bims-curels 2023-11-19 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2023–11–19
ten papers selected by
Cure Mito Foundation

Teamwork makes the dream work: functional collaborations between families, scientists, and healthcare providers to drive progress in the treatment of Leigh Syndrome.
Genetic analysis and multimodal imaging identify novel mtDNA 12148T>C leading to multisystem dysfunction with tissue-specific heteroplasmy.
Avenues for Strengthening PCORnet's Capacity to Advance Patient-Centered Economic Outcomes in Patient-Centered Outcomes Research (PCOR).
Interactions of mitochondrial and skeletal muscle biology in mitochondrial myopathy.
The Impact of Artificial Intelligence on Optimizing Diagnosis and Treatment Plans for Rare Genetic Disorders.
Dystonia in ATP Synthase Defects: Reconnecting Mitochondria and Dopamine.
UK first to approve CRISPR treatment for diseases: what you need to know.
The Lived Experience of Pediatric Gene Therapy - A Scoping Review.
The experience of diagnosis announcement in rare endocrine diseases: a survey of the French FIRENDO network.
Special FDA designations for drug development: orphan, fast track, accelerated approval, priority review, and breakthrough therapy.

Orphanet J Rare Dis. 2023 Nov 16. 18(1): 355

Teamwork makes the dream work: functional collaborations between families, scientists, and healthcare providers to drive progress in the treatment of Leigh Syndrome.

Jesse D Moreira, Karan K Smith, Sophia Zilber, Kasey Woleben, Jessica L Fetterman.

   BACKGROUND: Leigh syndrome, an inherited neurometabolic disorder, is estimated to be the most common pediatric manifestation of mitochondrial disease. No treatments are currently available for Leigh syndrome due to many hurdles in drug discovery efforts. Leigh syndrome causal variants span over 110 different genes and likely lead to both unique and shared biochemical alterations, often resulting in overlapping phenotypic features. The mechanisms by which pathogenic variants in mitochondrial genes alter cellular phenotype to promote disease remain poorly understood. The rarity of cases of specific causal variants creates barriers to drug discovery and adequately sized clinical trials. BODY: To address the current challenges in drug discovery and facilitate communication between researchers, healthcare providers, patients, and families, the Boston University integrative Cardiovascular Metabolism and Pathophysiology (iCAMP) Lab and Cure Mito Foundation hosted a Leigh Syndrome Symposium. This symposium brought together expert scientists and providers to highlight the current successes in drug discovery and novel models of mitochondrial disease, and to connect patients to providers and scientists to foster community and communication.
CONCLUSION: In this symposium review, we describe the research presented, the hurdles ahead, and strategies to better connect the Leigh syndrome community members to advance treatments for Leigh syndrome.

Keywords:  Community; Leigh syndrome; Mitochondria; Mitochondrial disease; Mitochondrial genetics; Patient registries; Symposium

DOI:  https://doi.org/10.1186/s13023-023-02871-7
medRxiv. 2023 Nov 05. pii: 2023.11.03.23297854. [Epub ahead of print]

Genetic analysis and multimodal imaging identify novel mtDNA 12148T>C leading to multisystem dysfunction with tissue-specific heteroplasmy.

Kinsley Belle, Alexander Kreymerman, Nirmal Vadgama, Marco H Ji, Sandeep Randhawa, Juan Caicedo, Megan Wong, Stephanie P Muscat, Casey A Gifford, Richard T Lee, Jamal Nasir, Jill L Young, Gregory Enns, Ioannis Karakikes, Mark Mercola, Edward H Wood.

Patients with mitochondrial disorders present with clinically diverse symptoms, largely driven by heterogeneous mutations in mitochondrial-encoded and nuclear-encoded mitochondrial genes. These mutations ultimately lead to complex biochemical disorders with a myriad of clinical manifestations, often accumulating during childhood on into adulthood, contributing to life-altering and sometimes fatal events. It is therefore important to diagnose and characterize the associated disorders for each mitochondrial mutation as early as possible since medical management might be able to improve the quality and longevity of life in mitochondrial disease patients. Here we identify a novel mitochondrial variant in a mitochondrial transfer RNA for histidine (mt-tRNA-his) [m.12148T>C], that is associated with the development of ocular, aural, neurological, renal, and muscular dysfunctions. We provide a detailed account of a family harboring this mutation, as well as the molecular underpinnings contributing to cellular and mitochondrial dysfunction. In conclusion, this investigation provides clinical, biochemical, and morphological evidence of the pathogenicity of m.12148T>C. We highlight the importance of multiple tissue testing and in vitro disease modeling in diagnosing mitochondrial disease.

