Online Issues

Journal Vol 50 (2)

Potential Large Animal Models for Gene Therapy of Human Genetic Diseases of Immune and Blood Cell Systems

Thomas R. Bauer Jr., Rima L. Adler, and Dennis D. Hickstein

Thomas R. Bauer Jr., PhD, is a staff scientist; Rima L. Adler, PhD, was a postdoctoral research fellow; and Dennis D. Hickstein, MD, is an investigator and Head of the Molecular Oncology and Gene Transfer Section, all in the Experimental Transplantation and Immunology Branch of the Center for Cancer Research at the National Cancer Institute of the National Institutes of Health in Bethesda, Maryland.

Address correspondence and reprint requests to Dr. Thomas R. Bauer Jr., NCI/ETIB, 10 Center Drive, MSC1203, Bldg 10-CRC, Rm 3-3264, Bethesda, MD 20892 or email bauert@mail.nih.gov.

Abstract

Genetic mutations involving the cellular components of the hematopoietic system—red blood cells, white blood cells, and platelets—manifest clinically as anemia, infection, and bleeding. Although gene targeting has recapitulated many of these diseases in mice, these murine homologues are limited as translational models by their small size and brief life span as well as the fact that mutations induced by gene targeting do not always faithfully reflect the clinical manifestations of such mutations in humans. Many of these limitations can be overcome by identifying large animals with genetic diseases of the hematopoietic system corresponding to their human disease counterparts. In this article, we describe human diseases of the cellular components of the hematopoietic system that have counterparts in large animal species, in most cases carrying mutations in the same gene (CD18 in leukocyte adhesion deficiency) or genes in interacting proteins (DNA cross-link repair 1C protein and protein kinase, DNA-activated catalytic polypeptide in radiation-sensitive severe combined immunodeficiency). Furthermore, we describe the potential of these animal models to serve as disease-specific preclinical models for testing the efficacy and safety of clinical interventions such as hematopoietic stem cell transplantation or gene therapy before their use in humans with the corresponding disease.

Key Words: anemia; gene therapy; genetic disease; hematopoietic; immunodeficiency; integrin; leukocyte; transplantation