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

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 approaches before their use in humans with the corresponding disease.

Phenotypic and functional characterization of a CD4+ CD25high FOXP3high regulatory T-cell population in the dog

“…55 In this study, we have characterized the phenotype and function of canine CD4 + CD25 high FOXP3 high T cells in vitro, providing direct evidence for the regulatory function of this T-cell subset in dogs -an important veterinary species that also serves as a model for several human diseases, including a number of cancers, [56][57][58] systemic lupus erythematosus 59,60 and several genetic diseases of the haemopoietic system. 61 …”

Optimizing culture conditions of a porcine epithelial cell line IPEC-J2 through a histological and physiological characterization

“…The currently available animal models and in vitro systems have provided significant insights into the basic properties of living cells, relevant to human biology, and numerous experimental models of human diseases have been established (Lloyd et al 2006;Schmid et al 2008;Bauer et al 2009;Wolfe 2009). As in vitro model, Caco-2, a human colon cell line, is frequently used because of its great morphological, ultrastructural, and biochemical similarities with small intestinal epithelial cells (Pinto et al 1983;Hidalgo et al 1989;Perlmutter et al 1989), although questions remain about their functional resemblance to the in vivo situation.…”

Repeated Lentivirus-Mediated Granulocyte Colony-Stimulating Factor Administration to Treat Canine Cyclic Neutropenia

“…Neutrophil counts of ‡ 500 cells/ll provide treatment for neutropenic patients (Morstyn et al, 2001), and our studies suggest this cell number could be attained with a lentivirus dose considerably less than the 10 7 IU/kg used in this study. The study of large-animal models has been important for the successful translation of gene therapy protocols to the clinic (Bauer et al, 2009). Overall, these data from a normal dog and a gray collie dog suggest the absence of immune response to lentivirus administered intramuscularly and indicate that dose escalation may be applied to achieve a desired level of neutrophil production toward the treatment of patients with severe chronic neutropenia.…”