bims-curels 2025-05-11 papers

Issue of 2025–05–11
six papers selected by
Cure Mito Foundation

Am J Med Genet A. 2025 May 09. e64112

Case Report: Unusual Neurological Features of Leigh Syndrome due to m.8993T>G Pathogenic Variant in the MT-ATP6 Gene.

Ramya Treitel, Julie McLaughlin, Marta Frigeni.

The MT-ATP6 gene m.8993T>G pathogenic variant has been associated with Leigh syndrome, especially in patients exhibiting a high degree of heteroplasmy. Although patients may present with a wide phenotypic spectrum, characteristic findings include bilateral, symmetric hyperintensities in the basal ganglia and brainstem on brain MRI, particularly on T2-weighted and fluid-attenuated inversion recovery sequences. Additionally, the biochemical phenotype associated with this pathogenic variant often mimics that of multiple carboxylase deficiency and proximal urea cycle disorders. This report describes a male infant with an atypical neurological presentation of Leigh syndrome. At 2 months of age, he presented with status epilepticus of left temporal origin that was refractory to treatment. Initial brain MRI revealed a large region of non-enhancing signal abnormality in the left temporal lobe, raising concern for an infectious etiology. However, biochemical testing revealed hypocitrullinemia, elevated 3-hydroxyisovalerylcarnitine, elevated propionylcarnitine, and urinary excretion of lactate and pyruvate, prompting further investigation for MT-ATP6 mitochondrial disease. Mitochondrial DNA analysis confirmed the presence of a homoplasmic m.8993T>G pathogenic variant in the MT-ATP6 gene. Despite treatment with citrulline and high-dose biotin, the patient died 5 weeks later due to cardiorespiratory failure following a severe respiratory infection. Retrospective review of his newborn screening revealed two screens positive for low citrulline that were ultimately cleared on a third screen, delaying the diagnosis. This case underscores the importance of considering MT-ATP6 mitochondrial disease in the differential diagnosis of patients presenting with atypical neurological symptoms and biochemical abnormalities. It also highlights the value of newborn screening in identifying potential mitochondrial disorders, where early diagnosis and timely intervention may improve outcomes, even in severe cases.

Keywords: MT‐ATP6 ; Leigh syndrome; hypocitrullinemia; newborn screening; status epilepticus

DOI: https://doi.org/10.1002/ajmg.a.64112

J Med Ethics. 2025 May 07. pii: jme-2024-110122. [Epub ahead of print]

Synthetic DNA and mitochondrial donation: no need for donor eggs?

Adrian Villalba, Iain Brassington, Anna Smajdor, Daniela Cutas.

Mitochondrial replacement therapy has been developed in order to prevent the transmission of mitochondrial mutations, yet it raises ethical concerns, particularly regarding the involvement of third-party DNA and the risks associated with donor procedures. This paper explores an alternative approach using synthetic DNA (synDNA) to construct mitochondrial organelles, thereby bypassing the need for donor oocytes and bypassing risks to donors. We argue that those who support mitochondrial replacement techniques as an ethically acceptable means of preventing the transmission of mitochondrial disease should consider the use of synthetic mitochondria as a preferable ethical alternative, should it prove technically viable. That this will be viable is more than we can demonstrate here. However, progress in synDNA technology suggests that it is not unreasonable to think that synthetic mitochondria creation is feasible, and perhaps even probable.

Keywords: Reproductive Medicine

DOI: https://doi.org/10.1136/jme-2024-110122

JAMA Netw Open. 2025 May 01. 8(5): e258330

Rare Disease Drug Repurposing.

Sally Nijim, Ania Korsunska, Joseph Zinski, Sarah E Bolden, Mary Zuccato, Mileva Repasky, David C Fajgenbaum.

