bims-curels 2024-02-18 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2024–02–18
fiveteen papers selected by
Cure Mito Foundation

Impact of dietary ketosis on volatile anesthesia toxicity in a model of Leigh syndrome.
Incidence and prevalence of mtDNA-related adult mitochondrial disease in Southwest Finland, 2009-2022: an observational, population-based study.
Renal manifestations in adults with mitochondrial disease from the mtDNA m.3243A>G pathogenic variant.
Perceived association of mood and symptom severity in adults with mitochondrial diseases.
Protocol for co-producing a framework and integrated resource platform for engaging patients in laboratory-based research.
Mitochondrial disorders: Emerging paradigms and the road ahead to personalized medicine.
Lived experiences of genetic diagnosis for rare disease patients: a qualitative interview study.
Rare Disease Day: Amplifying voices, advocating hope.
Draft Guidance for Industry Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, and Related Dystrophinopathies - Developing Potential Treatments for the Entire Spectrum of Disease.
Understanding what drives genetic study participation: Perspectives of patients, carers, and relatives.
The time for patient partnership in medical education has arrived: Critical reflection through autoethnography from a physician turned patient.
What motivates public collaborators to become and stay involved in health research?
Gastrointestinal Complications of Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-Like Episodes (MELAS) Syndrome Managed By Parenteral Nutrition.
Recommendations for optimal interdisciplinary management and healthcare settings for patients with rare neurological diseases.
Manufacturing Cell and Gene Therapies: Challenges in Clinical Translation.

Paediatr Anaesth. 2024 Feb 15.

Impact of dietary ketosis on volatile anesthesia toxicity in a model of Leigh syndrome.

Kira A Spencer, Miranda N Howe, Michael T Mulholland, Vivian Truong, Ryan W Liao, Yihan Chen, Monyreak Setha, John C Snell, Allison Hanaford, Katerina James, Philip G Morgan, Margaret M Sedensky, Simon C Johnson.

   BACKGROUND: Genetic mitochondrial diseases impact over 1 in 4000 individuals, most often presenting in infancy or early childhood. Seizures are major clinical sequelae in some mitochondrial diseases including Leigh syndrome, the most common pediatric presentation of mitochondrial disease. Dietary ketosis has been used to manage seizures in mitochondrial disease patients. Mitochondrial disease patients often require surgical interventions, leading to anesthetic exposures. Anesthetics have been shown to be toxic in the setting of mitochondrial disease, but the impact of a ketogenic diet on anesthetic toxicities in this setting has not been studied.
AIMS: Our aim in this study was to determine whether dietary ketosis impacts volatile anesthetic toxicities in the setting of genetic mitochondrial disease.
METHODS: The impact of dietary ketosis on toxicities of volatile anesthetic exposure in mitochondrial disease was studied by exposing young Ndufs4(-/-) mice fed ketogenic or control diet to isoflurane anesthesia. Blood metabolites were measured before and at the end of exposures, and survival and weight were monitored.
RESULTS: Compared to a regular diet, the ketogenic diet exacerbated hyperlactatemia resulting from isoflurane exposure (control vs. ketogenic diet in anesthesia mean difference 1.96 mM, Tukey's multiple comparison adjusted p = .0271) and was associated with a significant increase in mortality during and immediately after exposures (27% vs. 87.5% mortality in the control and ketogenic diet groups, respectively, during the exposure period, Fisher's exact test p = .0121). Our data indicate that dietary ketosis and volatile anesthesia interact negatively in the setting of mitochondrial disease.
CONCLUSIONS: Our findings suggest that extra caution should be taken in the anesthetic management of mitochondrial disease patients in dietary ketosis.

Keywords:  anesthesia; ketogenic diet; mitochondrial disease; neurodegenerative disease

DOI:  https://doi.org/10.1111/pan.14855
BMJ Neurol Open. 2024 ;6(1): e000546

Incidence and prevalence of mtDNA-related adult mitochondrial disease in Southwest Finland, 2009-2022: an observational, population-based study.

Mika H Martikainen, Kari Majamaa.

