bims-curels 2024-02-04 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2024–02–04
nine papers selected by
Cure Mito Foundation

Advancing the neuroimaging diagnosis and understanding of mitochondrial disorders.
Mitochondrial diseases and mtDNA editing.
Biomarkers of mitochondrial disorders.
Drug repurposing for rare: progress and opportunities for the rare disease community.
Expanding the genetic spectrum of mitochondrial diseases in Tunisia: novel variants revealed by whole-exome sequencing.
Redefining informed consent form in cell and gene therapy trials.
Mitochondrial damage and impaired mitophagy contribute to disease progression in SCA6.
A Drosophila model of mitochondrial disease phenotypic heterogeneity.
Bridging the gap between scientific research of rare diseases and the affected patients and families.

Neurotherapeutics. 2024 Feb 01. pii: S1878-7479(24)00010-2. [Epub ahead of print]21(1): e00324

Advancing the neuroimaging diagnosis and understanding of mitochondrial disorders.

César Augusto P F Alves, Matthew T Whitehead.

  Mitochondrial diseases, a diverse and intricate group of disorders, result from both nuclear DNA and mitochondrial DNA malfunctions, leading to a decrease in cellular energy (ATP) production. The increasing understanding of molecular, biochemical, and genetic irregularities associated with mitochondrial dysfunction has led to a wider recognition of varying mitochondrial disease phenotypes. This broadening landscape has led to a diverse array of neuroimaging findings, posing a challenge to radiologists in identifying the extensive range of possible patterns. This review meticulously describes the central imaging features of mitochondrial diseases in children, as revealed by neuroimaging. It spans from traditional imaging findings to more recent and intricate diagnoses, offering insights and highlighting advancements in neuroimaging technology that can potentially guide a more efficient and accurate diagnostic approach.

Keywords:  Mitochondrial dysfunction; Mitochondrial neuroimaging; Mitochondrial syndromes

DOI:  https://doi.org/10.1016/j.neurot.2024.e00324
Genes Dis. 2024 May;11(3): 101057

Mitochondrial diseases and mtDNA editing.

Min Song, Lingqun Ye, Yongjin Yan, Xuechun Li, Xinglong Han, Shijun Hu, Miao Yu.

  Mitochondrial diseases are a heterogeneous group of inherited disorders characterized by mitochondrial dysfunction, and these diseases are often severe or even fatal. Mitochondrial diseases are often caused by mitochondrial DNA mutations. Currently, there is no curative treatment for patients with pathogenic mitochondrial DNA mutations. With the rapid development of traditional gene editing technologies, such as zinc finger nucleases and transcription activator-like effector nucleases methods, there has been a search for a mitochondrial gene editing technology that can edit mutated mitochondrial DNA; however, there are still some problems hindering the application of these methods. The discovery of the DddA-derived cytosine base editor has provided hope for mitochondrial gene editing. In this paper, we will review the progress in the research on several mitochondrial gene editing technologies with the hope that this review will be useful for further research on mitochondrial gene editing technologies to optimize the treatment of mitochondrial diseases in the future.

Keywords:  Gene editing; Mitochondrial DNA mutation; Mitochondrialdisease; Transcription activator-like effector nucleases; Zinc finger nucleases

DOI:  https://doi.org/10.1016/j.gendis.2023.06.026
Neurotherapeutics. 2024 Jan 30. pii: S1878-7479(24)00011-4. [Epub ahead of print]21(1): e00325

Biomarkers of mitochondrial disorders.

Brian J Shayota.