Importance: Treatments are urgently needed for the more than 9500 rare diseases with no US Food and Drug Administration-approved therapies. Although repurposing can be less time- and cost-intensive compared with novel drug development, hurdles have impeded systematic repurposing. Rare disease nonprofit organizations (RDNPs) are well-positioned to overcome barriers and have spearheaded rare disease repurposing efforts for decades. However, no comprehensive data are available on the state of rare disease repurposing or features of successful efforts.
Objective: To characterize the state of rare disease drug repurposing, identify factors associated with successful outcomes, and share thematic insights using the interactive Repurposing of All Drugs, Mapping All Paths (ROADMAP) Project web tool.
Design, Setting, and Participants: The ROADMAP study was a qualitative study using a mixed-methods analysis of US-based RDNP leaders and their stakeholders, including a national survey and semistructured interviews of RDNP leaders, conducted from September 29, 2021, to January 6, 2022. Surveys and interviews revealed themes associated with RDNP strategies, timelines, and support mechanisms. Data were analyzed from January 22, 2024, to April 23, 2024.
Main Outcomes and Measures: The primary survey outcome was the repurposing project stage (abandoned, early, clinical, late, or successful). Qualitative outcomes included themes characterizing repurposing experiences. Two random forest models of drug- and disease- specific as well as organization-specific variables were used to evaluate factor importance toward inferring the project stage. Orthogonal significance testing was conducted using Spearman rank correlation, and P values in each model were corrected for multiple hypothesis testing using a Benjamini-Hochberg procedure.
Results: Representative organizations submitted survey responses, including 147 of 698 potential US-based RDNPs. The median RDNP age was 10 years (IQR, 5-20 years), and the median annual revenue was $355 390 (IQR, $90 028-$946 108). Among 34 leaders who were interviewed, representing 25 RDNPs, 23 were female (67.6%), and the RDNPs had a median age of 15 years (IQR, 6-19 years) and a median revenue of $670 719 (IQR, $193 587-$1 830 890). Among the surveyed RDNPs, 58 of 138 (42.0%) specifically identifying their involvement in repurposing supported repurposing projects, and 94 drugs were in various stages of repurposing, of which 23 met success criteria (5 with US Food and Drug Administration approval and 18 with off-label use with subjective benefit). Survey factors associated with successful outcomes included nonprofit-supported patient recruitment into trials (Gini importance, 3.90; ρ = 0.50; adjusted P < .001) and provision of nonfinancial research support (Gini importance, 0.69; ρ = 0.33; adjusted P = .02). Interview themes were synthesized into a 5-stage repurposing framework with roadblocks and recommendations that included (1) enabling drug repurposing, (2) identifying a drug therapy, (3) validating a drug therapy, (4) clinical use and testing, and (5) reaching an optimal end point for clinical practice.
Conclusions and Relevance: The findings of this qualitative study of RDNP repurposing suggest that several opportunities were associated with successful outcomes and can be considered to optimize systematic repurposing among RDNPs, external collaborators, and policymakers with the use of an interactive tool showcasing insights to facilitate data-driven drug repurposing.

DOI: https://doi.org/10.1001/jamanetworkopen.2025.8330

Int J Mol Sci. 2025 Apr 12. pii: 3670. [Epub ahead of print]26(8):

Uncovering a Novel Pathogenic Mechanism of BCS1L in Mitochondrial Disorders: Insights from Functional Studies on the c.38A>G Variant.

Valeria Capaci, Luisa Zupin, Martina Magistrati, Maria Teresa Bonati, Fulvio Celsi, Irene Marrone, Francesco Baldo, Blendi Ura, Beatrice Spedicati, Anna Morgan, Irene Bruno, Massimo Zeviani, Cristina Dallabona, Giorgia Girotto, Andrea Magnolato.