   Background: Mitochondrial diseases are common inherited metabolic disorders. Due to improved case ascertainment and diagnosis methods, the detection of new diagnoses of mitochondrial disease can be expected to increase. In December 2009, the prevalence of mitochondrial DNA (mtDNA)-related mitochondrial disease was 4.6/100 000 (95% CI, 2.7 to 7.2) in the adult population of Southwest Finland. We investigated the number of new diagnoses and the incidence of mitochondrial disease in Southwest Finland between December 2009 and December 2022.
Methods: We collected data on all adult patients from Southwest Finland diagnosed with mitochondrial disease on 31 December 2009 and 31 December 2022. Most patients had been diagnosed at the Turku University Hospital (TUH) neurology outpatient clinic. Patients were also identified by searching the TUH electronic patient database for relevant International Classification of Diseases, Tenth Revision codes and conducted mtDNA analyses.
Results: 42 new patients were diagnosed giving a mean annual rate of 3.2 new diagnoses. In 2022, the minimum prevalence estimate of adult mtDNA-related mitochondrial disease was 9.2/100 000 (95% CI, 6.5 to 12.7). The prevalence of adult mtDNA disease associated with m.3243A>G was 4.2/100 000 (95% CI, 2.5 to 6.7), and that with large-scale mtDNA deletions was 1.3/100 000 (95% CI, 0.4 to 2.9). During the 13-year period, the annual incidence of adult mtDNA disease was 0.6/100 000 and that of adult m.3243A>G-related disease 0.3/100 000.
Conclusion: Our results suggest that improved means of diagnostics and dedicated effort increase the detection of mitochondrial disease.

Keywords:  MITOCHONDRIAL DISORDERS; NEUROEPIDEMIOLOGY

DOI:  https://doi.org/10.1136/bmjno-2023-000546
Nefrologia (Engl Ed). 2023 Dec;pii: S2013-2514(24)00027-0. [Epub ahead of print]43 Suppl 2 1-7

Renal manifestations in adults with mitochondrial disease from the mtDNA m.3243A>G pathogenic variant.

Filipa Ferreira, Clara Gonçalves Bacelar, Pedro Lisboa-Gonçalves, Núria Paulo, Rita Quental, Ana Teresa Nunes, Roberto Silva, Isabel Tavares.

  Mitochondrial diseases are a phenotype and genotype heterogeneous group of disorders that typically have a multisystemic involvement. The m.3243A>G pathogenic variant is the most frequent mitochondrial DNA defect, and it causes several different clinical syndromes, such as mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS), and the maternally inherited diabetes and deafness (MIDD) syndromes. Not frequently reported, renal involvement in these diseases is probably underestimated, yet it increases morbidity. It generally manifests as subnephrotic proteinuria and progressive deterioration of kidney function. Adult presentation of mitochondrial diseases is hard to recognize, especially in oligosymptomatic patients or those with exclusive kidney involvement. However, suspicion should always arise when family history, particularly on the maternal side, and multisystemic symptoms, most often of the central nervous system and skeletal muscles, are present. In this review we discuss the clinical diagnosis and approach of patients with renal manifestations in the context of the mtDNA m.3243A>G pathogenic variant.

Keywords:  Enfermedades mitocondriales; Enfermedades renales; Focal segmental glomerulosclerosis; Glomeruloesclerosis focal y segmentaria; MELAS syndrome; Mitochondrial diseases; Renal disease; Síndrome MELAS; mtDNA m.3243A>G

DOI:  https://doi.org/10.1016/j.nefroe.2024.01.017
medRxiv. 2024 Feb 04. pii: 2024.02.02.24302076. [Epub ahead of print]

Perceived association of mood and symptom severity in adults with mitochondrial diseases.

Catherine Kelly, Alex Junker, Kris Englestad, Michio Hirano, Caroline Trumpff, Martin Picard.

