bims-curels 2023-01-29 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2023–01–29
seven papers selected by
Cure Mito Foundation

Arginine for the Treatment of Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes: A Systematic Review.
Gene-targeted therapies: Towards equitable development, diagnosis, and access.
Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes with an MT-TL1 m.3243A>G point mutation: Neuroradiological features and their implications for underlying pathogenesis.
Analysis of orphan designation status for FDA approved drugs, and case studies in oncology, neuroscience and metabolic diseases.
Laboratory testing for mitochondrial diseases: biomarkers for diagnosis and follow-up.
Diversity, equity, and inclusion in clinical trials: A practical guide from the perspective of a trial sponsor.
THE EVOLVING ROLE OF MEDICAL GENETICISTS IN THE ERA OF GENE THERAPY: AN URGENCY TO PREPARE.

Cureus. 2022 Dec;14(12): e32709

Arginine for the Treatment of Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes: A Systematic Review.

Jennifer M Argudo, Olga M Astudillo Moncayo, Walter Insuasti, Gabriela Garofalo, Alex S Aguirre, Sebastian Encalada, Jose Villamarin, Sebastian Oña, Maria Gabriela Tenemaza, Ahmed Eissa-Garcés, Sakina Matcheswalla, Juan Fernando Ortiz.

  Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a mitochondrial disease that lacks a definitive treatment. Lately, there has been an increased interest in the scientific community about the role of arginine in the short and long-term settings of the disease. We aim to conduct a systematic review of the clinical use of arginine in the management of MELAS and explore the role of arginine in the pathophysiology of the disease. We used PubMed advanced-strategy searches and only included full-text clinical trials on humans written in the English language. After applying the inclusion/exclusion criteria, four clinical trials were reviewed. We used the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol for this systematic review. We used the Cochrane Collaboration risk-of-bias tool to assess the bias encountered in each study. Overall, IV arginine seems to be effective in improving symptoms during acute attacks of MELAS, while oral arginine supplementation increases endothelial function, preventing further stroke-like episodes.

Keywords:  l-arginine; lactic acidosis; melas; melas syndrome; mitochondrial disease; mitochondrial encephalopathy; stroke

DOI:  https://doi.org/10.7759/cureus.32709
Am J Med Genet C Semin Med Genet. 2023 Jan 23.

Gene-targeted therapies: Towards equitable development, diagnosis, and access.

Amy M Gaviglio, Mark W Skinner, Lily J Lou, Richard S Finkel, Erika F Augustine, Aaron J Goldenberg.

Genomic and gene-targeted therapies hold great promise in addressing the global issue of rare diseases. To achieve this promise, however, it is critical the twin goals of equity in access to testing and diagnosis, and equity in access to therapy be considered early in the life cycle of development and implementation. Rare disease researchers and clinicians must simultaneously recognize the life-altering potential of early diagnosis and administration of gene-targeted therapeutics while acknowledging that not everyone who experiences a rare disease and needs these therapies will be able to afford or access them. Achieving equity in the development of and access to gene-targeted therapies will not only require innovations in research, clinical, regulatory, and reimbursement frameworks, but will also necessitate increased attention to the ethical, legal, and social implications when establishing research paradigms and the translation of research results into novel interventions for rare genetic diseases. This article highlights and discusses the growing importance and recognition of health equity across the spectrum of rare disease research and care delivery.

DOI: https://doi.org/10.1002/ajmg.c.32032
Front Neurosci. 2022 ;16 1028762

Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes with an MT-TL1 m.3243A>G point mutation: Neuroradiological features and their implications for underlying pathogenesis.

Helin Zheng, Xuemei Zhang, Lu Tian, Bo Liu, Xiaoya He, Longlun Wang, Shuang Ding, Yi Guo, Jinhua Cai.

