# CRISPR-Modified Cardiac Xenograft Transplantation

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $795,705

## Abstract

SUMMARY ABSTRACT: CRISPR-Modified Cardiac Xenograft Transplantation
 The past three years have witnessed two major breakthroughs in heart xenotransplantation. First, the
previously intractable barrier of delayed xenograft rejection (DXR) has been overcome in the pig-to-baboon
heart xeno model. In this model, DXR is manifest primarily as consumptive coagulopathy (CC) in the recipient
and thrombotic microangiopathy (TM) in the graft. Working in the heterotopic model in baboons, our
`Mohiuddin/NIH' group used genetically modified GTKO.hCPRP.hTBM hearts and a treatment regimen
including “induction” T and B depletion, MMF, and steroids – all clinically used drugs – with an experimental
monoclonal antibody directed against CD40. DXR was prevented for as long as CD40 treatment was
continued, and in one instance xenograft survival was extended beyond two years.
 The second major advance came from the Munich group, who reported consistent survival of orthotopic
pig heart xenograft recipients beyond 180 days using our immunomodulatory regimen and
GTKO.hCPRP.hTBM hearts. Accomplishing consistent survival of orthotopic heart xenografts had previously
been prevented by initial xenograft dysfunction (IXD), a phenomenon refractory to concerted efforts by multiple
experienced clinical transplant teams. Importantly, the Munich group found that minimizing graft ischemia was
necessary and sufficient to consistently prevent IXD. Discovering that ischemia minimization was sufficient to
overcome the IXD barrier is a `breakthrough' advance, even as the mechanism of improved graft protection by
ischemia minimization is not yet well understood.
 In this Project, we hypothesize that IXD mechanisms that injure GTKO.hCPRP.hTBM hearts may be
addressed by the additional xeno-focused genetic modifications expressed in one or more versions of Pig 2.0,
created by our collaborators at eGenesis using innovative CRISPR-driven gene editing tools. Pig 2.0 is
designed to address multiple known xeno-specific injury mechanisms through a combination of 12 xeno-
targeted genetic modifications. This Project takes advantage of availability of several well-defined versions of
Pig 2.0, our deep experience with multiple in vitro, ex vivo, and in vivo heart xeno models, and a robust
mechanistic assay capability to determine whether Pig 2.0 is protected from heart IXD, with or without ischemia
minimization (Aim 1). Specifically, we will use these unique resources to learn a) whether versions of Pig 2.0
containing a coagulation cascade regulatory gene cassette are protected from IXD; b) whether ischemia
minimization is necessary and/or sufficient to prevent IXD in susceptible Pig 2.0 hearts; and c) to define a
clinically acceptable immunosuppression regimen for Pig 2.0 hearts in baboons that is consistently safe and
effective (Aim 2). Results from this Project will yield insights likely to catalyze progress for other cell and organ
xenografts, and inform clinical heart xenotransplantation trial ...

## Key facts

- **NIH application ID:** 10033905
- **Project number:** 1R01AI153612-01
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Richard N Pierson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $795,705
- **Award type:** 1
- **Project period:** 2020-06-10 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10033905

## Citation

> US National Institutes of Health, RePORTER application 10033905, CRISPR-Modified Cardiac Xenograft Transplantation (1R01AI153612-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10033905. Licensed CC0.

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