The BCS1L gene encodes a mitochondrial chaperone which inserts the Fe2S2 iron-sulfur Rieske protein into the nascent electron transfer complex III. Variants in the BCS1L gene are associated with a spectrum of mitochondrial disorders, ranging from mild to severe phenotypes. Björnstad syndrome, a milder condition, is characterized by sensorineural hearing loss (SNHL) and pili torti. More severe disorders include Complex III Deficiency, which leads to neuromuscular and metabolic dysfunctions with multi-systemic issues and Growth Retardation, Aminoaciduria, Cholestasis, Iron Overload, and Lactic Acidosis syndrome (GRACILE). The severity of these conditions varies depending on the specific BCS1L mutation and its impact on mitochondrial function. This study describes a 27-month-old child with SNHL, proximal renal tubular acidosis, woolly hypopigmented hair, developmental delay, and metabolic alterations. Genetic analysis revealed a homozygous BCS1L variant (c.38A>G, p.Asn13Ser), previously reported in a patient with a more severe phenotype that, however, was not functionally characterized. In this work, functional studies in a yeast model and patient-derived fibroblasts demonstrated that the variant impairs mitochondrial respiration, complex III activity (CIII), and also alters mitochondrial morphology in affected fibroblasts. Interestingly, we unveil a new possible mechanism of pathogenicity for BCS1L mutant protein. Since the interaction between BCS1L and CIII is increased, this suggests the formation of a BCS1L-containing nonfunctional preCIII unable to load RISP protein and complete CIII assembly. These findings support the pathogenicity of the BCS1L c.38A>G variant, suggesting altered interaction between the mutant BCS1L and CIII.

Keywords: BCS1L; assembly chaperone; complex III; electron transfer chain; mitochondrial disorder

DOI: https://doi.org/10.3390/ijms26083670

Neth Heart J. 2025 May 08.

The PLN Foundation is striving for a cure, but who owns the disease?

Luuk Kerckhaert, Pieter Glijnis, Annet N Linders, Cor Oosterwijk, Pieter A Doevendans.

The PLN Foundation, established in 2012, supports about 1700 individuals with a phospholamban (PLN) gene mutation causing severe cardiomyopathy. It aims to cure this rare disease by collaborating with universities, research institutions, and biotechnology companies. However, the foundation often faces challenges in being recognised as an equal research partner, with legal departments and technology transfer offices (TTOs) prioritising institutional interests over the public good, leading to delays and inefficiencies. The scientific culture's 'publish or perish' mentality, patent ownership issues, and bureaucratic ethics review processes further complicate progress. To overcome these barriers, the foundation advocates IP co-ownership, patient leadership, streamlined agreements, provisional ethical approvals, improved research logistics, revised evaluation metrics for scientists, and a shift in TTO strategies towards co-creation. These measures aim to enhance collaboration, accelerate therapeutic development, and ensure the accessibility and affordability of new treatments for rare diseases.

Keywords: Foundation; Inherited cardiomyopathy; Intellectual property; Material transfer agreement; Ownership

DOI: https://doi.org/10.1007/s12471-025-01961-4

Trends Mol Med. 2025 May 06. pii: S1471-4914(25)00089-9. [Epub ahead of print]

Targeting mitochondrial transfer as a promising therapeutic strategy.

Bo Li, Bingzhi Li, Xianghe Qiao, Wanrong Meng, Yuhang Xie, Jiajing Gong, Yi Fan, Zhihe Zhao, Longjiang Li.

Despite the primary impression of mitochondria as energy factories, these organelles are increasingly recognized for their multifaceted roles beyond energy production. Intriguingly, mitochondria can transfer between cells, influencing physiological and pathological processes through intercellular trafficking termed 'mitochondrial transfer.' This phenomenon is important in maintaining metabolic homeostasis, enhancing tissue regeneration, exacerbating cancer progression, and facilitating immune modulation, depending on the cell type and microenvironment. Recently, mitochondrial transfer has emerged as a promising therapeutic target for tissue repair and antitumor therapy. Here, we summarize and critically review recent advances in this field. We aim to provide an updated overview of the mechanisms and potential therapeutic avenues associated with mitochondrial transfer in various diseases from the perspective of different donor cells.

Keywords: cancer; immunity; mesenchymal stem/stromal cells MSCs; mitochondrial transfer; regeneration

DOI: https://doi.org/10.1016/j.molmed.2025.04.002