Individuals with genetic mitochondrial diseases suffer from multisystemic symptoms that vary in severity from day-to-day and week-to-week, but the underlying causes of symptomatic fluctuations are not understood. Based upon observations that: i) patients and their families frequently report that stressful life events either trigger exacerbations of existing symptoms or the onset of new symptoms, ii) psychological states and stress hormones influence mitochondrial energy production capacity, and iii) epidemiological reports document a robust connection between traumatic/stressful life events and various neurologic disorders, we hypothesized that mitochondrial disease symptom severity may vary according to participant's mood. To investigate this we administered the Stress, Health and Emotion Survey (SHES) in 70 adults (majority white (84%) cisgender women (83%), ages 18-74) with self-reported mitochondrial diseases (MELAS, 18%; CPEO, 17%; Complex I deficiency, 13%). Participants rated the severity of each of their symptom(s) over the past year on either good or bad days. On days marked by more stress, sadness and other negative emotions, some but not all symptoms were reported to be worse, including fatigue, exercise intolerance, brain fog, and fine motor coordination. By contrast, on days marked by happiness and calmness, participants reported these and other symptoms to be better, or less severe. Other symptoms including diminished sweating, hearing problems, and dystonia were in general unrelated to mood. Thus, some individuals living with mitochondrial diseases, at times perceive a connection between their mood and symptom severity. These preliminary associative results constitute an initial step towards developing more comprehensive models of the factors that influence the clinical course of mitochondrial diseases.

DOI: https://doi.org/10.1101/2024.02.02.24302076
Res Involv Engagem. 2024 Feb 12. 10(1): 25

Protocol for co-producing a framework and integrated resource platform for engaging patients in laboratory-based research.

Manoj M Lalu, Dawn Richards, Madison Foster, Brittany French, Angela M Crawley, Kirsten M Fiest, Kathryn Hendrick, Kimberly F Macala, Asher A Mendelson, Pat Messner, Stuart G Nicholls, Justin Presseau, Cheryle A Séguin, Patrick Sullivan, Bernard Thébaud, Dean A Fergusson.

   BACKGROUND: Patient engagement in research is the meaningful and collaborative interaction between patients and researchers throughout the research process. Patient engagement can help to ensure patient-oriented values and perspectives are incorporated into the development, conduct, and dissemination of research. While patient engagement is increasingly prevalent in clinical research, it remains relatively unrealized in preclinical laboratory research. This may reflect the nature of preclinical research, in which routine interactions or engagement with patients may be less common. Our team of patient partners and researchers has previously identified few published examples of patient engagement in preclinical laboratory research, as well as a paucity of guidance on this topic. Here we propose the development of a process framework to facilitate patient engagement in preclinical laboratory research.
METHODS: Our team, inclusive of researchers and patient partners, will develop a comprehensive, empirically-derived, and stakeholder-informed process framework for 'patient engagement in preclinical laboratory research.' First, our team will create a 'deliberative knowledge space' to conduct semi-structured discussions that will inform a draft framework for preclinical patient engagement. Over the course of several sessions, we will identify actions, activities, barriers, and enablers (e.g. considerations and motivations for patient engagement in preclinical laboratory research, define roles of key players). The resulting draft process framework will be further populated with examples and refined through an international consensus-building Delphi survey with patients, researchers, and other collaborator organizations. We will then conduct pilot field tests to evaluate the framework with preclinical laboratory research groups paired with patient partners. These results will be used to create a refined framework enriched with real-world examples and considerations. All resources developed will be made available through an online repository.
DISCUSSION: Our proposed process framework will provide guidance, best practices, and standardized procedures to promote patient engagement in preclinical laboratory research. Supporting and facilitating patient engagement in this setting presents an exciting new opportunity to help realize the important impact that patients can make.

Keywords:  Basic science; Consumer involvement; Deliberative knowledge space; Delphi survey; Framework; Laboratory research; Patient and public involvement; Patient engagement; Patient oriented research; Pilot field test; Preclinical laboratory research; Preclinical research

DOI:  https://doi.org/10.1186/s40900-024-00545-7
Neurotherapeutics. 2024 Jan;pii: S1878-7479(24)00018-7. [Epub ahead of print]21(1): e00332

Mitochondrial disorders: Emerging paradigms and the road ahead to personalized medicine.