DOI: https://doi.org/10.1101/2023.11.03.23297854
Med Care. 2023 12 01. 61(12 Suppl 2): S153-S160

Avenues for Strengthening PCORnet's Capacity to Advance Patient-Centered Economic Outcomes in Patient-Centered Outcomes Research (PCOR).

Lemuel R Waitman, Leonard Charles Bailey, Michael J Becich, Katherine Chung-Bridges, Stacie B Dusetzina, Jessi U Espino, William R Hogan, Rainu Kaushal, James C McClay, James Greg Merritt, Russell L Rothman, Elizabeth A Shenkman, Xing Song, Elizabeth Nauman.

PCORnet, the National Patient-Centered Clinical Research Network, provides the ability to conduct prospective and observational pragmatic research by leveraging standardized, curated electronic health records data together with patient and stakeholder engagement. PCORnet is funded by the Patient-Centered Outcomes Research Institute (PCORI) and is composed of 8 Clinical Research Networks that incorporate at total of 79 health system "sites." As the network developed, linkage to commercial health plans, federal insurance claims, disease registries, and other data resources demonstrated the value in extending the networks infrastructure to provide a more complete representation of patient's health and lived experiences. Initially, PCORnet studies avoided direct economic comparative effectiveness as a topic. However, PCORI's authorizing law was amended in 2019 to allow studies to incorporate patient-centered economic outcomes in primary research aims. With PCORI's expanded scope and PCORnet's phase 3 beginning in January 2022, there are opportunities to strengthen the network's ability to support economic patient-centered outcomes research. This commentary will discuss approaches that have been incorporated to date by the network and point to opportunities for the network to incorporate economic variables for analysis, informed by patient and stakeholder perspectives. Topics addressed include: (1) data linkage infrastructure; (2) commercial health plan partnerships; (3) Medicare and Medicaid linkage; (4) health system billing-based benchmarking; (5) area-level measures; (6) individual-level measures; (7) pharmacy benefits and retail pharmacy data; and (8) the importance of transparency and engagement while addressing the biases inherent in linking real-world data sources.

DOI: https://doi.org/10.1097/MLR.0000000000001929
Biochem J. 2023 Nov 15. 480(21): 1767-1789

Interactions of mitochondrial and skeletal muscle biology in mitochondrial myopathy.

Valeria Di Leo, Tiago M Bernardino Gomes, Amy E Vincent.

  Mitochondrial dysfunction in skeletal muscle fibres occurs with both healthy aging and a range of neuromuscular diseases. The impact of mitochondrial dysfunction in skeletal muscle and the way muscle fibres adapt to this dysfunction is important to understand disease mechanisms and to develop therapeutic interventions. Furthermore, interactions between mitochondrial dysfunction and skeletal muscle biology, in mitochondrial myopathy, likely have important implications for normal muscle function and physiology. In this review, we will try to give an overview of what is known to date about these interactions including metabolic remodelling, mitochondrial morphology, mitochondrial turnover, cellular processes and muscle cell structure and function. Each of these topics is at a different stage of understanding, with some being well researched and understood, and others in their infancy. Furthermore, some of what we know comes from disease models. Whilst some findings are confirmed in humans, where this is not yet the case, we must be cautious in interpreting findings in the context of human muscle and disease. Here, our goal is to discuss what is known, highlight what is unknown and give a perspective on the future direction of research in this area.

Keywords:  function; metabolism; mitochondria; mitochondrial dysfunction; structure

DOI:  https://doi.org/10.1042/BCJ20220233
Cureus. 2023 Oct;15(10): e46860

The Impact of Artificial Intelligence on Optimizing Diagnosis and Treatment Plans for Rare Genetic Disorders.

Shenouda Abdallah, Mouhammad Sharifa, Mohammed Khaleel I Kh Almadhoun, Muhammad Muneeb Khawar, Unzla Shaikh, Khaled M Balabel, Inam Saleh, Amima Manzoor, Arun Kumar Mandal, Osatohanmwen Ekomwereren, Wai Mon Khine, Oluwaseyi T Oyelaja.

