# Liver Xenotransplantation using CRISPR-modified Porcine Organs

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $771,875

## Abstract

PROJECT SUMMARY / ABSTRACT
Liver transplantation has failed to reach its full potential for saving lives due to the inadequate organ supply.
Every year thousands of potentially salvageable patients die awaiting an allograft, hundreds of others receive a
`marginal” donor organ, often in desperate circumstances, and a many times this number of potential recipients
are never offered listing for lifesaving organs due to the need to ration this precious but limited resource. Liver
xenotransplantation offers a potential solution to the organ shortage but clinical application has been stymied
by four principle hurdles: 1) risk of zoonotic infection of humans, 2) the vigorous immune response mounted to
xenogeneic tissues, and 3) physiologic incompatibilities due to species divergence arising in a rarity of protein:
protein interactions, and if these obstacles can be consistently overcome, the 4) need to identify a clinically
applicable IS regimen.
A new tool with unprecedented potential to address these barriers to widespread application of
xenotransplantation is found in technology such as CRISPR-Cas9 that dramatically increases gene editing
specificity and efficiency. A powerful example is found in recent work by our industry partner, eGenesis, who
used CRISPR-Cas9 to rid the pig genome of 62 copies of functional porcine endogenous retroviruses
(PERVs), essentially eliminating the risk of PERV transmission to an organ recipient. In the current proposal,
we explore the ability of advanced gene editing to address immunologic and physiologic barriers that cause
immediate graft dysfunction of liver xenografts when transplanted into a translational baboon model.
With the general goal preventing initial xenograft dysfunction (IXD) to gain long term survival of pig liver
xenografts in baboon recipients, studies in Aim I will focus on two recently identified potential impediments to
xenograft survival: 1) ischemia reperfusion injury, and 2) platelet consumption. Recent findings in cardiac
xenotransplantation studies have exposed the critical contribution of IR injury to early heart xenograft demise.
Our wealth of experience with ex vivo liver perfusion and also xeno liver perfusion with human blood and the
recently reported technique for ischemia free liver transplants should yield a definitive answer to this question.
Aim II will focus on understanding the impact of gene edits that: 1) eliminate expression of the three major
antibody targets of preformed human anti-pig antibodies, 2) gain expression of human proteins designed to
address complement and coagulation dysregulation occurring with porcine liver xenotransplants in NHP, and
3) mitigate innate and cell-mediated immunity and inflammation. To accomplish this, we will take advantage of
liver transplant, ex vivo liver perfusion with human blood and in vitro assays well established in our lab and a
panel of CRISPR modified pigs with varied expression of genetic edits.

## Key facts

- **NIH application ID:** 9974026
- **Project number:** 1R01AI146248-01A1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** JAMES FRANCIS MARKMANN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $771,875
- **Award type:** 1
- **Project period:** 2020-02-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9974026

## Citation

> US National Institutes of Health, RePORTER application 9974026, Liver Xenotransplantation using CRISPR-modified Porcine Organs (1R01AI146248-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9974026. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*