Abstract
ABSTRACTFor many genetic diseases, researchers are developing personalized medicine approaches. These sometimes employ custom genetic interventions such as antisense-mediated exon skipping or genome editing, aiming to restore protein function in a mutation-specific manner. Animal models can facilitate the development of personalized medicine approaches; however, given that they target human mutations and therefore human genetic sequences, scientists rely on the availability of humanized animal models. Here, we outline the usefulness, caveats and potential of such models, using the example of the hDMDdel52/mdx model, a humanized model recently generated for Duchenne muscular dystrophy (DMD).
Highlights
Genetic mutations underlie thousands of different inherited diseases
Gene addition therapy has historically been an obvious choice for genetic diseases caused by the inactivation of a particular gene
Progress has been made for personalized medicine approaches aimed at modifying the diseasecausing gene through genome editing (Box 1), or its transcript through modulation of splicing (Box 1) to allow production of the missing protein (Verhaart and Aartsma-Rus, 2019)
Summary
Genetic mutations underlie thousands of different inherited diseases. With the advance of DNA sequencing approaches, such as massively parallel sequencing (see Box 1, Glossary), it is feasible to provide a genetic diagnosis for more and more diseases (Lochmüller et al, 2018; Boycott et al, 2019). Progress has been made for personalized medicine approaches aimed at modifying the diseasecausing gene through genome editing (Box 1), or its transcript through modulation of splicing (Box 1) to allow production of the missing protein (Verhaart and Aartsma-Rus, 2019) Most such genetic diseases are caused by a variety of mutations and mutation types, distributed over the gene. AON binding renders this target exon inaccessible to the splicing machinery and it is not included in the mRNA This way, the genetic deletion becomes enlarged at the mRNA level, because exon skipping restores the reading frame, this mRNA can be translated into shorter, BMD-like dystrophins. Clinical trials of exon 45 and exon 53 skipping AONs from various companies are currently ongoing, Actin-BD
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