Contemporary Animal Models For Human Gene Therapy Applications

Abstract

Over the past three decades, gene therapy has been making considerable progress as an alternative strategy in the treatment of many diseases. Since 2009, several studies have been reported in humans on the successful treatment of various diseases. Animal models mimicking human disease conditions are very essential at the preclinical stage before embarking on a clinical trial. In gene therapy, for instance, they are useful in the assessment of variables related to the use of viral vectors such as safety, efficacy, dosage and localization of transgene expression. However, choosing a suitable disease-specific model is of paramount importance for successful clinical translation. This review focuses on the animal models that are most commonly used in gene therapy studies, such as murine, canine, non-human primates, rabbits, porcine, and a more recently developed humanized mice. Though small and large animals both have their own pros and cons as disease-specific models, the choice is made largely based on the type and length of study performed. While small animals with a shorter life span could be well-suited for degenerative/aging studies, large animals with longer life span could suit longitudinal studies and also help with dosage adjustments to maximize therapeutic benefit. Recently, humanized mice or mouse-human chimaeras have gained interest in the study of human tissues or cells, thereby providing a more reliable understanding of therapeutic interventions. Thus, animal models are of great importance with regard to testing new vector technologies in vivo for assessing safety and efficacy prior to a gene therapy clinical trial.

Harnessing the Potential of Stem Cells for Disease Modeling: Progress and Promises

“…Briefly, gene therapy can be achieved through the use of advanced viral vectors (e.g., lentiviral, adeno-associated, adenoviral, retroviral [80][81][82][83][84][85]) or non-viral vector systems (e.g., liposomes systems) [86] that drive the therapeutic gene to the host cells [87][88][89][90][91]. The safety and efficacy of these strategies may be evaluated in engineered stem cell models, that are suitable for the treatment validation and for the screening of potential mutational insertions caused by the integration of the target gene in the host DNA [92][93][94][95].…”

“…The safety and efficacy of these strategies may be evaluated in engineered stem cell models, that are suitable for the treatment validation and for the screening of potential mutational insertions caused by the integration of the target gene in the host DNA [92][93][94][95]. Thus, even if the use of animal models is still essential before these treatments reach the clinical phase, stem cells are an alternative models enable to test the effectiveness of treatments in a highly efficient, reproducible and fast manner [84][85][86]90,91,96]. For instance, in Adenosine Deaminase Activity (ADA-SCID) immunodeficiency therapy (Strimvelis, GlaxoSmithKline (GSK), approved by EMA in 2016 [97]) ADA-genetically engineered hematopoietic stem cells served as basic cell model for validating the effectiveness of the gene delivery procedure and ultimately were used as therapeutic vehicle in vivo [97].…”

Rabbit Biomodels of Human Diseases Developed Using New Genomic Technologies. Crispr/Cas9 (Review)

“…При равных концентрациях sgRNA Cas9 mRNA в количестве 200 нг/мкл была токсичнее для развития эмбрионов, чем 100 нг/мкл: выживаемость эмбрионов перед трансплантацией составляла 70% против 89%. Отмечены факты съедания неполноценного потомства матерями [27]. Концентрация плазмидных форм компонентов CRISPR/Cas9 (pX330) для введения в пронуклеус, как правило, не превышает 5-10 нг/мкл [31].…”

“…Почти у половины крольчат были индели в обоих экзонах, у двух -большие делеции. По сравнению с предыдущей работой, у Mstn KO новорожденных крольчат был повышенный вес [27]. Такие исследования важны для выяснения безопасности КО MSTN с/х животных, получаемых с целью увеличения мясной продуктивности.…”

“…Животные-модели, имитирующие условия заболевания человека, в генной терапии необходимы при оценке использования вирусных векторов -их безопасности, эффективности, дозировки, локализация экспрессии трансгена в доклинических испытаниях препаратов генной терапии. Наиболее часто в исследованиях генной терапии используются мыши, крысы, кролики, свиньи, гуманизированные мыши [27]. Кролик, классическая модель для изучения офтальмологических и сердечно-сосудистых заболеваний, используется в качестве модели генной терапии этих же заболеваний.…”