Andrea Gropman, Bharatendu Chandra.

DOI: https://doi.org/10.1016/j.neurot.2024.e00332
Orphanet J Rare Dis. 2024 Feb 14. 19(1): 68

Lived experiences of genetic diagnosis for rare disease patients: a qualitative interview study.

Antonia Modelhart, Dominique Sturz, Lydia Kremslehner, Barbara Prainsack.

   BACKGROUND: Genetic diagnosis is often understood as a single event within the care pathway of rare disease patients. Legal, policy and ethical scholarship focusing on rare diseases and genetic information discusses questions of how to best deal with the process of genetic diagnosis and the communication of genetic information within a given health system. We co-created a research design with rare disease patients and their families in Austria to explore in-depth the experiences of genetic diagnosis for people affected by rare diseases. Our objective was to trace the whole pathway of genetic testing and understand how rare disease patients experience genetic diagnosis as part of their care pathway in the healthcare system.
RESULTS: Data was collected through in-depth semi-structured qualitative interviews with 14 patients with a suspected or diagnosed rare disease or their parents, focusing on their perception of the pathway of genetic diagnosis in Austria. This pathway included the initial triggering of genetic diagnosis, the process of testing and its immediate (communication of results, counselling) and long-term, wider aftermath. Patients missed a clear link to already established forms of care such as their primary care/treating physicians. They also advocate for an integrated and interdisciplinary care pathway.
CONCLUSIONS: Our study underscores the importance of a continuous care and communication pathway spanning from the initial genetic diagnosis process to post-test phases. It further shows the importance of exploring patients' perspectives through qualitative research methods to understand the intricate workings of public health policies and tools. Integrating genetic diagnosis into a broader care trajectory is crucial for a holistic approach to care for rare disease patients who often rely on regular interactions with the healthcare system. Achieving this holistic approach requires collaboration between experts in specific rare disease areas, primary care physicians, and support networks.

Keywords:  Genetic diagnosis; Healthcare system; Patient experiences; Qualitative interview study; Rare diseases

DOI:  https://doi.org/10.1186/s13023-024-03058-4
Med. 2024 Feb 09. pii: S2666-6340(24)00033-3. [Epub ahead of print]5(2): 103-105

Rare Disease Day: Amplifying voices, advocating hope.

Helene Cederroth, William A Gahl, Guida Landouré, Shuyang Zhang, Matt Bolz-Johnson.

Every year on February 28, the global community comes together to observe Rare Disease Day, a day dedicated to raising awareness and understanding for the millions of individuals who live with rare disorders. While individual rare diseases may seem uncommon, their collective impact is significant, affecting the lives of countless families and communities worldwide. This day serves as a crucial platform to amplify the voices of those affected, advocate for increased research and support, and inspire hope for a future where rare diseases can be prevented, diagnosed earlier, and effectively treated.

DOI: https://doi.org/10.1016/j.medj.2024.01.003
J Neuromuscul Dis. 2024 Feb 13.

Draft Guidance for Industry Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, and Related Dystrophinopathies - Developing Potential Treatments for the Entire Spectrum of Disease.

Craig McDonald, Eric Camino, Rafael Escandon, Richard S Finkel, Ryan Fischer, Kevin Flanigan, Pat Furlong, Rose Juhasz, Ann S Martin, Chet Villa, H Lee Sweeney.

   Background: Duchenne muscular dystrophy (DMD) and related dystrophinopathies are neuromuscular conditions with great unmet medical needs that require the development of effective medical treatments.
Objective: To aid sponsors in clinical development of drugs and therapeutic biological products for treating DMD across the disease spectrum by integrating advancements, patient registries, natural history studies, and more into a comprehensive guidance.
Methods: This guidance emerged from collaboration between the FDA, the Duchenne community, and industry stakeholders. It entailed a structured approach, involving multiple committees and boards. From its inception in 2014, the guidance underwent revisions incorporating insights from gene therapy studies, cardiac function research, and innovative clinical trial designs.
Results: The guidance provides a deeper understanding of DMD and its variants, focusing on patient engagement, diagnostic criteria, natural history, biomarkers, and clinical trials. It underscores patient-focused drug development, the significance of dystrophin as a biomarker, and the pivotal role of magnetic resonance imaging in assessing disease progression. Additionally, the guidance addresses cardiomyopathy's prominence in DMD and the burgeoning field of gene therapy.
Conclusions: The updated guidance offers a comprehensive understanding of DMD, emphasizing patient-centric approaches, innovative trial designs, and the importance of biomarkers. The focus on cardiomyopathy and gene therapy signifies the evolving realm of DMD research. It acts as a crucial roadmap for sponsors, potentially leading to improved treatments for DMD.

