bims-curels 2023-11-12 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2023‒11‒12
eleven papers selected by
Cure Mito Foundation

Induced pluripotent stem cells derived from patients carrying mitochondrial mutations exhibit altered bioenergetics and aberrant differentiation potential.
Trends in rare disease drug development.
Operationalizing the principles of patient engagement through a Patient Advisory Council: Lessons and recommendations.
Mitochondrial Inherited Disorders and their Correlation with Neurodegenerative Diseases.
Including Patient Voices in Continuing Medical Education: One Provider's Experience.
Development of mitochondrial gene-editing strategies and their potential applications in mitochondrial hereditary diseases: a review.
A century of mitochondrial research, 1922-2022.
The Importance of Mitochondrial Disease Testing in Young Adults With New Onset Sensorineural Hearing Loss.
Real-world evidence generation from patients, their caregivers and physicians supporting clinical, regulatory and guideline decisions: an update on Disease Specific Programmes.
The State of Cell and Gene Therapy in 2023.
Nothing About Patients Without Patients: More Than Just a Catchphrase!

Stem Cell Res Ther. 2023 Nov 07. 14(1): 320

Induced pluripotent stem cells derived from patients carrying mitochondrial mutations exhibit altered bioenergetics and aberrant differentiation potential.

Fibi Meshrkey, Kelly M Scheulin, Christopher M Littlejohn, Joshua Stabach, Bibhuti Saikia, Vedant Thorat, Yimin Huang, Thomas LaFramboise, Edward J Lesnefsky, Raj R Rao, Franklin D West, Shilpa Iyer.

  BACKGROUND: Human mitochondrial DNA mutations are associated with common to rare mitochondrial disorders, which are multisystemic with complex clinical pathologies. The pathologies of these diseases are poorly understood and have no FDA-approved treatments leading to symptom management. Leigh syndrome (LS) is a pediatric mitochondrial disorder that affects the central nervous system during early development and causes death in infancy. Since there are no adequate models for understanding the rapid fatality associated with LS, human-induced pluripotent stem cell (hiPSC) technology has been recognized as a useful approach to generate patient-specific stem cells for disease modeling and understanding the origins of the phenotype.METHODS: hiPSCs were generated from control BJ and four disease fibroblast lines using a cocktail of non-modified reprogramming and immune evasion mRNAs and microRNAs. Expression of hiPSC-associated intracellular and cell surface markers was identified by immunofluorescence and flow cytometry. Karyotyping of hiPSCs was performed with cytogenetic analysis. Sanger and next-generation sequencing were used to detect and quantify the mutation in all hiPSCs. The mitochondrial respiration ability and glycolytic function were measured by the Seahorse Bioscience XFe96 extracellular flux analyzer.
RESULTS: Reprogrammed hiPSCs expressed pluripotent stem cell markers including transcription factors POU5F1, NANOG and SOX2 and cell surface markers SSEA4, TRA-1-60 and TRA-1-81 at the protein level. Sanger sequencing analysis confirmed the presence of mutations in all reprogrammed hiPSCs. Next-generation sequencing demonstrated the variable presence of mutant mtDNA in reprogrammed hiPSCs. Cytogenetic analyses confirmed the presence of normal karyotype in all reprogrammed hiPSCs. Patient-derived hiPSCs demonstrated decreased maximal mitochondrial respiration, while mitochondrial ATP production was not significantly different between the control and disease hiPSCs. In line with low maximal respiration, the spare respiratory capacity was lower in all the disease hiPSCs. The hiPSCs also demonstrated neural and cardiac differentiation potential.
CONCLUSION: Overall, the hiPSCs exhibited variable mitochondrial dysfunction that may alter their differentiation potential and provide key insights into clinically relevant developmental perturbations.

Keywords:  Bioenergetics; Differentiation; Mitochondrial disease; Pluripotent stem cell; Reprogramming; Respiration; hiPSC

DOI:  https://doi.org/10.1186/s13287-023-03546-7
Nat Rev Drug Discov. 2023 Nov 06.

Trends in rare disease drug development.

Rui Chen, Sen Liu, Jiashu Han, Shuhua Zhou, Yang Liu, Xiaoyuan Chen, Shuyang Zhang.

DOI: https://doi.org/10.1038/d41573-023-00177-8
Health Expect. 2023 Nov 09.

Operationalizing the principles of patient engagement through a Patient Advisory Council: Lessons and recommendations.

