Inborn errors of metabolism are a group of rare genetic disorders that result from the impaired function of an enzymatic protein, thus leading to a defective metabolic pathway. This classically results in the buildup of toxic intermediates, loss of energy production or depletion of essential metabolites, or a combination of these mechanisms. Many of these diseases require life-long treatments heavily impacting on the quality of life of the patients and their families. Moreover, in many cases the available treatment options are only palliative and patients remain at risk of severe metabolic and/or neurological complications. Since many of these conditions involve the liver metabolic activity, liver transplantation can represent an effective treatment. However, due to the limited availability of compatible organs and the complications related to the procedure, new therapeutic options are needed.

The liver has been demonstrated to be a relevant target organ for gene therapy, because of its high metabolic and secretory activity, its abundant blood supply and extensive highly permeable microvasculature, which facilitates access of viral and non-viral particles to hepatocytes. The recent development of genome editing technologies enable the precise and permanent modification of a target DNA sequence. In this context, the combination of liver targeted gene delivery methods and genome editing platforms can allow for the correction of specific disease-causing mutations via base or prime editing, or the insertion of a correct copy of the mutated gene at a specific genomic locus. These strategies could potentially overcome some limitations of the canonical gene replacement therapy with viral vectors, because they offer the possibility of correcting the gene defect at the endogenous site, thus maintaining the physiological gene regulation. Moreover, they would guarantee a stable expression of the therapeutic protein after a single administration of the treatment, even when treating young paediatric patients whose liver is actively growing. Important challenges remain to be addressed, such as the potential off-target effects on the genome, the editing efficiency required to achieve therapeutic benefit and the potential immune-response against the bacteria-derived nucleases.

Areas to be covered in this Research Topic may include, but are not limited to:

• Genome editing platform engineering and delivery optimization for liver specific targeting (viral and non-viral vehicles optimization)
• Biodistribution of genome editing components with particular focus on liver zonation
• Correlation between the state of the liver (e.g. healthy or diseased liver) and the delivery efficiency of genome editing components and their mode of action
• Corrective strategies for the treatment of genetic disorders: gene replacement, gene disruption, genome targeting, and precise correction of disease-causing mutations by base and prime editing
• Cross-correction of extra-hepatic tissue by liver gene targeting
• Safety and efficacy of genome editing approaches: evaluation of long-term therapeutic correction on in vivo disease models, evaluation of on-target and off-target genomic modifications, and immune-responses against the editing components

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Frontiers in Genome Editing

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