bims-curels 2025-07-20 papers

Issue of 2025–07–20
eight papers selected by
Cure Mito Foundation

JIMD Rep. 2025 Jul;66(4): e70036

Mitochondrial DNA Pathogenic Variant Prevalence in Primary Mitochondrial Disease Patients With African (L) Mitochondrial Genome Haplogroups.

Surita Meldau, Elizabeth M McCormick, Ibrahim George-Sankoh, Gillian T Riordan, Kashief Khan, Laura E MacMullen, Shrinav Dawlat, Dee Blackhurst, Marni J Falk, Joanna L Elson.

Primary mitochondrial diseases (PMD) are caused by pathogenic variants in over 350 genes, 37 of which are located in mitochondrial DNA (mtDNA). While more than 100 mtDNA variants have confirmed disease associations, there are few reports of mtDNA-related PMD in patients with African heritage, even in well-studied populations. We investigated the frequency of pathogenic mtDNA variants in African L-haplogroups in patients with confirmed PMD from two diagnostic cohorts. Data from genetically confirmed mtDNA-related cases were extracted from existing databases at the National Health Laboratory Service Inherited Metabolic Disease Laboratory in South Africa (SA), and the Children's Hospital of Philadelphia (CHOP) Mitochondrial Medicine Frontier Program (USA). Mitochondrial genome haplogroup context was recorded from existing sequence report data. Stored DNA from the remaining cases was sequenced for mitochondrial genome haplogroup determination. Haplogroup context was obtained for 82 SA and 165 CHOP PMD cases. Sixty-two (47 SA; 15 USA) PMD cases from at least 50 maternal lineages were found to carry L Haplogroups. Unique L sub-haplogroups were identified in 11 (9 SA, 2 USA) families with the m.3243A>G MELAS variant, 6 SA families with the m.11778G>A LHON variant, and 20 (15 SA, 5 USA) cases with single large-scale mtDNA deletions (4 of whom had the 4977 bp common deletion). Several additional well-documented mtDNA pathogenic variants were identified in L-haplogroup context. PMD patient clinical features correlated closely with those described in other haplogroup cohorts. This study demonstrates that common pathogenic mtDNA variants occur in the context of multiple African mtDNA lineages. Disproportionately low diagnostic rates highlight ongoing diagnostic inequalities affecting those on the African continent and African patients globally.

Keywords: African American; South Africa; haplogroup L; haplogroup context; primary mitochondrial disease

DOI: https://doi.org/10.1002/jmd2.70036

N Engl J Med. 2025 Jul 16.

Mitochondrial Donation and Preimplantation Genetic Testing for mtDNA Disease.

BACKGROUND: Children born to women who carry pathogenic variants in mitochondrial DNA (mtDNA) are at risk for a range of clinical syndromes collectively known as mtDNA disease. Mitochondrial donation by pronuclear transfer involves transplantation of nuclear genome from a fertilized egg from the affected woman to an enucleated fertilized egg donated by an unaffected woman. Thus, pronuclear transfer offers affected women the potential to have a genetically related child with a reduced risk of mtDNA disease.
METHODS: We offered mitochondrial donation (by pronuclear transfer) or preimplantation genetic testing (PGT) to a series of women with pathogenic mtDNA variants who sought to reduce the transmission of these variants to their children. Patients with heteroplasmy (variants present in a proportion of copies of mtDNA) were offered PGT, and patients with homoplasmy (variants present in all copies of mtDNA) or elevated heteroplasmy were offered pronuclear transfer.
RESULTS: Clinical pregnancies were confirmed in 8 of 22 patients (36%) and 16 of 39 patients (41%) who underwent an intracytoplasmic sperm injection procedure for pronuclear transfer or for PGT, respectively. Pronuclear transfer resulted in 8 live births and 1 ongoing pregnancy. PGT resulted in 18 live births. Heteroplasmy levels in the blood of the 8 infants whose mothers underwent pronuclear transfer ranged from undetectable to 16%. Levels of the maternal pathogenic mtDNA variant were 95 to 100% lower in 6 newborns and 77 to 88% lower in 2 newborns than in the corresponding enucleated zygotes. Heteroplasmy levels were known for 10 of the 18 infants whose mothers underwent PGT and ranged from undetectable to 7%.
CONCLUSIONS: We found that mitochondrial donation through pronuclear transfer was compatible with human embryo viability. An integrated program involving pronuclear transfer and PGT was effective in reducing the transmission of homoplasmic and heteroplasmic pathogenic mtDNA variants. (Funded by NHS England and others.).

DOI: https://doi.org/10.1056/NEJMoa2415539

Orphanet J Rare Dis. 2025 Jul 16. 20(1): 363

A father's crusade in rare disease drug development: a case study of Elpida therapeutics and Melpida.

Deanna Portero, Qingyang Xu, Aaliya Hussain, Andrew W Lo.

