project ISITE-BFC (ANR-15-IDEX-0003). Philippe Bonniaud acknowledges funding from the Agence Nationale de la Recherche (ANR-16-CE14-0004-01 SHOT-IPF).