Ingrid Nielssen, Maria Santana, Surakshya Pokharel, Kimberly Strain, Veronika Kiryanova, Sandra Zelinsky, Zoha Khawaja, Prachi Khanna, Anni Rychtera, Anshula Ambasta.

  BACKGROUND: Inclusiveness, Support, Mutual Respect and Co-Build are the four pillars of patient engagement according to the Strategy for Patient-Oriented Research (SPOR). The aim of this manuscript is to describe the operationalization of these principles through the creation of a Patient Advisory Council (PAC) for the research study titled 'Re-Purposing the Ordering of Routine laboratory Tests (RePORT)'.METHODS: Researchers collaborated with the Alberta SPOR SUPPORT Unit (AbSPORU) Patient Engagement Team to create a diverse PAC. Recruitment was intentional and included multiple perspectives and experiences. PAC meetings were held monthly, and patient research partners received support to function as co-chairs of the PAC. Patient research partners were offered training, support and tailored modalities of compensation to actively engage with the PAC. Regular member check-ins occurred through reflexivity and a formal evaluation of PAC member engagement.
RESULTS: The PAC included between 9 and 11 patient research partners, principal investigator, research study coordinator, improvement scientist, resident physician and support members from the AbSPORU team. Twelve monthly PAC meetings were held during the first phase of the project. The PAC made course-changing contributions to study design including study objectives, recruitment poster, interview guide and development of codes for thematic analysis. Patient research partners largely felt that their opinions were valued. Diversity in the PAC membership enhanced access to diverse patient participants. Furthermore, support for co-chairs and patient research partner members enabled active engagement in research. In addition, a culture of mutual respect facilitated patient partner engagement, and co-design approaches yielded rich research outputs.
CONCLUSIONS: Collaboration between research teams and Patient Engagement Teams can promote effective patient engagement through a PAC. Deliberate and flexible strategies are needed to manage the PAC to create an ecology of Inclusiveness, Support, Mutual Respect, and Co-Build for meaningful patient engagement.
PATIENT OR PUBLIC CONTRIBUTION: Patient research partners were involved in the decision to write this manuscript and collaborated equitably in the conception and development of this manuscript, including providing critical feedback. Patient research partners were active members of the PAC and informed the research project design, participant recruitment strategies, data collection and analysis, and will be involved in the implementation and dissemination of results. They are currently involved in the co-development of a patient engagement strategy using a Human-Centered Design process.

Keywords:  Patient Engagement Framework; co-design; patient engagement; patient research partner

DOI:  https://doi.org/10.1111/hex.13909
Endocr Metab Immune Disord Drug Targets. 2023 Nov 01.

Mitochondrial Inherited Disorders and their Correlation with Neurodegenerative Diseases.

Sofjana Gushi, Dr Vasileios Balis PhD Mrsb.

  Mitochondria are essential organelles for the survival of a cell because they produce energy. The cells that need more mitochondria are neurons because they perform a variety of tasks that are necessary to support brain homeostasis. The build-up of abnormal proteins in neurons, as well as their interactions with mitochondrial proteins, or MAM proteins, cause serious health issues. As a result, mitochondrial functions, such as mitophagy, are impaired, resulting in the disorders described in this review. They are also due to mtDNA mutations, which alter the heritability of diseases. The topic of disease prevention, as well as the diagnosis, requires further explanation and exploration. Finally, there are treatments that are quite promising, but more detailed research is needed.

Keywords:  Mitochondria; diagnosis; heritability.; mitochondrial DNA; mitophagy; neurodegeneration; prevention; treatment

DOI:  https://doi.org/10.2174/0118715303250271231018103202
J CME. 2023 ;12(1): 2275504

Including Patient Voices in Continuing Medical Education: One Provider's Experience.

Jennifer McKay, Emma Needham, Wendy Walsh.

  In 2021, UpToDate began offering continuing medical education (CME) planned and delivered by patients. The patient-authored medical topic reviews focus on lessons learned from interactions with the healthcare system and emphasise quality of life for those living with specific conditions. Having access to the patient voice at the point of care provides clinicians with a perspective that can improve patient-provider communication and promote shared decision-making. Participants who viewed the patient-authored topics were emailed a survey about the content; several responses indicated that the new topics were useful in clinical practice. While positive responses demonstrate that clinicians value the patient perspective, we also received replies from participants and from the patient authors themselves indicating there is more work to be done in developing patient-led CME. As more patients are invited to join the conversation, their expertise will be increasingly recognised as integral to CME.