  Mitochondrial diseases encompass a heterogeneous group of disorders with a wide range of clinical manifestations, most classically resulting in neurological, muscular, and metabolic abnormalities, but having the potential to affect any organ system. Over the years, substantial progress has been made in identifying and characterizing various biomarkers associated with mitochondrial diseases. This review summarizes the current knowledge of mitochondrial biomarkers based on a literature review and discusses the evidence behind their use in clinical practice. A total of 13 biomarkers were thoroughly reviewed including lactate, pyruvate, lactate:pyruvate ratio, creatine kinase, creatine, amino acid profiles, glutathione, malondialdehyde, GDF-15, FGF-21, gelsolin, neurofilament light-chain, and circulating cell-free mtDNA. Most biomarkers had mixed findings depending on the study, especially when considering their utility for specific mitochondrial diseases versus mitochondrial conditions in general. However, in large biomarker comparison studies, GDF-15 followed by FGF-21, seem to have the greatest value though they are still not perfect. As such, additional studies are needed, especially in light of newer biomarkers that have not yet been thoroughly investigated. Understanding the landscape of biomarkers in mitochondrial diseases is crucial for advancing early detection, improving patient management, and developing targeted therapies.

Keywords:  Biomarker; Mitochondrial disease; Mitochondrial dysfunction

DOI:  https://doi.org/10.1016/j.neurot.2024.e00325
Front Med (Lausanne). 2024 ;11 1352803

Drug repurposing for rare: progress and opportunities for the rare disease community.

Anneliene Hechtelt Jonker, Daniel O'Connor, Maria Cavaller-Bellaubi, Christine Fetro, Maria Gogou, Peter A C 't Hoen, Martin de Kort, Heather Stone, Nivedita Valentine, Anna Maria Gerdina Pasmooij.

  Repurposing is one of the key opportunities to address the unmet rare diseases therapeutic need. Based on cases of drug repurposing in small population conditions, and previous work in drug repurposing, we analyzed the most important lessons learned, such as the sharing of clinical observations, reaching out to regulatory scientific advice at an early stage, and public-private collaboration. In addition, current upcoming trends in the field of drug repurposing in rare diseases were analyzed, including the role these trends could play in the rare diseases' ecosystem. Specifically, we cover the opportunities of innovation platforms, the use of real-world data, the use of artificial intelligence, regulatory initiatives in repurposing, and patient engagement throughout the repurposing project. The outcomes from these emerging activities will help progress the field of drug repurposing for the benefit of patients, public health and medicines development.

Keywords:  drug repurposing; innovation; orphan drugs; rare diseases; therapy development; unmet need

DOI:  https://doi.org/10.3389/fmed.2024.1352803
Front Genet. 2023 ;14 1259826

Expanding the genetic spectrum of mitochondrial diseases in Tunisia: novel variants revealed by whole-exome sequencing.

Ismail Gouiza, Meriem Hechmi, Abir Zioudi, Hamza Dallali, Nadia Kheriji, Majida Charif, Morgane Le Mao, Said Galai, Lilia Kraoua, Ilhem Ben Youssef-Turki, Ichraf Kraoua, Guy Lenaers, Rym Kefi.

  Introduction: Inherited mitochondrial diseases are the most common group of metabolic disorders caused by a defect in oxidative phosphorylation. They are characterized by a wide clinical and genetic spectrum and can manifest at any age. In this study, we established novel phenotype-genotype correlations between the clinical and molecular features of a cohort of Tunisian patients with mitochondrial diseases. Materials and methods: Whole-exome sequencing was performed on five Tunisian patients with suspected mitochondrial diseases. Then, a combination of filtering and bioinformatics prediction tools was utilized to assess the pathogenicity of genetic variations. Sanger sequencing was subsequently performed to confirm the presence of potential deleterious variants in the patients and verify their segregation within families. Structural modeling was conducted to study the effect of novel variants on the protein structure. Results: We identified two novel homozygous variants in NDUFAF5 (c.827G>C; p.Arg276Pro) and FASTKD2 (c.496_497del; p.Leu166GlufsTer2) associated with a severe clinical form of Leigh and Leigh-like syndromes, respectively. Our results further disclosed two variants unreported in North Africa, in GFM2 (c.569G>A; p.Arg190Gln) and FOXRED1 (c.1261G>A; p.Val421Met) genes, and we described the first case of fumaric aciduria in a Tunisian patient harboring the c.1358T>C; p.Leu453Pro FH variant. Conclusion: Our study expands the mutational and phenotypic spectrum of mitochondrial diseases in Tunisia and highlights the importance of next-generation sequencing to decipher the pathomolecular mechanisms responsible for these disorders in an admixed population.

