Gene-Editing Technologies in the Treatment of Inherited Metabolic Disorders

Inherited metabolic diseases (IMDs), or inborn errors of metabolism, are a varied set of genetic illnesses caused by pathogenic variations in enzymes, transporters, cofactors and other proteins involved in metabolic processes. Such problems may result in accumulation of toxic metabolites, shortage of critical metabolic products or disturbance of cellular homeostasis leading to progressive neurological, hepatic, cardiovascular and other systemic consequences. Although clinical outcomes have improved with dietary modification, pharmaceutical treatment, enzyme replacement therapy and organ transplantation, many IMDs remain difficult to cure and may require life-long management. Gene-editing technologies provide a promising method to tackle inherited illnesses by allowing the precise change of genomic sequences to fix pathogenic mutations, restore gene function, or decrease the generation of toxic metabolites. The major platforms include zinc-finger nucleases, transcription activator-like effector nucleases, CRISPR-associated nucleases, base editors and prime editors. Some metabolic illnesses affecting hepatic pathways, such as hereditary tyrosinaemia, ornithine transcarbamylase deficiency and phenylketonuria have shown treatment potential in preclinical investigations. However, clinical translation is limited by delivery efficiency, off-target modifications, unintentional genetic alterations, immunological responses and uncertainty surrounding long-term safety. This review is focused on the main genetic editing methods, its possible application in inherited metabolic diseases, existing limits and future perspectives for clinical application. Genetic editing may ultimately supplement or supplant traditional treatment but its suitability will have to be determined on a case-by-case basis for each condition and editing modality.