A review of gene therapy in canine and feline models of lysosomal storage disorders

Abstract

Lysosomal storage disorders (LSDs) are inherited diseases that result from the intracellular accumulation of incompletely degraded macromolecules. The majority of LSDs affect both the peripheral and central nervous systems and are not effectively treated by enzyme replacement therapy, substrate reduction therapy, or bone marrow transplantation. Advances in adeno-associated virus and retroviral vector development over the past decade have resurged gene therapy as a promising therapeutic intervention for these monogenic diseases. Animal models of LSDs provide a necessary intermediate to optimize gene therapy protocols and assess the safety and efficacy of treatment prior to initiating human clinical trials. Numerous LSDs are naturally occurring in large animal models and closely reiterate the lesions, biochemical defect, and clinical phenotype observed in human patients, and whose lifetime is sufficiently long to assess the effect on symptoms that develop later in life. Herein, we review that gene therapy in large animal models (dogs and cats) of LSDs improved many manifestations of disease, and may be used in patients in the near future.

Australian Cattle Dogs with Neuronal Ceroid Lipofuscinosis are Homozygous for aCLN5Nonsense Mutation Previously Identified in Border Collies

“…The ovine model is involved with ongoing and planned experiments to evaluate potential therapies for human CLN5 patients . Several canine models have been used to develop therapies for lysosomal storage diseases, and dogs have obvious advantages over sheep in urban research settings. A TPP1 ‐deficient canine NCL model has proven useful in the evaluation of therapies for the human CLN2 form of NCL including an enzyme replacement therapy that is currently in clinical trials in human patients (https://clinicaltrials.gov/ct2/show/NCT01907087).…”

Prolonged Expression of Secreted Enzymes in Dogs After Liver-Directed Delivery ofSleeping BeautyTransposons: Implications for Non-Viral Gene Therapy of Systemic Disease

“…27,28 These animals have been used as translational models for preclinical studies with gammaretroviral and adeno-associated viral vectors. [29][30][31][32][33][34][35][36] Amelioration of the disease has been achieved with liver-directed gamma retroviral gene therapy of neonatal dogs. 36 However, intravenous (i.v.)…”

“…[29][30][31][32][33][34][35][36] Amelioration of the disease has been achieved with liver-directed gamma retroviral gene therapy of neonatal dogs. 36 However, intravenous (i.v.) injection of gamma-retroviral vectors into adult animals was ineffective, even in mice, unless immune responses were blocked.…”

“…37 Immune responses can override achievements of gene therapy by eliminating either the transgenic protein activity or the transduced cells. [36][37][38] Construction of vectors with species-specific therapeutic transgenes and liverspecific promoters that restrict expression to hepatocytes have been shown to reduce, although not eliminate, deleterious immunological responses. [38][39][40] In mice, success of hydrodynamics-based DNA delivery to the liver depends primarily on two parameters: volume and speed of infusion.…”