   Objective: Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is one of the most common inherited mitochondrial disorders. Due to the high clinical and genetic heterogeneity of MELAS, it is still a major challenge for clinicians to accurately diagnose the disease at an early stage. Herein, we evaluated the neuroimaging findings of MELAS with an m.3243A>G mutation in MT-TL1 and analyzed the possible underlying pathogenesis of stroke-like episodes.
Materials and methods: Fifty-nine imaging studies in 24 patients who had a confirmed genetic diagnosis of m.3243A>G (MT-TL1; tRNA Leu) associated with MELAS were reviewed in our case series. The anatomic location, morphological features, signal/intensity characteristics and temporal evolution of lesions were analyzed on magnetic resonance imaging (MRI), and computed tomography (CT) images. The supplying vessels and metabolite content of the lesions were also evaluated by using MR angiography (MRA)/CT angiography (CTA), and MR spectroscopy (MRS), respectively.
Results: The lesions were most commonly located in the posterior brain, with 37 (37/59, 63%) in the occipital lobe, 32 (32/59, 54%) in the parietal lobe, and 30 (30/59, 51%) in the temporal lobe. The signal characteristics of the lesions varied and evolved over time. Bilateral basal ganglia calcifications were found in 6 of 9 (67%) patients who underwent CT. Cerebral and cerebellar atrophy were found in 38/59 (64%) and 40/59 (68%) patients, respectively. Lesion polymorphism was found in 37/59 (63%) studies. MRS showed elevated lactate doublet peaks in 9/10 (90%) cases. MRA or CTA revealed that the lesion-related arteries were slightly dilated compared with those of the contralateral side in 4 of 6 (67%) cases.
Conclusion: The imaging features of MELAS vary depending on the disease stage. Polymorphic lesions in a single imaging examination should be considered a diagnostic clue for MELAS. Stroke-like episodes may be involved in a complex pathogenetic process, including mitochondrial angiopathy, mitochondrial cytopathy, and neuronal excitotoxicity.

Keywords:  MELAS; m.3243A>G; neuroradiological features; polymorphic lesions; stroke-like episodes

DOI:  https://doi.org/10.3389/fnins.2022.1028762
Bioorg Med Chem. 2023 Jan 18. pii: S0968-0896(23)00018-4. [Epub ahead of print]80 117170

Analysis of orphan designation status for FDA approved drugs, and case studies in oncology, neuroscience and metabolic diseases.

Dean G Brown, Heike J Wobst.

  Many new drugs have been approved over the past decade for rare or orphan diseases. The passage of the Orphan Drug Act (ODA) in 1983 has provided key economic and regulatory incentives to provide medicines for patients who are suffering from rare diseases that may not be commercially attractive for research and development. We have analyzed 497 novel drugs approved from 2010 - June 13, 2022, of which 220 were given orphan designation status. We discuss trends over this time period, potential risks for long development times, and provide example case studies of successful development and launch of novel drugs for rare diseases.

Keywords:  Approved drugs; FDA; Orphan Drug Act (ODA); Orphan drug; Rare disease

DOI:  https://doi.org/10.1016/j.bmc.2023.117170
Crit Rev Clin Lab Sci. 2023 Jan 24. 1-20

Laboratory testing for mitochondrial diseases: biomarkers for diagnosis and follow-up.

Abraham J Paredes-Fuentes, Clara Oliva, Roser Urreizti, Delia Yubero, Rafael Artuch.

  The currently available biomarkers generally lack the specificity and sensitivity needed for the diagnosis and follow-up of patients with mitochondrial diseases (MDs). In this group of rare genetic disorders (mutations in approximately 350 genes associated with MDs), all clinical presentations, ages of disease onset and inheritance types are possible. Blood, urine, and cerebrospinal fluid surrogates are well-established biomarkers that are used in clinical practice to assess MD. One of the main challenges is validating specific and sensitive biomarkers for the diagnosis of disease and prediction of disease progression. Profiling of lactate, amino acids, organic acids, and acylcarnitine species is routinely conducted to assess MD patients. New biomarkers, including some proteins and circulating cell-free mitochondrial DNA, with increased diagnostic specificity have been identified in the last decade and have been proposed as potentially useful in the assessment of clinical outcomes. Despite these advances, even these new biomarkers are not sufficiently specific and sensitive to assess MD progression, and new biomarkers that indicate MD progression are urgently needed to monitor the success of novel therapeutic strategies. In this report, we review the mitochondrial biomarkers that are currently analyzed in clinical laboratories, new biomarkers, an overview of the most common laboratory diagnostic techniques, and future directions regarding targeted versus untargeted metabolomic and genomic approaches in the clinical laboratory setting. Brief descriptions of the current methodologies are also provided.

