bims-curels 2024-08-18 papers

Issue of 2024–08–18
seven papers selected by
Cure Mito Foundation

Neurol Neurochir Pol. 2024 Aug 12.

Effects of idebenone treatment in a patient with DNAJC30-associated Leigh Syndrome.

Kamil Dzwilewski, Karol Chojnowski, Magdalena Krygier, Marta Zawadzka, Magdalena Chylińska, Maria Mazurkiewicz-Bełdzińska.

Keywords: DNAJC30; Leigh Syndrome; dystonia; idebenone; mitochondrial disease; optic neuropathy

DOI: https://doi.org/10.5603/pjnns.100423

Sci China Life Sci. 2024 Aug 08.

MSC-mediated mitochondrial transfer restores mitochondrial DNA and function in neural progenitor cells of Leber's hereditary optic neuropathy.

Rui Wang, Feixiang Bao, Manjiao Lu, Xiaoyun Jia, Jiahui Xiao, Yi Wu, Qingjiong Zhang, Xingguo Liu.

Leber's hereditary optic neuropathy (LHON) is a debilitating mitochondrial disease associated with mutations in mitochondrial DNA (mtDNA). Unfortunately, the available treatment options for LHON patients are limited due to challenges in mitochondrial replacement. In our study, we reprogramming LHON urine cells into induced pluripotent stem cells (iPSCs) and differentiating them into neural progenitor cells (NPCs) and neurons for disease modeling. Our research revealed that LHON neurons exhibited significantly higher levels of mtDNA mutations and reduced mitochondrial function, confirming the disease phenotype. However, through co-culturing LHON iPSC-derived NPCs with mesenchymal stem cells (MSCs), we observed a remarkable rescue of mutant mtDNA and a significant improvement in mitochondrial metabolic function in LHON neurons. These findings suggest that co-culturing with MSCs can enhance mitochondrial function in LHON NPCs, even after their differentiation into neurons. This discovery holds promise as a potential therapeutic strategy for LHON patients.

Keywords: energy; induced pluripotent stem cells; mesenchymal stem cells; metabolism; mitochondria; mitochondrial DNA; mitochondrial diseases; stem cells

DOI: https://doi.org/10.1007/s11427-024-2647-8

Clin Pharmacol Ther. 2024 Aug 15.

Pediatric Rare Diseases Development in the Pharmaceutical Industry: An International Consortium for Innovation and Quality in Pharmaceutical Development, Clinical Pharmacology Leadership Group-Pediatrics Working Group, Rare Diseases Subteam Whitepaper Examining the Current Landscape and Recommendations for the Future.

Rajesh Krishna, Bernard Sebastien, Solange Corriol-Rohou, S Y Amy Cheung, Jing Liu, Satyendra Suryawanshi.

Many new opportunities surround rare pediatric disease drug development, thanks to key advances in regulatory thinking and in the scientific community. As rare disease drug development brings challenges to the developers in terms of limited understanding of natural history, heterogeneity in drug response, as well as difficulty recruiting patients in pivotal trials, there has never been a greater need for quantitative integration. To understand how International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) member companies approach pediatric rare disease drug development, the rare pediatric subteam of the Clinical Pharmacology Leadership Group (CPLG) sponsored Pediatrics Working Group conducted a baseline survey to assess the four main pillars of this quantitative innovation, namely, biomarkers and surrogate end points, statistical methodologies, model-informed drug development, as well as public-private partnerships. The survey was administered by IQ and yielded 13 evaluable responders from represented companies. This article presents the key findings from this baseline identifying survey, highlighting the key blind spots, and providing insightful expert opinions to address those gaps. In summary, we call an urgent attention to the community on the opportunities to enhance integration and within-industry learnings from this analysis on aspects related to platform studies, end-to-end quantitative integration, and sharing of trial-level placebo data for better understanding of disease progression and more efficient trial designs. We collectively hope that these findings will stimulate discussion and debate around cross-industry sharing and collaboration to better delineate principles and further enhance the efficiency of rare pediatric disease drug development.

