bims-curels 2023-06-11 papers

bims-curels

Biomed News

on Leigh syndrome

Issue of 2023‒06‒11
twelve papers selected by
Cure Mito Foundation

Multimodal single-cell analysis of non-random heteroplasmy distribution in human retinal mitochondrial disease.
Pharmacists are initiators in palliative care for patients with rare diseases.
FDA approves first topical gene therapy.
Late-onset mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes syndrome with mitochondrial DNA 3243A>G mutation masquerading as autoimmune encephalitis: A case report.
Special Section Patient Engagement in Informatics: Engaging patients and other stakeholders in "designing for dissemination" record linkage methods and tools.
Barriers and facilitators to the implementation of guidelines in rare diseases: a systematic review.
[Patient and Public Involvement in Family Medicine Research].
Medicaid coverage practices for approved gene and cell therapies: Existing barriers and proposed policy solutions.
Metabolomics of infectious diseases in the era of personalized medicine.
Genomics Research with Undiagnosed Children: Ethical Challenges at the Boundaries of Research and Clinical Care.
Partnering With Patients, Caregivers, and Clinicians to Determine Research Priorities for Concussion.
The Cost of Biotech Innovation: Exploring Research and Development Costs of Cell and Gene Therapies.

JCI Insight. 2023 Jun 08. pii: e165937. [Epub ahead of print]

Multimodal single-cell analysis of non-random heteroplasmy distribution in human retinal mitochondrial disease.

Nathaniel K Mullin, Andrew P Voigt, Miles J Flamme-Wiese, Xiuying Liu, Megan J Riker, Katayoun Varzavand, Edwin M Stone, Budd A Tucker, Robert F Mullins.

  Variants within the high copy number mitochondrial genome (mtDNA) can disrupt organelle function and lead to severe multi-system disease. The wide range of manifestations observed in mitochondrial disease patients results from varying fractions of abnormal mtDNA molecules in different cells and tissues, a phenomenon termed heteroplasmy. However, the landscape of heteroplasmy across cell types within tissues and its influence on phenotype expression in affected patients remains largely unexplored. Here, we identify non-random distribution of a pathogenic mtDNA variant across a complex tissue using single-cell RNA sequencing, mitochondrial single-cell ATAC sequencing, and multimodal single-cell sequencing. We profile the transcriptome, chromatin accessibility state, and heteroplasmy in cells from the eyes of a patient with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and healthy control donors. Utilizing the retina as a model for complex multi-lineage tissues, we found that the proportion of the pathogenic m.3243A>G allele was neither evenly nor randomly distributed across diverse cell types. All neuroectoderm-derived neural cells exhibited a high percentage of the mutant variant. However, a subset of mesoderm-derived lineage, namely the vasculature of the choroid, was near homoplasmic for the wildtype allele. Gene expression and chromatin accessibility profiles of cell types with high and low proportions of m.3243A>G implicate mTOR signaling in the cellular response to heteroplasmy. We further found by multimodal single-cell sequencing of retinal pigment epithelial cells that a high proportion of the pathogenic mtDNA variant was associated with transcriptionally and morphologically abnormal cells. Together, these findings show the non-random nature of mitochondrial variant partitioning in human mitochondrial disease and underscore its implications for mitochondrial disease pathogenesis and treatment.

Keywords:  Genetic diseases; Genetics; Mitochondria; Ophthalmology; Retinopathy

DOI:  https://doi.org/10.1172/jci.insight.165937
Orphanet J Rare Dis. 2023 Jun 08. 18(1): 141

Pharmacists are initiators in palliative care for patients with rare diseases.

M Dooms.

  The World Health Organization supports early delivery of palliative care as it reduces unnecessary hospital admissions and the inappropriate use of health care services. A community pharmacist can play a key role in advocating timely access to palliative care. Medication reconciliation must alert them to start communicating with the patient and/or his relatives about refocusing treatment and care as part of palliative and terminal care. Pharmaceutical activities for these patients include dispensing of devices and medicinal products, compounding personalized medication and participating as a member of the Palliative Support Team. Most of the several thousands of rare diseases are caused by genetic defects and up to now have no cure and a late diagnosis.

Keywords:  Deprescribing; Medication review; Orphan drugs; Palliative care; Pharmaceutical care; Rare diseases

DOI:  https://doi.org/10.1186/s13023-023-02765-8
Nat Rev Drug Discov. 2023 Jun 07.

FDA approves first topical gene therapy.

Asher Mullard.

DOI: https://doi.org/10.1038/d41573-023-00095-9
World J Clin Cases. 2023 May 16. 11(14): 3275-3281

Late-onset mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes syndrome with mitochondrial DNA 3243A>G mutation masquerading as autoimmune encephalitis: A case report.

Jian-Wei Wang, Xiao-Bo Yuan, Hong-Fang Chen.

