Genetically modified animal models of hereditary diseases for testing of gene-directed therapy

Abstract

Disease-causing genes have been identified for many severe muscular and neurological genetic disorders. Advances in the gene therapy field offer promising solutions for drug development to treat these life-threatening conditions. Depending on how the mutation affects the function of the gene product, different gene therapy approaches may be beneficial. Gene replacement therapy is appropriate for diseases caused by mutations that result in the deficiency of the functional protein. Gene suppression strategy is suggested for disorders caused by the toxic product of the mutant gene. Splicing modulators, genome editing, and base editing techniques can be applied to disorders with different types of underlying mutations. Testing potential drugs in animal models of human diseases is an indispensable step of development. Given the specific gene therapy approach, appropriate animal models can be generated using a variety of technologies ranging from transgenesis to precise genome editing. In this review, we discuss technologies used to generate small and large animal models of the most common muscular and neurological genetic disorders. We specifically focus on animal models that were used to test gene therapies based on adeno-associated vectors and antisense nucleotides.

CRISPR/Cas9-generated mouse model with humanizing single-base substitution in the Gnao1 for safety studies of RNA therapeutics

“…Personalized medicine holds a huge promise for severe genetic diseases ( Kim et al, 2019 ; Wang et al, 2020 ; Diener et al, 2022 ), and requires the appropriate animal models ( Kalmykov et al, 2018 ; Aartsma-Rus and van Putten, 2019 ; Polikarpova et al, 2022 ; Vázquez-Domínguez and Garanto, 2022 ). Sequence-specific RNA-based drugs, such as antisense oligonucleotides (ASO) and RNAi therapeutics ( Zhu et al, 2022 ; Zogg et al, 2022 ), are currently in development as a new generation of medicine to treat dominant neurological disorders such as Huntington’s disease, amyotrophic lateral sclerosis, spinocerebellar ataxia, and several others ( Zhao et al, 2017 ; Iannitti et al, 2018 ; Miniarikova et al, 2018 ; Southwell et al, 2018 ; Martier et al, 2019 ; Aimiuwu et al, 2020 ).…”

The effect of dalargin on growth factors content in experimental ulcerative colitis

“…The effectiveness of modern methods of UC treatment is fairy moderate, which makes it urgent to search for new ways of treating it (Le Berre et al 2023). Considering the important role of genetic factors in the development of UC, innovative methods, including gene therapy, have an undoubted future (Polikarpova et al 2022); however, new directions for the use of the already known drugs are also important.…”