Therapeutic development for rare diseases is difficult for pharmaceutical companies due to significant scientific challenges, extensive costs, and low financial returns. It is increasingly common for caregivers and patient advocacy groups to partner with biomedical professionals to finance and develop treatments for rare diseases. This case study illustrates the story of Terry Pirovolakis, a father who partnered with biomedical professionals to develop the novel gene therapy, Melpida, within 36 months of the diagnosis of his infant son. We identify the factors that led to the success of Melpida and analyze the business model of Elpida Therapeutics, a social purpose corporation founded by Pirovolakis to reproduce the success of Melpida for other rare diseases. We conclude with four lessons from Melpida to inform caregivers like Pirovolakis on developing novel gene therapies to save their loved ones.

DOI: https://doi.org/10.1186/s13023-025-03892-0

Ther Adv Rare Dis. 2025 Jan-Dec;6:6 26330040251357318

Enhancing and leveraging principal investigator and patient advocacy group collaboration in rare disease clinical research-meeting report from the rare Diseases Clinical Research Network.

Kristen Wheeden, Sheridan Meyers, Kristin Anthony, Mirna Chehade, Rogerwene C Gifford, Eileen C King, Michael Seid.

The Rare Diseases Clinical Research Network (RDCRN) works toward faster diagnosis and better treatment for people living with rare diseases, specifically by advancing clinical trial readiness. Inclusion of patient advocacy groups (PAGs) is mandated for each RDCRN consortia; principal investigator (PI)-PAG collaboration is expected to accelerate clinical trial readiness. Real-world examples of PI-PAG collaboration in rare disease clinical research (RDCR) are often not documented nor shared. We report on the Spring 2023 RDCRN meeting, which was dedicated to (a) capturing examples of ways that PAGs and PIs in the RDCRN collaborate, and (b) describing challenges and potential best practices for PAG-PI collaboration. PI and PAG attendees included 50 investigators and staff from 19 consortia and 41 PAG members from 21 consortia. Examples of collaboration in Study Design, Planning and Execution, Funding, and Stakeholder Engagement were captured, as were best practices and challenges to PI-PAG collaboration. Strengthening PI-PAG collaboration can accelerate rare disease research. Documenting real-world examples, and barriers and facilitators of collaboration, from across the RDCRN, supports existing frameworks for accelerating clinical trial readiness.

Keywords: clinical trial readiness; patient-researcher collaboration; rare disease

DOI: https://doi.org/10.1177/26330040251357318

Stem Cells. 2025 Jul 16. pii: sxaf050. [Epub ahead of print]

Neuronal branching in stem cell models of mitochondrial and neurological diseases.

Selene Lickfett, Carmen Menacho, Sidney Cambridge, Alessandro Prigione.

Neuronal branching, the extension and arborization of neurites, is critical for establishing and maintaining functional neural circuits. Emerging evidence suggests that mitochondria play an important role in regulating this process. In this review, we explore how the use of human induced pluripotent stem cell (iPSC)-derived neuronal models in two dimensions (2D) and three dimensions (3D) could help uncover possible mechanisms linking mitochondrial function and dysfunction to neuronal branching capacity. We highlight examples of iPSC-based models of mitochondrial and neurological diseases where aberrant neurite growth has been observed and discuss the potential therapeutic implications. Additionally, we review current methodologies for assessing neurite outgrowth in 2D and 3D neuronal models, addressing their strengths and limitations. Insights gained from these models emphasize the significance of mitochondrial health in neuronal branching and demonstrate the potential of iPSC-derived neurons and brain organoids for studying disrupted neuronal morphology. Harnessing these human stem cell models to devise phenotypic drug discovery platforms can eventually pave the way for innovative therapeutic interventions, particularly in the context of disorders with poorly understood genetic mechanisms and limited therapeutic options.

Keywords: iPSCs; mitochondria; mitochondrial diseases; neurodegeneration; neuronal branching; neurons

DOI: https://doi.org/10.1093/stmcls/sxaf050

Trends Cell Biol. 2025 Jul 10. pii: S0962-8924(25)00146-1. [Epub ahead of print]

Mitochondrial DNA: how does it leave mitochondria?

Vladimir Gogvadze, Boris Zhivotovsky.

In recent years, studies have reported the presence of mitochondrial DNA (mtDNA) in the cytosol. However, a certain number of publications on the mechanisms of mtDNA release contain uncertainties. mtDNA is located in the mitochondrial matrix and cannot be released through the same pathways as intermembrane space proteins. This forum article aims to examine the assumptions and elucidate the processes underlying this phenomenon.

Keywords: Bcl-2 family proteins; inner mitochondrial membrane; mitochondria; mtDNA; outer mitochondrial membrane

DOI: https://doi.org/10.1016/j.tcb.2025.06.005