bims-curels 2024-06-30 papers

Issue of 2024–06–30
three papers selected by
Cure Mito Foundation

Expert Opin Biol Ther. 2024 Jun;24(6): 521-528

Gene therapy for Leber hereditary optic neuropathy.

Marco Battista, Valerio Carelli, Leonardo Bottazzi, Francesco Bandello, Maria Lucia Cascavilla, Piero Barboni.

INTRODUCTION: Leber hereditary optic neuropathy (LHON) is among the most frequent inherited mitochondrial disease, causing a severe visual impairment, mostly in young-adult males. The causative mtDNA variants (the three common are m.11778 G>A/MT-ND4, m.3460 G>A/MT-ND1, and m.14484T>C/MT-ND6) by affecting complex I impair oxidative phosphorylation in retinal ganglion cells, ultimately leading to irreversible cell death and consequent functional loss. The gene therapy based on allotopic expression of a wild-type transgene carried by adeno-associated viral vectors (AVV-based) appears a promising approach in mitochondrial disease and its efficacy has been explored in several large clinical trials.
AREAS COVERED: The review work employed basic concepts in mitochondrial diseases, LHON, and gene therapy procedures. Reports from completed trials in LHON (i.e. RESCUE) were reviewed and critically compared.
EXPERT OPINION: New challenges, as the improvement of the contralateral untreated eye or the apparently better outcome in patients treated in later stages (6-12 months), were highlighted by the latest gene therapy trials. A better understanding of the pathogenetic mechanisms of the disease together with combined therapy (medical and gene therapy) and optimization in genetic correction approaches could improve the visual outcome of treated eyes.

Keywords: Leber hereditary optic neuropathy; allotopic expression; gene therapy; mitochondria; viral vector

DOI: https://doi.org/10.1080/14712598.2024.2359015

Parkinsonism Relat Disord. 2024 Jun 19. pii: S1353-8020(24)01056-3. [Epub ahead of print]125 107044

Mitochondrial DNA variants, haplogroups and risk of Parkinson's disease: A systematic review and meta-analysis.

Camille Sena-Dos-Santos, Dafne Dalledone Moura, Matheus Caetano Epifane-de-Assunção, Ândrea Ribeiro-Dos-Santos, Bruno Lopes Santos-Lobato.

BACKGROUND: Growing evidence has shown that mitochondrial dysfunction is part of the pathogenesis of Parkinson's disease (PD). However, the role of mitochondrial DNA (mtDNA) variants on PD onset is unclear.
OBJECTIVES: The present study aims to evaluate the effect of mtDNA variants and haplogroups on risk of developing PD.
METHODS: Systematic review and meta-analysis of studies investigating associations between PD and mtDNA variants and haplogroups.
RESULTS: A total of 33 studies were eligible from 957 screened studies. Among 13,640 people with PD and 22,588 control individuals, the association with PD was consistently explored in 13 mtDNA variants in 10 genes and 19 macrohaplogroups. Four mtDNA variants were associated with PD: m.4336C (odds ratio [OR] = 2.99; 95 % confidence interval [CI] = 1.79-5.02), m.7028T (OR = 0.80; 95 % CI = 0.70-0.91), m.10398G (OR = 0.92; 95 % CI = 0.85-0.98), and m.13368A (OR = 0.74; 95 % CI = 0.56-0.98). Four mtDNA macrohaplogroups were associated with PD: R (OR = 2.25; 95 % CI = 1.92-2.65), F (OR = 1.18; 95 % CI = 1.01-1.38), H (OR = 1.12; 95 % CI = 1.06-1.18), and B (OR = 0.77; 95 % CI = 0.65-0.92).
CONCLUSIONS: Despite most studies may be underpowered by the underrepresentation of people without dominant European- and Asian-ancestry, low use of next-generation sequencing for genotyping and small sample sizes, the identification of mtDNA variants and macrohaplogroups associated with PD strengthens the link between the disease and mitochondrial dysfunction and mtDNA genomic instability.

Keywords: Macrohaplogroups; Parkinson's disease; mitochondrial DNA genomic instability; mitochondrial dysfunction; mitochondrial genome

DOI: https://doi.org/10.1016/j.parkreldis.2024.107044