Large Animal Models of Neurological Disorders for Gene Therapy

Abstract

The development of therapeutic interventions for genetic disorders and diseases that affect the central nervous system (CNS) has proven challenging. There has been significant progress in the development of gene therapy strategies in murine models of human disease, but gene therapy outcomes in these models do not always translate to the human setting. Therefore, large animal models are crucial to the development of diagnostics, treatments, and eventual cures for debilitating neurological disorders. This review focuses on the description of large animal models of neurological diseases such as lysosomal storage diseases, Parkinson’s disease, Huntington’s disease, and neuroAIDS. The review also describes the contributions of these models to progress in gene therapy research.

Gene Therapy in Large Animal Models of Human Genetic Diseases

“…Among these six, 31% of the diseases fall into just five categories—congenital heart disease (63), lysosomal storage disease (57), dwarfism (38), inherited bleeding disorders (33), and inborn errors of metabolism (31)—three of which are the subject of reviews in this issue (Bauer et al 2009; Haskins 2009; Sleeper et al 2009). Other important groups of human diseases for which there are excellent large animal models are the muscular dystrophies and neurological disorders (Gagliardi and Bunnell 2009; Wang et al 2009). …”

Large Animal Models of Genetic Disease: Pertinent IACUC Issues

“…Thus, although some of the articles in this issue discuss bovine, nonhuman primate, and other large animal models of some disorders (e.g., Bauer et al 2009;Stieger et al 2009), these species may make poor models to study interventional therapy because of constraints of time, space, and cost. In cases where the species (e.g., nonhuman primates) mirrors human development (as with brain physiology) or human infectious diseases (such as HIV), these large animal species have become indispensable to the study of conditions such as Parkinsonism and neuroAIDS (Gagliardi and Bunnell 2009). The models may also stand in a hierarchy of appropriateness as therapeutic development progresses; thus the murine model of Krabbe disease supersedes as a fi rst line of study the canine model, which itself precedes the macaque model (Haskins 2009;Gagliardi and Bunnell 2009).…”

“…In cases where the species (e.g., nonhuman primates) mirrors human development (as with brain physiology) or human infectious diseases (such as HIV), these large animal species have become indispensable to the study of conditions such as Parkinsonism and neuroAIDS (Gagliardi and Bunnell 2009). The models may also stand in a hierarchy of appropriateness as therapeutic development progresses; thus the murine model of Krabbe disease supersedes as a fi rst line of study the canine model, which itself precedes the macaque model (Haskins 2009;Gagliardi and Bunnell 2009).…”

“…Scientists identifi ed many of these diseases because of striking and obvious clinical signs, often in the veterinary pediatric period (e.g., Haskins 2009;Bauer et al 2009;Sleeper et al 2009;Koeberl et al 2009;Wang et al 2009). Some of the diseases are serious multisystem disorders-the lysosomal and glycogen storage diseases, metabolic diseases, and neurologic disorders (Gagliardi and Bunnell 2009;Haskins 2009;Koeberl et al 2009). Others are evident at birth, such as gray collie syndrome, or emerge shortly thereafter in conditions such as pneumonia or omphalophlebitis (with canine leukocyte adhesion deficiency or canine X-linked severe combined immune deficiency; Bauer et al 2008).…”

“…For example, hemophilia A and B, most nonneuropathic lysosomal storage diseases, and many immunological diseases may require only a small percentage (5-25%) of normal levels of cells, proteins, or function to achieve substantial clinical benefi t or cure. Some approaches focus on types of tissues or discrete targets such as the retina (Stieger et al 2009), the central nervous system (Gagliardi and Bunnell 2009), skeletal muscle (Wang et al 2009), or cardiomyocytes (Sleeper et al 2009), and in many cases achieve therapeutic levels with current techniques. As interventional genetic methods improve, scientists may develop and use new models suitable for the next generation of more challenging diseases, which may include diffi cult or widespread targets for therapy, such as skin or connective tissue disorders.…”