  Rare genetic disorders (RDs), characterized by their low prevalence and diagnostic complexities, present significant challenges to healthcare systems. This article explores the transformative impact of artificial intelligence (AI) and machine learning (ML) in addressing these challenges. It emphasizes the need for accurate and early diagnosis of RDs, often hindered by genetic and clinical heterogeneity. This article discusses how AI and ML are reshaping healthcare, providing examples of their effectiveness in disease diagnosis, prognosis, image analysis, and drug repurposing. It highlights AI's ability to efficiently analyze extensive datasets and expedite diagnosis, showcasing case studies like Face2Gene. Furthermore, the article explores how AI tailors treatment plans for RDs, leveraging ML and deep learning (DL) to create personalized therapeutic regimens. It emphasizes AI's role in drug discovery, including the identification of potential candidates for rare disease treatments. Challenges and limitations related to AI in healthcare, including ethical, legal, technical, and human aspects, are addressed. This article underscores the importance of data ethics, privacy, and algorithmic fairness, as well as the need for standardized evaluation techniques and transparency in AI research. It highlights second-generation AI systems that prioritize patient-centric care, efficient patient recruitment for clinical trials, and the significance of high-quality data. The integration of AI with telemedicine, the growth of health databases, and the potential for personalized therapeutic recommendations are identified as promising directions for the field. In summary, this article provides a comprehensive exploration of how AI and ML are revolutionizing the diagnosis and treatment of RDs, addressing challenges while considering ethical implications in this rapidly evolving healthcare landscape.

Keywords:  deep learning artificial intelligence; genetic basis of congenital heart disease; genetic syndromes; genetic variant; rare genetic diseases

DOI:  https://doi.org/10.7759/cureus.46860
Mov Disord. 2023 Nov 14.

Dystonia in ATP Synthase Defects: Reconnecting Mitochondria and Dopamine.

Elisabetta Indelicato, Sylvia Boesch, Niccolo' E Mencacci, Daniele Ghezzi, Holger Prokisch, Juliane Winkelmann, Michael Zech.



Keywords:  ATP synthase; dystonia; mitochondrial diseases; movement disorder

DOI:  https://doi.org/10.1002/mds.29657
Nature. 2023 Nov 16.

UK first to approve CRISPR treatment for diseases: what you need to know.

Carissa Wong.



Keywords:  Gene therapy; Genetics

DOI:  https://doi.org/10.1038/d41586-023-03590-6
Hum Gene Ther. 2023 Nov 15.

The Lived Experience of Pediatric Gene Therapy - A Scoping Review.

Laura Kimberly, Cara Hunt, Katherine Beaverson, Emma James, Alison Bateman-House, Richard McGowan, Jennifer DeSante-Bertkau.

Little is known about patients' and families' lived experience of participating in pediatric gene therapy (GT) clinical trials. Currently, pediatric GT research targets a broad range of indications--including rare and ultra-rare diseases--which vary in severity and in the availability of alternative therapies. Pediatric GT differs meaningfully from adult GT because the decision to participate involves a dyad of both the child and parent or caregiver/s. It is critical to understand patients' and caregivers' perceptions and experiences of the social, emotional, physical, and logistical burdens or benefits of participating in such trials, and how they weigh and prioritize these factors when deciding whether to participate. We conducted a scoping review of the current literature in this subject area with objectives to a) provide an overview of existing literature, b) identify gaps and areas for further research, and c) better understand the lived impact of pediatric GT research on patients and their parents/caregivers. , Four themes emerged, including 1) weighing risks and benefits 2) timing of GT trial participation 3) value of clear communication, and 4) potential impact on quality of life. Notably, our sample surfaced articles about how patients/parents/caregivers were thinking about GT - their understanding of its safety, efficacy, and risks - rather than accounts of their experiences, which was our initial intention. Nevertheless, our findings offer useful insights to improve the informed consent process and promote a more patient- and family-centered approach. Moreover, our findings can contribute to patient advocacy organizations' efforts to develop educational materials tailored to patients' and families' expressed informational needs and perspectives, and can inform more patient- and family-centered policies from GT clinical trial sponsors.

DOI: https://doi.org/10.1089/hum.2023.157
Ann Endocrinol (Paris). 2023 Nov 09. pii: S0003-4266(23)00726-6. [Epub ahead of print]

The experience of diagnosis announcement in rare endocrine diseases: a survey of the French FIRENDO network.

Haifa Rahabi, Maria Givony, Béatrice Demaret, Frédérique Albarel, Marie-Reine Aubron, Beate Bartès, Lucie Bernard, Hendy Abdoul, Naim Bouazza, Philippe Brun, Delphine Drui, Véronique Dujardin, Catherine Lançon, Sabine Malivoir, Irène Netchine, Bénédicte Perrotin, Virginie Picard, Rachel Reynaud, Murielle Ribeiro, Véronique Tardy Guidollet, Amélie Victor, Jérôme Bertherat, Claudine Colin, Thierry Brue.