Keywords:  Cardiomyopathy In DMD; Duchenne Muscular Dystrophy (DMD); Dystrophinopathies; Gene Therapy for DMD; Genetic Testing and Diagnosis; Natural History of DMD; Outcome Measures; Patient Experience and Engagement; Patient-Focused Drug Development (PFDD); Regulatory Guidance and Considerations

DOI:  https://doi.org/10.3233/JND-230219
Pulm Circ. 2024 Jan;14(1): e12346

Understanding what drives genetic study participation: Perspectives of patients, carers, and relatives.

Emilia M Swietlik, Michaela Fay, Nicholas W Morrell.

  Genetic research's growing importance in understanding pulmonary arterial hypertension (PAH) and developing effective treatments prompted the RAPID-PAH study. This study sought feedback from stakeholders who participated in two genomic studies to enhance genetic study delivery and clinical integration. Stakeholders from nine UK PH centres, representing various roles, ages, genders, and mutation statuses, took part in 53 semi-structured interviews and focus groups. Transcripts were thematically coded using inductive analysis. Clustering analysis was conducted to identify patient groups that shared attitudes. In this paper, we focus on patients', carers', and relatives' perspectives. The key interview themes revealed insights into participants' attitudes toward genetic research and testing more generally, expertise and knowledge of the disease itself, motivations and barriers to participating in genetic research, awareness of and interest in consent procedures and the use of personal and genetic data, as well as the process of communicating individual genetic results. Factors influencing genetic research participation included altruistic motives, personal diagnostic experiences, and family-related hopes. Clustering analysis produced distinct clusters based on the presence of barriers and motivators for research participation; however, hardly any patients shared identical sets of attitudes, emphasising the need for personalised approaches to recruitment. Most patients reported poor engagement with study-related materials. Patients who received individual genetic results expressed satisfaction with the process, whereas those who did not were disappointed with the lack of feedback. Reflecting on patient perspectives, we offer recommendations to improve the genetic study delivery process. Enhancing genetic research integration into clinical practice requires tailored engagement, clear communication, and support from healthcare stakeholders.

Keywords:  genetic research; informed consent; motivations and barriers to participation; pulmonary arterial hypertension; return of individual genetic results

DOI:  https://doi.org/10.1002/pul2.12346
Med Teach. 2024 Jan 31. 1-6

The time for patient partnership in medical education has arrived: Critical reflection through autoethnography from a physician turned patient.

Lynn Ashdown, Linda Jones.

   PURPOSE: This paper explores experiences of a physician who in one life-altering day awoke in intensive care and had to embark on a complex journey as full-time patient. It identifies the important literature, albeit limited, from a unique dual lens view of physician turned patient, and analyzes the potential for advancing medical education by recognizing the expertise that patients possess from lived experience.
METHODOLOGY: An autoethnography study was undertaken to unpack data obtained from lived patient experience during a two-and-a-half-year long hospitalization. Themes were captured in a series of eleven scenarios. Findings included critical reflection from the patient, medical educator, and research perspectives. Data was cross-referenced with relevant literature.
RESULTS: Seven themes emerged upon critical analysis of the eleven scenarios that described real-life healthcare encounters of the physician turned patient. These often-neglected themes from medical education include experiential learning, reflection, what counts as medical care, vulnerability, patient-centred care, agency, and patient expertise.
CONCLUSIONS: This study highlights differences between intellectual-experiential knowledge, and challenges medical education to harness the expertise that patients possess. It contributes to scholarly discourses by demonstrating the utility of autoethnography in medical education, critiques traditional medical education models, expands the breadth of what constitutes knowledge, and invites medical educators to actively involve patients as equal stakeholders in curricula.