Keywords:  Mitochondrial diseases; biomarkers; laboratory diagnosis; mass spectrometry; metabolomics

DOI:  https://doi.org/10.1080/10408363.2023.2166013
Contemp Clin Trials. 2023 Jan 23. pii: S1551-7144(23)00015-0. [Epub ahead of print] 107092

Diversity, equity, and inclusion in clinical trials: A practical guide from the perspective of a trial sponsor.

Stacey Versavel, Alicia Subasinghe, Kenasha Johnson, Nicole Golonski, Janna Muhlhausen, Pamela Perry, Raymond Sanchez.

   BACKGROUND: Considering diversity, equity, and inclusion (DEI) in clinical trials ensures that data collected for investigational treatments reflect the populations most likely to benefit from those therapies. Resources and recommendations regarding DEI were assembled by the trial sponsor to assist clinical trial development.
METHODS: A cross-disciplinary team from the sponsoring organization was assembled to inform trial planning and collate resources that promote DEI throughout the clinical trial life cycle.
RESULTS: Representatives from clinical operations, health economic outcomes research, medical affairs, patient advocacy, procurement, and research and development functional groups united together to implement DEI strategies in clinical trials. Planning strategies focus on eligibility, participant/patient engagement, feedback through patient advocacy organizations, and community interactions. Informed site, investigator, and vendor selection at trial startup supports efforts to recruit diverse target trial populations and engage underrepresented businesses; establishing relationships and demographic target-goal tracking should be maintained throughout trial management. Continued communication during trial closeout consolidates learnings and enhances partnerships with trial participants and patient advocacy organizations. The sponsoring organization continuously updates an internal library of resources to facilitate implementation of outlined strategies.
CONCLUSIONS: This first iteration of guidance intends to improve the representation of target populations who will ultimately benefit from investigational therapies; to assist sponsor clinical trial teams in developing recruitment and retention plans; and to ensure compliance with federal granting agencies. The sponsoring organization anticipates data from future clinical trials will help characterize the impact of these initiatives to ensure evidence-based practices are used in future clinical trials to enhance DEI.

Keywords:  And inclusion (DEI); Clinical trial protocols as topic [MeSH term]; Clinical trials as topic [MeSH term]; Cultural diversity [MeSH term]; Diversity; Equity; Patient selection [MeSh term]

DOI:  https://doi.org/10.1016/j.cct.2023.107092
Genet Med. 2023 Jan 19. pii: S1098-3600(23)00028-X. [Epub ahead of print] 100022

THE EVOLVING ROLE OF MEDICAL GENETICISTS IN THE ERA OF GENE THERAPY: AN URGENCY TO PREPARE.

Jerry Vockley, Nicola Brunetti-Pierri, Wendy K Chung, Angus J Clarke, Nina Gold, Robert C Green, Stephen Kagan, Tara Moroz, Christian P Schaaf, Martin Schulz, Elfride De Baere.

  By 2030, it is estimated that at least 30 non-oncology gene therapies will be approved in the United States alone. These therapies could be used to treat up to 50,000 patients annually and have the potential to result in major shifts in disease management pathways. Medical geneticists have well-established roles in the direct management of many rare genetic diseases and often provide support in the diagnosis and care of patients with such diseases. Because an increasing number of gene therapies are likely to become available over the next decade, there is a need to better define the role of medical geneticists within current and future gene therapy pathways and prepare for their expected role within the context of this new treatment paradigm. This commentary examines the current and potential future roles of medical geneticists in gene therapy and identifies specific needs that must be addressed for medical geneticists to assume an expanded leadership role in this area.

Keywords:  Gene therapy; Medical genetics education; Rare diseases

DOI:  https://doi.org/10.1016/j.gim.2023.100022