   CONTEXT: Diagnosis announcement of a chronic disease is a crucial moment for patients as well as for their families and an important step in the management of severe conditions such as rare endocrine diseases. Little is known of how diagnosis is communicated to patients and families. The FIRENDO network was created by the third French Plan for Rare Diseases, to promote autonomy, care and research on rare endocrine diseases.
OBJECTIVES: The aim of this study was to characterize, for the first time, the experience and needs of patients and/or their parents around the announcement of diagnosis to ensure optimal quality of care.
METHODS: A quantitative self-administered survey on diagnosis announcement procedures in rare endocrine diseases was launched in April 2017 by the ad hoc FIRENDO thematic working group in collaboration with its 11 partnering patient associations and support groups. The questionnaire was designed and revised by patient support group representatives, adult and pediatric endocrinologists, psychologists and biologists, all expert in rare endocrine diseases. It was made available on the FIRENDO network website and distributed mainly by email with electronic links on their respective websites to members of all affiliated patient support groups.
RESULTS: Questionnaires were filled out by 391 patients and 223 parents (median age of patients: 39 years). The following conditions were associated with at least 30 answers: Addison's disease, classical forms of congenital adrenal hyperplasia (CAH), Russell-Silver syndrome, Cushing's syndrome, acromegaly and craniopharyngioma. Overall, some announcement modalities were judged favorably by patients: physician's empathy, availability and use of clear terms, and presence of family at the time of announcement. However, a lack of psychological care and information documents was reported, as well as some inadequate procedures such as postal mail announcements.
CONCLUSION: This work suggests that better knowledge of the patient's experience is useful for improving the diagnosis announcement of rare endocrine disorders. The main recommendations derived from the survey were the need for several announcement visits, information on patient support groups and reference centers, imperatively avoiding impersonal announcement, and the usefulness of a written accompanying document.

Keywords:  Addison’s disease; Cushing’s syndrome; Diagnosis announcement; Russell-Silver syndrome; acromegaly; congenital adrenal hyperplasia; craniopharyngioma; endocrine disease; rare disease

DOI:  https://doi.org/10.1016/j.ando.2023.10.008
Eur J Health Econ. 2023 Nov 14.

Special FDA designations for drug development: orphan, fast track, accelerated approval, priority review, and breakthrough therapy.

Daniel Tobias Michaeli, Thomas Michaeli, Sebastian Albers, Tobias Boch, Julia Caroline Michaeli.

   BACKGROUND: Over the past decades, US Congress enabled the US Food and Drug Administration (FDA) to facilitate and expedite drug development for serious conditions filling unmet medical needs with five special designations and review pathways: orphan, fast track, accelerated approval, priority review, and breakthrough therapy.
OBJECTIVES: This study reviews the FDA's five special designations for drug development regarding their safety, efficacy/clinical benefit, clinical trials, innovation, economic incentives, development timelines, and price.
METHODS: We conducted a keyword search to identify studies analyzing the impact of the FDA's special designations (orphan, fast track, accelerated approval, priority review, and breakthrough therapy) on the safety, efficacy/clinical benefit, trials, innovativeness, economic incentives, development times, and pricing of new drugs. Results were summarized in a narrative overview.
RESULTS: Expedited approval reduces new drugs' time to market. However, faster drug development and regulatory review are associated with more unrecognized adverse events and post-marketing safety revisions. Clinical trials supporting special FDA approvals frequently use small, non-randomized, open-label designs. Required post-approval trials to monitor unknown adverse events are often delayed or not even initiated. Evidence suggests that drugs approved under special review pathways, marketed as "breakthroughs", are more innovative and deliver a higher clinical benefit than those receiving standard FDA approval. Special designations are an economically viable strategy for investors and pharmaceutical companies to develop drugs for rare diseases with unmet medical needs, due to financial incentives, expedited development timelines, higher clinical trial success rates, alongside greater prices. Nonetheless, patients, physicians, and insurers are concerned about spending money on drugs without a proven benefit or even on drugs that turn out to be ineffective. While European countries established performance- and financial-based managed entry agreements to account for this uncertainty in clinical trial evidence and cost-effectiveness, the pricing and reimbursement of these drugs remain largely unregulated in the US.
CONCLUSION: Special FDA designations shorten clinical development and FDA approval times for new drugs treating rare and severe diseases with unmet medical needs. Special-designated drugs offer a greater clinical benefit to patients. However, physicians, patients, and insurers must be aware that special-designated drugs are often approved based on non-robust trials, associated with more unrecognized side effects, and sold for higher prices.

Keywords:  Accelerated approval; Breakthrough therapy; Clinical trial; Drug development; Drug price; Efficacy; European medicines agency; Fast track; Healthcare policy; Innovation; Orphan designation; Pharmaceutical policy; Priority review; Safety; Special designation; US food and drug administration

DOI:  https://doi.org/10.1007/s10198-023-01639-x