Keywords:  Active patient involvement in medical education; autoethnography; patient partnerships; patient-centred curriculum (curricula); patient–physicians

DOI:  https://doi.org/10.1080/0142159X.2024.2308065
Res Involv Engagem. 2024 Feb 12. 10(1): 24

What motivates public collaborators to become and stay involved in health research?

Toril Beate Røssvoll, Kristin Liabo, Tove Aminda Hanssen, Jan H Rosenvinge, Elisabeth Sundkvist, Gunn Pettersen.

   BACKGROUND: People with lived experience of health and illness are increasingly being involved in research. Knowing what creates interest in becoming involved in health research may help identify appropriate ways of facilitating meaningful involvement. The study aimed to investigate why people became public collaborators in health research and what helped sustain their commitment to staying involved.
METHODS: Semistructured individual qualitative interviews were conducted with 11 Norwegian public collaborators recruited from patient organisations. To enhance the quality and relevance of this study, three public collaborators were involved in framing the study and in the data analysis. One of them is a coauthor of this paper. The interviews were analysed through reflexive thematic analysis, and two themes were generated.
RESULTS: The first theme, 'research as a vehicle to impact' showed how interest in becoming involved in research was founded on the possibility of impacting healthcare through research. Other inspiring factors were how they appraised the relevance of the research, in addition to the public collaborators' own sense of moral duty to advocate for research related to their own as well as others, illnesses or diseases. The second theme, ''Acknowledgement and accessibility', framed how the participants perceived appreciation of experiential knowledge as crucial for maintaining motivation in their role as public collaborators. Other promoters of sustained involvement presented were training for both public collaborators and researchers, adequate allowance as a means for visualising and valuing PPI, and accessible language.
CONCLUSIONS: This study contributes to the understanding of how to facilitate meaningful and sustainable PPI, which requires a safe space for collaboration and attention to accessibility. Facilitating meaningful involvement may, in turn, increase the potential impact and sustainability of PPI.

Keywords:  Maintaining motivation; Patient and public involvement; Public collaborator; Qualitative research; Reflexive thematic analysis

DOI:  https://doi.org/10.1186/s40900-024-00555-5
Eur J Case Rep Intern Med. 2024 ;11(2): 004268

Gastrointestinal Complications of Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-Like Episodes (MELAS) Syndrome Managed By Parenteral Nutrition.

Simona Horná, Martin Jozef Péč, Juraj Krivuš, Renáta Michalová, Štefan Sivák, Peter Galajda, Marián Mokáň.

  MELAS - an acronym for mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes - is a multiorgan disease caused by a mutation in mitochondrial DNA (mtDNA). Its clinical manifestations are highly variable; mainly stroke-like episodes, seizures, recurrent headaches, or muscle weakness. However, gastrointestinal complications such as chronic intestinal pseudo-obstruction (IPO), pancreatitis, gastroparesis and hepatopathy are also common. In this report we describe a young patient with gastrointestinal complication of MELAS which led to superior mesenteric artery syndrome (SMAS). It is rare but not surprising combination and should be considered in cases with significant weight loss and resistance to symptomatic treatment. The optimal energy support is the main pillar of the treatment.
LEARNING POINTS: Gastrointestinal complications of MELAS such as chronic intestinal pseudo-obstruction, pancreatitis and gastroparesis can lead to undernutrition.Superior mesenteric artery syndrome is a rare condition but should be considered in cases with significant weight loss and resistance to symptomatic treatment.Optimal caloric intake and energy support can improve the condition of patients with MELAS.

Keywords:  MELAS; nutrition; superior mesenteric artery syndrome

DOI:  https://doi.org/10.12890/2024_004268
Orphanet J Rare Dis. 2024 Feb 13. 19(1): 62

Recommendations for optimal interdisciplinary management and healthcare settings for patients with rare neurological diseases.