Keywords:  3D structural modeling; Leigh syndrome; North Africa; Tunisia; fumaric aciduria; genetic diagnosis; mitochondrial diseases; whole-exome sequencing

DOI:  https://doi.org/10.3389/fgene.2023.1259826
Perspect Clin Res. 2024 Jan-Mar;15(1):15(1): 4-9

Redefining informed consent form in cell and gene therapy trials.

Varsha Dalal, Geeta Jotwani, Munna Lal Yadav.

  Informed consent is a foundation of the ethical conduct of research involving human participants. Based on the ethical principle of respect for persons, the goal of informed consent is to ensure that participants are aware of the risks and potential benefits and make a voluntary decision about participating in clinical trial research. The extraordinary scientific advances happening globally, have demonstrated the potential of regenerative therapies in transforming the health of the nation by providing a therapeutic option for diseases that were previously considered incurable. These therapies, which include cells and gene therapy (GT) labeled as Advanced Therapeutic Medicinal Products globally, have complex mechanisms of action. Owing to their highly personalized and intricate nature of these therapies, developing the latter often presents unique challenges above and beyond those encountered for small molecule drugs. We recently looked through some cell and GT clinical trials and realized the lacunae in the informed consent form (ICF) provided by the investigators. Especially in a country like India, where the general understanding and perception of patients is limited regarding clinical trials, it is felt that any lapses in the consent process may jeopardize the informed decision-making and safety of the participants and tarnish the reputation of India globally. The present article highlights the need for appropriate patient and public education on the various aspects of cell and gene therapies and aims to address all the elements of ICF in light of the challenges associated with these innovative therapies.

Keywords:  Cell and gene therapy; clinical trial; governance; guidelines; informed consent form; legislation; medical ethics; medical innovation; regulation; transforming healthcare

DOI:  https://doi.org/10.4103/picr.picr_244_22
Acta Neuropathol. 2024 Jan 29. 147(1): 26

Mitochondrial damage and impaired mitophagy contribute to disease progression in SCA6.

Tsz Chui Sophia Leung, Eviatar Fields, Namrata Rana, Ru Yi Louisa Shen, Alexandra E Bernstein, Anna A Cook, Daniel E Phillips, Alanna J Watt.

  Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease that manifests in midlife and progressively worsens with age. SCA6 is rare, and many patients are not diagnosed until long after disease onset. Whether disease-causing cellular alterations differ at different disease stages is currently unknown, but it is important to answer this question in order to identify appropriate therapeutic targets across disease duration. We used transcriptomics to identify changes in gene expression at disease onset in a well-established mouse model of SCA6 that recapitulates key disease features. We observed both up- and down-regulated genes with the major down-regulated gene ontology terms suggesting mitochondrial dysfunction. We explored mitochondrial function and structure and observed that changes in mitochondrial structure preceded changes in function, and that mitochondrial function was not significantly altered at disease onset but was impaired later during disease progression. We also detected elevated oxidative stress in cells at the same disease stage. In addition, we observed impairment in mitophagy that exacerbates mitochondrial dysfunction at late disease stages. In post-mortem SCA6 patient cerebellar tissue, we observed metabolic changes that are consistent with mitochondrial impairments, supporting our results from animal models being translatable to human disease. Our study reveals that mitochondrial dysfunction and impaired mitochondrial degradation likely contribute to disease progression in SCA6 and suggests that these could be promising targets for therapeutic interventions in particular for patients diagnosed after disease onset.