DOI: https://doi.org/10.1002/cpt.3422

Gene. 2024 Aug 13. pii: S0378-1119(24)00734-0. [Epub ahead of print] 148853

Dysregulation of mitochondria, apoptosis and mitophagy in Leber's hereditary optic neuropathy with MT-ND1 3635G>A mutation.

Yingqi Chen, Xiaoyang Wei, Xiaorui Ci, Yanchun Ji, Juanjuan Zhang.

Leber's hereditary optic neuropathy (LHON) is a maternal inherited disorder, primarily due to mitochondrial DNA (mtDNA) mutations. This investigation aimed to assess the pathogenicity of m.3635G>A alteration known to confer susceptibility to LHON. The disruption of electrostatic interactions among S110 of the MT-ND1 and the side chain of E4, along with the carbonyl backbone of M1 in the NDUFA1, was observed in complex I of cybrids with m.3635G>A. This disturbance affected the complex I assembly activity by changing the mitochondrial respiratory chain composition and function. In addition, the affected cybrids exhibited notable deficiencies in complex I activities, including impaired mitochondrial respiration and depolarization of its membrane potential. Apoptosis was also stimulated in the mutant group, as witnessed by the secretion of cytochrome c and activation of PARP, caspase 3, 7, and 9 compared to the control. Furthermore, the mutant group exhibited decreased levels of autophagy protein light chain 3, accumulation of autophagic substrate P62, and impaired PINK1/Parkin-dependent mitophagy. Overall, the current study has confirmed the crucial involvement of the alteration of the m.3635G>A gene in the development of LHON. These findings contribute to a deeper comprehension of the pathophysiological mechanisms underlying LHON, providing a fundamental basis for further research.

Keywords: Apoptosis; Leber’s hereditary optic neuropathy (LHON); MT-ND1 mutation; Mitochondrial dysfunction; Mitophagy

DOI: https://doi.org/10.1016/j.gene.2024.148853

J Clin Med. 2024 Aug 01. pii: 4510. [Epub ahead of print]13(15):

Navigating the Unique Challenges of Caregiving for Children with Rare Diseases: Are the Care Experiences of All Caregivers the Same? A Focus on Life-Limiting Rare Diseases.

Dariusz Walkowiak, Jan Domaradzki, Renata Mozrzymas, Łukasz Kałużny, Jarosław Walkowiak.

Background: Caregiving experiences in rare diseases (RDs) vary based on factors such as specific clinical entity, disease severity, the child's age, and available support and resources, leading to challenges that significantly impact caregivers' lives. This study investigates whether caregivers of children with different RDs encounter varied aspects of care. Methods: This study was conducted as a self-administered, anonymous, computer-assisted online survey, focusing on the challenges of caregiving for children with RDs. Questions covered aspects such as information availability on RDs, diagnostic processes, modern treatment accessibility, family physicians and specialists, the impact of caregiving on personal life, family dynamics, and financial challenges. To achieve our study objectives, we categorized caregivers of children with RDs into two groups to compare various aspects of caregiving: caregivers of children with phenylketonuria (PKU) (n = 175) and those caring for children with life-limiting rare diseases (LLRD) (n = 226). Results: Caregivers of children with LLRD reported greater emotional challenges, personal sacrifices, and financial burdens compared to caregivers of children with PKU. Significant differences included heightened emotional distress, more frequent conflicts, and lower assessments of healthcare support among LLRD caregivers. Although family support ratings were similar between the groups, perceptions of financial concerns and interactions with the healthcare system varied significantly. Conclusions: This study, representing the inaugural systematic comparison of specific caregiver cohorts overseeing children with RDs across a substantial sample size, provides valuable insights. The findings lay a crucial foundation for precisely tailoring assistance and support initiatives to meet the unique needs of caregivers facing various RDs in diverse contexts.