Keywords:  Continuing medical education; continuing education; patient engagement; patient involvement; patient perspective; patient voice; point-of-care education

DOI:  https://doi.org/10.1080/28338073.2023.2275504
Cytotherapy. 2023 Nov 06. pii: S1465-3249(23)01076-9. [Epub ahead of print]

Development of mitochondrial gene-editing strategies and their potential applications in mitochondrial hereditary diseases: a review.

Yanyan Gao, Linlin Guo, Fei Wang, Yin Wang, Peifeng Li, Dejiu Zhang.

  Mitochondrial DNA (mtDNA) is a critical genome contained within the mitochondria of eukaryotic cells, with many copies present in each mitochondrion. Mutations in mtDNA often are inherited and can lead to severe health problems, including various inherited diseases and premature aging. The lack of efficient repair mechanisms and the susceptibility of mtDNA to damage exacerbate the threat to human health. Heteroplasmy, the presence of different mtDNA genotypes within a single cell, increases the complexity of these diseases and requires an effective editing method for correction. Recently, gene-editing techniques, including programmable nucleases such as restriction endonuclease, zinc finger nuclease, transcription activator-like effector nuclease, clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeats-associated 9 and base editors, have provided new tools for editing mtDNA in mammalian cells. Base editors are particularly promising because of their high efficiency and precision in correcting mtDNA mutations. In this review, we discuss the application of these techniques in mitochondrial gene editing and their limitations. We also explore the potential of base editors for mtDNA modification and discuss the opportunities and challenges associated with their application in mitochondrial gene editing. In conclusion, this review highlights the advancements, limitations and opportunities in current mitochondrial gene-editing technologies and approaches. Our insights aim to stimulate the development of new editing strategies that can ultimately alleviate the adverse effects of mitochondrial hereditary diseases.

Keywords:  DddA-derived cytosine base editors (DdCBEs); adenoviruses; mitochondrial DNA (mtDNA); mitochondrially targeted nucleases; mtDNA editing technology; mtDNA heteroplasmy

DOI:  https://doi.org/10.1016/j.jcyt.2023.10.004
Enzymes. 2023 ;pii: S1874-6047(23)00008-2. [Epub ahead of print]54 37-70

A century of mitochondrial research, 1922-2022.

Howard T Jacobs.

  Although recognized earlier as subcellular entities by microscopists, mitochondria have been the subject of functional studies since 1922, when their biochemical similarities with bacteria were first noted. In this overview I trace the history of research on mitochondria from that time up to the present day, focussing on the major milestones of the overlapping eras of mitochondrial biochemistry, genetics, pathology and cell biology, and its explosion into new areas in the past 25 years. Nowadays, mitochondria are considered to be fully integrated into cell physiology, rather than serving specific functions in isolation.

Keywords:  Apoptosis; Calcium homeostasis; Cell signalling; Chemiosmotic hypothesis; DNA replication; Endosymbiosis; Eukaryote origins; Heteroplasmy; Immunity; Krebs cycle; Mitochondrial DNA; Mitochondrial disease; Mitochondrial dynamics; Mitophagy; Oxidative phosphorylation; Reactive oxygen species; Supercomplexes

DOI:  https://doi.org/10.1016/bs.enz.2023.07.002
Ear Hear. 2023 Nov 06.

The Importance of Mitochondrial Disease Testing in Young Adults With New Onset Sensorineural Hearing Loss.

Alaa Koleilat, Gayla L Poling, Lisa A Schimmenti, Linda Hasadsri.

OBJECTIVES: Sensorineural hearing loss (SNHL) occurs commonly as part of mitochondriopathies and varies in severity and onset. In this study, we characterized hearing with specific consideration for hearing loss as a potential early indicator of mitochondrial disease (MD). We hypothesize that genetic testing at the earliest detection of SNHL may lead to an earlier MD diagnosis.DESIGN: We reviewed the clinical and audiometric data of 49 patients undergoing genetic testing for MD.
RESULTS: One-third of individuals with molecularly confirmed MD presented with SNHL. On average, patients had hearing loss at least 10 years before genetic testing. The collective audiometric profile includes mild to moderate SNHL at lower frequencies and moderate SNHL at 2 kHz and higher frequencies.
CONCLUSIONS: This study suggests that screening for SNHL could be an early indicator of MD. We propose that the audiometric profile for those with a MD diagnosis may have clinical triage utility.

DOI: https://doi.org/10.1097/AUD.0000000000001442
Curr Med Res Opin. 2023 Nov 07. 1-16

Real-world evidence generation from patients, their caregivers and physicians supporting clinical, regulatory and guideline decisions: an update on Disease Specific Programmes.

