# Hepatocyte Transplantation for Liver Based Metabolic Disease

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $958,429

## Abstract

Transplantation of isolated parenchymal cells has great promise as a minimally invasive therapy and partial
success has been reported for several rare metabolic liver diseases. Major limitations to the technique include
an inability to transplant an adequate mass of donor hepatocytes, and lack of a sensitive enough technology to
monitor the status of transplanted cells. This proposal includes several major innovations in understanding
hepatocyte transplant biology and optimizing its application. In animal models liver-directed radiation facilitates
repopulation of the native liver by transplanted hepatocytes. Unfortunately, the standard clinical and laboratory
signs that identify rejection in solid organ transplantation are not useful in recipients of cell transplants, and the
sensitivity of functional changes following hepatocyte transplant is inadequate to diagnose rejection before
damage to the allograft is irreversible. The availability of assays that would allow non-invasive monitoring of
graft function and assessment of rejection risk would facilitate more rational management of patients following
hepatocyte transplantation. As diseases targeted for treatment by hepatocyte transplantation are rare, and
most reports involve anecdotal experience in a diverse patient population, we will transplant patients with
phenylketonuria (PKU), a disease with an incidence that will make adequate patient enrollment possible.
Phenylalanine hydroxylase (PAH) deficiency, traditionally known as PKU was the original motivation for
population-based newborn screening. However, standard dietary management strategies have failed in older
adolescents and adults due to difficulty in adhering to diet, leading to diminished executive function, and other
neurologic and neuropsychiatric problems. The proposal has three specific aims. Aim 1 is to confirm the safety
of liver-directed radiation conditioning and document 5-10% replacement of host hepatocytes by donor
hepatocytes. We hypothesize that use of multiple donors and pre-transplant hepatic radiation conditioning will
lead to competitive repopulation of the host liver and clinical correction of PAH deficiency in patients with PKU,
a model disease for treatment of liver-based metabolic diseases. Aim 2 is to identify graft rejection by
immunologic monitoring and to successfully treat it before the process is irreversible. We hypothesize that
monitoring rejection risk by a proven assay of donor-specific T cell immune reactivity can be used to assess
the adequacy of immune suppression following cell transplantation. Aim 3 is to determine the extent to which
use of real-time measures of donor hepatocyte function, rather than use of surrogates, will allow assessment of
graft function after hepatocyte transplantation. We hypothesize that isotopic Phe turnover studies in PKU
patients can more effectively measure changes in Phe metabolism than standard measures. These results will
be important for the possible transplantatio...

## Key facts

- **NIH application ID:** 9966995
- **Project number:** 5R01DK117916-03
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Ira J. Fox
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $958,429
- **Award type:** 5
- **Project period:** 2018-08-10 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9966995

## Citation

> US National Institutes of Health, RePORTER application 9966995, Hepatocyte Transplantation for Liver Based Metabolic Disease (5R01DK117916-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9966995. Licensed CC0.

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