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bioRxiv · 10.1101/2024.10.08.617298

Interstitial infusion of purified collagenase Clostridium histolyticum in the cirrhotic liver causes rapid reduction in fibrosis with minimal liver toxicity

Leaker, B. D.·Fuchs, C.·Wise, E.·Tam, J.·Anderson, R. R.
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Abstract

Crude mixtures of matrix-degrading enzymes called collagenase Clostridium histolyticum (CCH) have been used to efficiently breakdown tissue for many years. Recently, direct injection of purified CCH has been successfully developed as a treatment for Dupuytrens contracture (DC), a fibrotic disorder of the hand. Given similar histologic and mechanical features between the fibrous bands in DC and cirrhosis, a similar approach may be feasible for the treatment of cirrhosis. Crude and purified CCH were first compared through composition and substrate specificity. The biodistribution of a macromolecule delivered via interstitial infusion in the liver was mapped and quantified with a fluorescent dextran tracer to design a protocol for efficient delivery throughout the liver with minimal off-target exposure. Safety and efficacy of interstitial CCH infusion in the liver was investigated in cirrhotic mice using serum markers of injury and histological analysis of fibrosis. Purified CCH showed high purity and efficient degradation of type I collagen. Tracer experiments showed that interstitial infusion in one lobe of the liver will reach the entire organ in the mouse. A significant amount of the tracer was also found to enter the bloodstream where it is cleared by the kidneys, but was not found to significantly infiltrate other organs. Mild elevation in liver enzymes AST and ALT were observed 1d after infusion of purified CCH, but this was not significantly different than infusion with saline. No elevation in creatinine was observed. Cirrhotic mice infused with purified CCH showed 38% reduction in collagen proportionate area compared to mice infused with saline. These results show interstitial delivery of purified CCH in the cirrhotic liver rapidly decreases collagen content with minimal liver toxicity. This strategy merits further study as a potential treatment for cirrhosis.

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Leaker, B. D., Fuchs, C., Wise, E., Tam, J., Anderson, R. R.. 2024-10-09. Interstitial infusion of purified collagenase Clostridium histolyticum in the cirrhotic liver causes rapid reduction in fibrosis with minimal liver toxicity. https://doi.org/10.1101/2024.10.08.617298

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