An analysis of gene therapy for mitochondrial diseases

After the discovery of the first disease related to mitochondrial genome disorder in the late ۱۹۸۰s, thenumber of diseases related to mitochondrial genome defects is increasing. Mitochondrial diseases are agroup of genetic disorders that are characterized by defects in oxidative phosphorylation and caused bymutations in genes in the nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) that encodestructural mitochondrial proteins or proteins involved in mitochondrial function. Mitochondrial diseasesare the most common group of inherited metabolic disorders and are among the most common forms ofinherited neurological disorders. One of the challenges of mitochondrial diseases is the marked clinicalvariation seen in patients, which can delay diagnosis. However, advances in next-generation sequencingtechniques have substantially improved diagnosis, particularly in children. Establishing a geneticdiagnosis allows patients with mitochondrial diseases to have reproductive options, but this is morechallenging for women with pathogenetic mtDNA mutations that are strictly maternally inherited.Recent advances in in vitro fertilization techniques, including mitochondrial donation, will offer a betterreproductive choice for these women in the future. The treatment of patients with mitochondrial diseasesremains a challenge, but guidelines are available to manage the complications of disease. Moreover, anincreasing number of therapeutic options are being considered, and with the development of largecohorts of patients and biomarkers, several clinical trials are in progress. Despite countless advances inthe understanding of mitochondrial disorders, both at the genetic and biochemical levels, there is stillno satisfactory treatment for most of these patients. A major part of this problem is due to the fact thatthe majority of these patients have defects in the respiratory chain that is responsible for energyproduction, and so far no alternative way to deliver energy to these people artificially has been known,as a result, most of the attention has been directed towards the gene therapy of these diseases. Currently,there are three strategies for gene therapy of mitochondrial diseases: inhibiting the replication of thedefective genome using antisense technology, introducing a healthy gene into the mitochondria, andintroducing a healthy gene into the nucleus with the aim of transferring the protein product of the healthygene to the mitochondria. Any success in mitochondrial gene therapy depends on the availability ofsuitable mitochondria-specific carriers. Mitochondrial diseases (MD) are a heterogeneous group ofmultisystem disorders involving metabolic errors. MD are characterized by extremely heterogeneoussymptoms, ranging from organ-specific to multisystem dysfunction with different clinical courses. Mostprimary MD are autosomal recessive but maternal inheritance (from mtDNA), autosomal dominant, andX-linked inheritance is also known. Mitochondria are unique energy-generating cellular organellesdesigned to survive and contain their own unique genetic coding material, a circular mtDNA fragmentof approximately ۱۶,۰۰۰ base pairs. The mitochondrial genetic system incorporates closely interactingbi-genomic factors encoded by the nuclear and mitochondrial genomes. Understanding the dynamics ofmitochondrial genetics supporting mitochondrial biogenesis is especially important for the developmentof strategies for the treatment of rare and difficult-to-diagnose diseases. Gene therapy is one of themethods for correcting mitochondrial disorders.

کلیدواژه ها:

mitochondria ، mitochondrial DNA ، mitochondrial disease ، gene therapy ، precisionmedicine.