Holm Graessner, Carola Reinhard, Tobias Bäumer, Annette Baumgärtner, Knut Brockmann, Norbert Brüggemann, Eva Bültmann, Jeanette Erdmann, Kirstin Heise, Günter Höglinger, Irina Hüning, Frank J Kaiser, Christine Klein, Thomas Klopstock, Ingeborg Krägeloh-Mann, Markus Kraemer, Kerstin Luedtke, Martin Mücke, Thomas Musacchio, Andreas Nadke, Alma Osmanovic, Gabriele Ritter, Katharina Röse, Christopher Schippers, Ludger Schöls, Rebecca Schüle, Jörg B Schulz, Joachim Sproß, Eveline Stasch, Gilbert Wunderlich, Alexander Münchau.

   BACKGROUND: In 2017, the German Academy for Rare Neurological Diseases (Deutsche Akademie für Seltene Neurologische Erkrankungen; DASNE) was founded to pave the way for an optimized personalized management of patients with rare neurological diseases (RND) in all age groups. Since then a dynamic national network for rare neurological disorders has been established comprising renowned experts in neurology, pediatric neurology, (neuro-) genetics and neuroradiology. DASNE has successfully implemented case presentations and multidisciplinary discussions both at yearly symposia and monthly virtual case conferences, as well as further educational activities covering a broad spectrum of interdisciplinary expertise associated with RND. Here, we present recommendation statements for optimized personalized management of patients with RND, which have been developed and reviewed in a structured Delphi process by a group of experts.
METHODS: An interdisciplinary group of 37 RND experts comprising DASNE experts, patient representatives, as well as healthcare professionals and managers was involved in the Delphi process. First, an online collection was performed of topics considered relevant for optimal patient care by the expert group. Second, a two-step Delphi process was carried out to rank the importance of the selected topics. Small interdisciplinary working groups then drafted recommendations. In two consensus meetings and one online review round these recommendations were finally consented.
RESULTS: 38 statements were consented and grouped into 11 topics: health care structure, core neurological expertise and core mission, interdisciplinary team composition, diagnostics, continuous care and therapy development, case conferences, exchange / cooperation between Centers for Rare Diseases and other healthcare partners, patient advocacy group, databases, translation and health policy.
CONCLUSIONS: This German interdisciplinary Delphi expert panel developed consented recommendations for optimal care of patients with RND in a structured Delphi process. These represent a basis for further developments and adjustments in the health care system to improve care for patients with RND and their families.

Keywords:  Healthcare settings; Interdisciplinary management; Optimal care; Rare neurological diseases

DOI:  https://doi.org/10.1186/s13023-024-03023-1
Ann Lab Med. 2024 Feb 16.

Manufacturing Cell and Gene Therapies: Challenges in Clinical Translation.

Na Kyung Lee, Jong Wook Chang.

  The safety and efficacy of both cell and gene therapies have been demonstrated in numerous preclinical and clinical trials. Chimeric antigen receptor T (CAR-T) cell therapy, which leverages the technologies of both cell and gene therapies, has also shown great promise for treating various cancers. Advancements in pertinent fields have also highlighted challenges faced while manufacturing cell and gene therapy products. Potential problems and obstacles must be addressed to ease the clinical translation of individual therapies. Literature reviews of representative cell-based, gene-based, and cell-based gene therapies with regard to their general manufacturing processes, the challenges faced during manufacturing, and QC specifications are limited. We review the general manufacturing processes of cell and gene therapies, including those involving mesenchymal stem cells, viral vectors, and CAR-T cells. The complexities associated with the manufacturing processes and subsequent QC/validation processes may present challenges that could impede the clinical progression of the products. This article addresses these potential challenges. Further, we discuss the use of the manufacturing model and its impact on cell and gene therapy.

Keywords:  Cell therapy; Chimeric antigen receptor T; Clinical translation; Gene therapy; Manufacturing; Mesenchymal stem cells; Viral vectors

DOI:  https://doi.org/10.3343/alm.2023.0382