Emerging Therapies for Inborn Errors of Metabolism: Enzyme Replacement, Gene Therapy, Genome Editing

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Abstract Inborn Errors of Metabolism (IEMs) are a heterogeneous collection of inherited genetic illnesses resulting from abnormalities in enzymes, transport proteins, or cofactors involved in important metabolic pathways. These deficiencies interfere with normal biochemical processes leading to buildup of harmful metabolites, deficiency of important metabolic products and gradual multisystem dysfunction. Vitamin supplementation, dietary modification and supportive care remain the mainstay of treatment for many metabolic disorders, but these traditional treatments do not address the underlying molecular defects. Molecular medicine has revolutionised the treatment landscape through disease-modifying methods that address the underlying genetic or enzymatic abnormality. Enzyme Replacement Therapy (ERT) has emerged as an established treatment for several lysosomal storage disorders, with a relevant positive impact on survival and quality of life. More recently, gene therapy and genome editing technologies have emerged as promising approaches to restore normal gene function or permanently fix disease-causing mutations. In addition, emerging novel therapeutic modalities for inherited metabolic diseases, such as messenger RNA (mRNA)-based therapies, pharmacological chaperones and substrate reduction therapy, are expanding the treatment options for patients. Despite the tremendous advances, there are still challenges such as immune related adverse effects, poor tissue targeting, high cost of treatment, ethical issues and uncertainty in long-term efficacy and safety. Many of these restrictions are likely to be solved by improvements in genomic medicine, vector engineering and precision medicines. This review summarises concepts, mechanisms, clinical uses, current limits and future possibilities of enzyme replacement therapy, gene therapy and genome-editing technologies for the management of inborn errors of metabolism.

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