Keywords: PKU; caregivers; children with rare diseases; life-limiting rare diseases; phenylketonuria; rare diseases

DOI: https://doi.org/10.3390/jcm13154510

Aging Dis. 2024 Jul 30.

Mitochondrial Transfer in the Neurovascular Unit, Not Only for Energy Rescue: A Systematic Review.

Daqiang Zhou, Sibo Yang, Jiehong Wu, Yanan Li, Huijuan Jin, Yan Luo, Feng Zhang, Junjie Jiang, Bo Hu, Yifan Zhou.

Despite substantial evidence highlighting molecular communication within the components of neurovascular units (NVU), the interactions at the organelle level have been insufficiently explored in recent decades. Mitochondria, for instance, beyond their traditional role as energy supply for intracellular metabolism and survival, provide a novel perspective on intercellular connections through mitochondrial transfer. These transferred mitochondria not only carry bioactive molecules but also signal to mitigate risks in both healthy and pathological conditions. In this review, we summarized mitochondrial transfer events, relevant routes, and underlying molecular mechanisms originating from diverse cell populations within NVU. We particularly focus on the therapeutic potential of this mechanism in treating central nervous system disorders, notably neurodegenerative diseases marked by mitochondrial dysfunction and then highlight the promising prospects of exogenous mitochondrial supplementation as a treatment target.

DOI: https://doi.org/10.14336/AD.2024.0461

Orphanet J Rare Dis. 2024 Aug 14. 19(1): 298

How to customize common data models for rare diseases: an OMOP-based implementation and lessons learned.

BACKGROUND: Given the geographical sparsity of Rare Diseases (RDs), assembling a cohort is often a challenging task. Common data models (CDM) can harmonize disparate sources of data that can be the basis of decision support systems and artificial intelligence-based studies, leading to new insights in the field. This work is sought to support the design of large-scale multi-center studies for rare diseases.
METHODS: In an interdisciplinary group, we derived a list of elements of RDs in three medical domains (endocrinology, gastroenterology, and pneumonology) according to specialist knowledge and clinical guidelines in an iterative process. We then defined a RDs data structure that matched all our data elements and built Extract, Transform, Load (ETL) processes to transfer the structure to a joint CDM. To ensure interoperability of our developed CDM and its subsequent usage for further RDs domains, we ultimately mapped it to Observational Medical Outcomes Partnership (OMOP) CDM. We then included a fourth domain, hematology, as a proof-of-concept and mapped an acute myeloid leukemia (AML) dataset to the developed CDM.
RESULTS: We have developed an OMOP-based rare diseases common data model (RD-CDM) using data elements from the three domains (endocrinology, gastroenterology, and pneumonology) and tested the CDM using data from the hematology domain. The total study cohort included 61,697 patients. After aligning our modules with those of Medical Informatics Initiative (MII) Core Dataset (CDS) modules, we leveraged its ETL process. This facilitated the seamless transfer of demographic information, diagnoses, procedures, laboratory results, and medication modules from our RD-CDM to the OMOP. For the phenotypes and genotypes, we developed a second ETL process. We finally derived lessons learned for customizing our RD-CDM for different RDs.
DISCUSSION: This work can serve as a blueprint for other domains as its modularized structure could be extended towards novel data types. An interdisciplinary group of stakeholders that are actively supporting the project's progress is necessary to reach a comprehensive CDM.
CONCLUSION: The customized data structure related to our RD-CDM can be used to perform multi-center studies to test data-driven hypotheses on a larger scale and take advantage of the analytical tools offered by the OHDSI community.

Keywords: Artificial intelligence; Common data model; Data standardization; Genotypes and phenotypes; Interoperability; Multi-center studies; OHDSI; OMOP; Rare disease

DOI: https://doi.org/10.1186/s13023-024-03312-9