Peter Anderson, Victoria Higgins, Jonathan de Courcy, Katerina Doslikova, Victoria A Davis, Maria Karavali, James Piercy.

  Objective: To update on and describe the role of Disease Specific Programmes (DSPs), a multi-perspective real-world data (RWD) source, in the context of the evolution of the value and acceptance of real-world evidence (RWE) in clinical, regulatory and guideline decision-making.Methods: DSPs are multinational, multi-subscriber, multi-therapy cross-sectional surveys incorporating retrospective data collection from patient, caregiver and physician perspectives. Information collected covers the patient journey, including treatment/prescribing patterns and rationale, patient-reported outcomes, impact on work and everyday activities, attitudes towards and perceptions of the condition, adherence to treatment and burden of illness. Published peer-reviewed DSP papers were aligned with current key RWE themes identified in the literature, alongside their contribution to RWE.Results: RWE themes examined were: using RWE to inform clinical practice, patient and caregiver engagement, RWE role in supporting health technology assessments and regulatory submissions, informing value-driven healthcare decisions, real-world patient subgroup differences and therapeutic inertia/unmet needs; highlighting patients' and caregivers' experience of living with a disease, disconnect from their physicians, unmet needs and educational gaps.Conclusions: DSPs provide a wealth of RWD in addition to evidence generated by registries, clinical trials and observational research, with wide use for the pharmaceutical industry, government, funding/regulatory bodies, clinical practice guideline insights and, most importantly, informing improvements in people's lives. The depth, breadth and heritage of information collected via DSPs since 1995 is unparalleled, extending understanding of how diseases are managed by physicians in routine clinical practice and why treatment choices are made, patients' perceptions of their disease management and caregiver burden.

Keywords:  Caregivers; Cross-sectional; Outcome assessment; Patients; Physicians; Real-world evidence; healthcare

DOI:  https://doi.org/10.1080/03007995.2023.2279679
Mol Ther. 2023 Nov 04. pii: S1525-0016(23)00602-0. [Epub ahead of print]

The State of Cell and Gene Therapy in 2023.

Daniel Chancellor, David Barrett, Ly Nguyen-Jatkoe, Shardha Millington, Fenwick Eckhardt.

Progress in the understanding of human diseases has coincided with the advent of precision medicine, whereby the underlying genetic and molecular contributors can be used as diagnostic and therapeutic biomarkers. To address these, drug developers have designed a range of different treatment strategies, including gene therapy, which the American Society of Gene and Cell Therapy defines as the use of genetic material to treat or prevent disease. A number of approaches exist, including the delivery of genetic material in vivo or ex vivo, as well as the use of RNA species to alter gene expression in particular disease states. Through the end of the first quarter of 2023, there are more than 100 different approved gene, cell, and RNA therapies throughout the world, with over 3,700 more in clinical and preclinical development. This review comprehensively captures the landscape for such advanced therapies, including the different genetic technologies employed and diseases targeted in clinical trials.

DOI: https://doi.org/10.1016/j.ymthe.2023.11.001
Perm J. 2023 Nov 06. 1-5

Nothing About Patients Without Patients: More Than Just a Catchphrase!

Ramin Davidoff, Kerry Litman, Barbara Lewis.

  Health care is sometimes called a "team sport," yet patients were traditionally not considered to be "on the team" in medicine. In 2001, the Institute of Medicine (now National Academy of Medicine) published its seminal book Crossing the Quality Chasm, in which patient-centered care was identified as 1 of 6 quality aims. Many organizations have since included patient-centered care as an important aspect of quality, including The Joint Commission, Centers for Medicare and Medicaid, and many large employers. In the past 10 years, the focus on patient-centered care has expanded in the Kaiser Permanente, Southern California region to include innovative ways for patients to collaborate with health care teams to codesign improvement efforts that are truly patient-centered. We will describe 3 important approaches that have greatly increased the patient-centeredness of our organization: individual patient approaches; adding patients onto health care teams; and effectively utilizing patient and family advisory councils. We will provide examples of how all health care organizations can better partner with their patients to improve their ability to provide higher quality, safer, more equitable, and affordable health care. The slogan "Nothing About Patients Without Patients" was an early rallying cry of the patient engagement movement. It conveyed the idea that as with everything else in our society, patients now expect to have a say in the design and implementation of their care. We show that this is not only possible, but also highly effective and even necessary to improving care.

Keywords:  Patient Engagement; Patient and Family Advisory Councils; Patient-Centered Care

DOI:  https://doi.org/10.7812/TPP/23.103