Genetically modified large animal models for investigating neurodegenerative diseases

Abstract

Neurodegenerative diseases represent a large group of neurological disorders including Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, and Huntington’s disease. Although this group of diseases show heterogeneous clinical and pathological phenotypes, they share important pathological features characterized by the age-dependent and progressive degeneration of nerve cells that is caused by the accumulation of misfolded proteins. The association of genetic mutations with neurodegeneration diseases has enabled the establishment of various types of animal models that mimic genetic defects and have provided important insights into the pathogenesis. However, most of genetically modified rodent models lack the overt and selective neurodegeneration seen in the patient brains, making it difficult to use the small animal models to validate the effective treatment on neurodegeneration. Recent studies of pig and monkey models suggest that large animals can more faithfully recapitulate pathological features of neurodegenerative diseases. In this review, we discuss the important differences in animal models for modeling pathological features of neurodegenerative diseases, aiming to assist the use of animal models to better understand the pathogenesis and to develop effective therapeutic strategies.

Recognising the potential of large animals for modelling neuromuscular junction physiology and disease

“…For example age-dependent changes effect readouts in ALS, and mutations in superoxide dismutase 1 (SOD1) are among those linked to familial forms of ALS. [In a SOD1 -G93A transgenic pig model, movement disorders along with SOD1 nuclear accumulation and ubiquitinated nuclear aggregates appeared (Yang et al, 2014), something not observed in SOD1-G93A mouse models (Yang et al, 2021).] Thus, phenotypic differences between transgenic SOD1 mice and pigs suggest that large animal models might recapitulate better the age-dependent change observed in human patients.…”

“…As outlined in the previous section, for a model to be successful, it needs to mimic the human condition; in the context of NMJ research at least, large mammalian models might offer a solution to some phenotypic and physiological translational issues. The longer lifespan of larger mammals (for example), in comparison to rodents, has great appeal for research, as this could allow for more accurate modelling of chronic neurodegenerative disorders such as Parkinson's Disease, Spinal muscular atrophy (SMA) and Amyotrophic lateral sclerosis (ALS) (Duque et al, 2015;Eaton & Wishart, 2017;Holm et al, 2016;Yang et al, 2021) at pre-clinical levels or for following long term treatments. For example age-dependent changes effect readouts in ALS, and mutations in superoxide dismutase 1 (SOD1) are among those linked to familial forms of ALS.…”

Application of CRISPR/Cas9 System in Establishing Large Animal Models

“…CRISPR/Cas9 editing monkeys have already shown better phenotypes in human diseases than mouse models despite a limited number of successfully established models ( Seita et al, 2020 ; Yang et al, 2021 ; Yin et al, 2022 ). Yang et al generated PTEN-induced kinase 1 ( PINK1 , whose mutations cause early-onset Parkinson’s disease (PD) mutant monkeys by targeting two exons in the PINK1 gene ( Yang et al, 2019a ; Yang et al, 2019b ), which showed remarkable neuronal loss in the cortex, substantia nigra and striatum. However, neuronal loss was not reported in Pink1 KO mice ( Kitada et al, 2007 ; Dawson et al, 2010 ) or pigs ( Zhou et al, 2015 ; Wang et al, 2016b ).…”

Huntingtin Co-Isolates with Small Extracellular Vesicles from Blood Plasma of TgHD and KI-HD Pig Models of Huntington’s Disease and Human Blood Plasma

“…Several HD animal models have been generated, including nematode, insect, fish, rodent or large mammals [ 18 , 19 , 20 , 21 , 22 , 23 ]. The pig models, rather than small mammals, share anatomical, physiological, and pathophysiological similarities with human, and allow the generation of genetically modified models for translational research [ 22 , 24 , 25 , 26 ]. Minipigs have adult body weight of 80–110 kg and a long life span (15–20 years), have a gyrencephalic brain with human like neuroanatomy, and blood supply which makes them an ideal representative model of human neurodegenerative disease pathology, progression, and therapeutic interventions [ 22 , 27 , 28 ].…”