Impact of gene therapy for canine monogenic diseases on the progress of preclinical studies

Abstract

Rapid progress in knowledge of the organization of the dog genome has facilitated the identification of the mutations responsible for numerous monogenic diseases, which usually present a breed-specific distribution. The majority of these diseases have clinical and molecular counterparts in humans. The affected dogs have thus become valuable models for preclinical studies of gene therapy for problems such as eye diseases, immunodeficiency, lysosomal storage diseases, hemophilia, and muscular dystrophy. Successful gene therapies in dogs have significantly contributed to decisions to run clinical trials for several human diseases, such as Leber's congenital amaurosis 2-LCA2 (caused by a mutation of RPE65), X-linked retinitis pigmentosa-XLRP (caused by mutation RPGR), and achromatopsia (caused by mutation of CNGB3). Promising results were also obtained for canine as follows: hemophilia (A and B), mucopolysaccharidoses (MPS I, MPS IIIB, MPS VII), leukocyte adhesion deficiency (CLAD), and muscular dystrophy (a counterpart of human Duchenne dystrophy). Present knowledge on molecular background of canine monogenic diseases and their successful gene therapies prove that dogs have an important contribution to preclinical studies.

Genetics of retinal degeneration in 2023

“…Numerous animal models of different genetic subtypes of IRDs replicated the human phenotypes enough to develop and test novel therapies to improve outcomes for IRD patients. 1,2 The first gene replacement therapy indicated for IRD, Luxturna (voretigene neparvovec-rzyl), was approved by Health Canada in October 2020 and is now available to patients with vision loss due to inherited retinal dystrophy caused by confirmed biallelic RPE65 mutations. Clinicians from Ontario, Quebec and Alberta can now access this treatment through their province's public health plan.…”

Gene Editing and Gene Therapy: Entering Uncharted Territory in Veterinary Oncology

“…The domestic dog has also been recognized as a valuable model of monogenic diseases in humans and possesses key advantages over inbred rodent models classically used for preclinical studies regarding gene therapy. Not only do causative mutations spontaneously occur in dogs as they do in humans, detailed pedigrees and opportunities to evaluate treatments over a long-term, often years, provide crucial advantages in a preclinical setting (Switonski, 2020).…”

“…As of 2017, hundreds of gene therapy trials have been undertaken to deal with monogenic diseases and researchers have recently been able to shed light on the molecular mechanisms underpinning many disorders to pave the way for novel interventions utilizing gene therapy. Beginning in 1993, the First International DogMap Meeting in Oslo, Norway sought to gain a more in-depth understanding of the genetics driving approximately 700 monogenic diseases known to afflict dog breeds (Switonski, 2020). Although analysis of genome sequence variations between different dog breeds is currently underway (Ostrander et al, 2019), known causative mutations are continuously being identified and approximately 430 monogenic diseases in dogs have the potential to serve as preclinical models for homologous human diseases (Switonski, 2020).…”

“…Beginning in 1993, the First International DogMap Meeting in Oslo, Norway sought to gain a more in-depth understanding of the genetics driving approximately 700 monogenic diseases known to afflict dog breeds (Switonski, 2020). Although analysis of genome sequence variations between different dog breeds is currently underway (Ostrander et al, 2019), known causative mutations are continuously being identified and approximately 430 monogenic diseases in dogs have the potential to serve as preclinical models for homologous human diseases (Switonski, 2020). In fact, gene therapy has shown efficacy in treating many monogenic diseases that afflict both canines and humans and positive results in preclinical canine studies have resulted in the initiation of multiphase clinical trials.…”

“…Gene editing and gene therapy are increasingly used in the human clinic today and their application in companion animals is beginning to emerge. About 700 monogenic diseases have been reported in various dog breeds, with at least 200 of these diseases harboring known causative mutations (Switonski, 2020). About 400 of these spontaneous diseases in dogs are considered potential models for human disorders (https://omia.org/home).…”