Keywords:  Ataxia; Disease progression; Metabolomics; Mitochondria; Purkinje cell; Transcriptome

DOI:  https://doi.org/10.1007/s00401-023-02680-z
Biol Open. 2024 Feb 02. pii: bio.060278. [Epub ahead of print]

A Drosophila model of mitochondrial disease phenotypic heterogeneity.

Lucy Granat, Debbra Y Knorr, Daniel C Ranson, Ram Prosad Chakrabarty, Navdeep S Chandel, Joseph M Bateman.

  Mutations in genes that affect mitochondrial function cause primary mitochondrial diseases. Mitochondrial diseases are highly heterogeneous and even patients with the same mitochondrial disease can exhibit broad phenotypic heterogeneity, which is poorly understood. Mutations in subunits of mitochondrial respiratory complex I cause complex I deficiency, which can result in severe neurological symptoms and death in infancy. However, some complex I deficiency patients present with much milder symptoms. The most common nuclear gene mutated in complex I deficiency is the highly conserved core subunit NDUFS1. To model the phenotypic heterogeneity in complex I deficiency we used RNAi lines targeting the Drosophila NDUFS1 homolog ND-75 with different efficiencies. Strong knockdown of ND-75 in Drosophila neurons resulted in severe behavioural phenotypes, reduced lifespan, altered mitochondrial morphology, reduced endoplasmic reticulum (ER)-mitochondria contacts and activation of the unfolded protein response (UPR). By contrast, weak ND-75 knockdown caused much milder behavioural phenotypes and changes in mitochondrial morphology. Moreover, weak ND-75 did not alter ER-mitochondria contacts or activate the UPR. Weak and strong ND-75 knockdown resulted in overlapping but distinct transcriptional responses in the brain, with weak knockdown specifically affecting proteosome activity and immune response genes. Metabolism was also differentially affected by weak and strong ND-75 knockdown including gamma-aminobutyric acid (GABA) levels, which may contribute to neuronal dysfunction in ND-75 knockdown flies. Several metabolic processes were only affected by strong ND-75 knockdown including the pentose phosphate pathway and the metabolite 2-hydroxyglutarate (2-HG), suggesting 2-HG as a candidate biomarker of severe neurological mitochondrial disease. Thus, our Drosophila model provides the means to dissect the mechanisms underlying phenotypic heterogeneity in mitochondrial disease.

Keywords:  Complex I deficiency; Metabolism; Mitochondria; Phenotypic heterogeneity; Signalling

DOI:  https://doi.org/10.1242/bio.060278
J Commun Healthc. 2024 Feb 02. 1-3

Bridging the gap between scientific research of rare diseases and the affected patients and families.

Olivia Lannom.

  In 2015, my father was diagnosed with primary progressive aphasia (PPA), a type of frontotemporal dementia that my family and I knew nothing about. Medical professionals told us that there was no research on the disease, and I believed this until very recently. I took a class in neurobiology, leading me to attempt to document this lack of research and create a call to action for the research and treatment of rare disorders. However, I was met with an overwhelming amount of information regarding PPA that I was not expecting to find. I was frustrated that I was not given this information; moreover, I did not understand why it was all being 'hidden' from me. After discussion with my mother, I realized that my science education allowed me to find and interpret this information, but more importantly, that not everyone has this same privilege. My call to action pivoted into a call for better communication and for open access to biomedical information. Regardless of the existence and quality of literature about rare diseases, most of the information is out of reach of the public.The public often does not have the scientific literacy to understand the complexities of the genre that is required for comprehension. I recognize that not every patient and family may wish to access the information generated by biomedical research. I argue that they have a right to examine these findings because they are the ones that are being the most deeply affected by these disorders. While the translation of information may seem cumbersome , the impact it could have on patients, caregivers, and providers is worth the effort.

Keywords:  Primary progressive aphasia; aphasia; dementia; frontotemporal dementia; rare diseases

DOI:  https://doi.org/10.1080/17538068.2024.2309708