  BACKGROUND: Here, we present a unique case of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome, which initially appeared to be autoimmune encephalitis and was ultimately confirmed as MELAS with the mitochondrial DNA 3243A>G mutation.CASE SUMMARY: A 58-year-old female presented with acute-onset speech impediment and auditory hallucinations, symmetrical bitemporal lobe abnormalities, clinical and laboratory findings, and a lack of relevant prodromal history, which suggested diagnosis of autoimmune encephalitis. Further work-up, in conjunction with the patient's medical history, family history, and lactate peak on brain lesions on magnetic resonance imaging, suggested a mitochondrial disorder. Mitochondrial genome analysis revealed the m.3243A>G variant in the MT-TL1 gene, which led to a diagnosis of MELAS syndrome.
CONCLUSION: This case underscores the importance of considering MELAS as a potential cause of autoimmune encephalitis even if patients are over 40 years of age, as the symptoms and signs are atypical for MELAS syndrome.

Keywords:  Case report; Encephalitis; MELAS; Mitochondrial DNA mutation

DOI:  https://doi.org/10.12998/wjcc.v11.i14.3275
Appl Clin Inform. 2023 Jun 05.

Special Section Patient Engagement in Informatics: Engaging patients and other stakeholders in "designing for dissemination" record linkage methods and tools.

Jenna E Reno, Toan C Ong, Chan Voong, Brad Morse, Kate Ytell, Romona Koren, Bethany W Kwan.

BACKGROUND: Novel record linkage (RL) methods have the potential to enhance clinical informatics by integrating patient data from multiple sources-including electronic health records, insurance claims, and digital health devices-to inform patient-centered care. Engaging patients and other stakeholders in the use of RL methods in patient-centered outcomes research (PCOR) is a key step in ensuring RL methods are viewed as acceptable, appropriate, and useful. The CU Record Linkage (CURL) platform empowers the use of RL in PCOR.OBJECTIVE: Describe the process of engaging patients and other stakeholders in the design of a RL dissemination package to support the use of RL methods in PCOR.
METHODS: Customer discovery, value proposition design, and user-experience methods were used to iteratively develop an RL dissemination package that includes animated explainer videos for patients and an RL research planning workbook for researchers. Patients and other stakeholders (researchers, data managers, and regulatory officials) were engaged in the RL dissemination package design.
RESULTS: Patient partners emphasized the importance of conveying how RL methods may benefit patients and the rules researchers must follow to protect the privacy and security of patient data. Other stakeholders described accuracy, flexibility, efficiency, and data security compared to other available RL solutions. Dissemination package communication products reflect the value propositions identified by key stakeholders. As prioritized by patients, the animated explainer videos emphasize the data privacy and security processes and procedures employed when performing research using RL. The RL workbook addresses researchers' and data managers' needs to iteratively design RL projects and provides accompanying resources to alleviate leadership and regulatory officials' concerns about data regulation compliance.
CONCLUSIONS: Dissemination products to promote adoption and use of CURL include materials to facilitate patient engagement in RL research and investigator step-by-step decision-making materials about the integration of RL methods in patient-centered outcomes research.

DOI: https://doi.org/10.1055/a-2105-6505
Orphanet J Rare Dis. 2023 Jun 07. 18(1): 140

Barriers and facilitators to the implementation of guidelines in rare diseases: a systematic review.

Matthew Gittus, Jiehan Chong, Anthea Sutton, Albert C M Ong, James Fotheringham.

BACKGROUND: Rare diseases present a challenge to guideline implementation due to a low prevalence in the general population and the unfamiliarity of healthcare professionals. Existing literature in more common diseases references barriers and facilitators to guideline implementation. This systematic review aims to identify these barriers and facilitators in rare diseases from existing literature.METHODS: A multi-stage strategy included searching MEDLINE PubMed, EMBASE Ovid, Web of Science and Cochrane library from the earliest date available to April 2021, Orphanet journal hand-search, a pearl-growing strategy from a primary source and reference/citation search was performed. The Integrated Checklist of Determinants of Practice which comprises of twelve checklists and taxonomies, informed by 57 potential determinants was selected as a screening tool to identify determinants that warrant further in-depth investigation to inform design of future implementation strategies.
RESULTS: Forty-four studies were included, most of which were conducted in the United States (54.5%). There were 168 barriers across 36 determinants (37 studies) and 52 facilitators across 22 determinants (22 studies). Fifteen diseases were included across eight WHO ICD-11 disease categories. Together individual health professional factors and guideline factors formed the majority of the reported determinants (59.5% of barriers and 53.8% of facilitators). Overall, the three most reported individual barriers were the awareness/familiarity with the recommendation, domain knowledge and feasibility. The three most reported individual facilitators were awareness/familiarity with the recommendation, agreement with the recommendation and ability to readily access the guidelines. Resource barriers to implementation included technology costs, ancillary staff costs and more cost-effective alternatives. There was a paucity of studies reporting influential people, patient advocacy groups or opinion leaders, or organisational factors influencing implementation.
CONCLUSIONS: Key barriers and facilitators to the implementation of clinical practice guidelines in the setting of rare diseases were at the individual health professional and guideline level. Influential people and organisational factors were relatively under-reported and warrant exploration, as does increasing the ability to access the guidelines as a potential intervention.

DOI: https://doi.org/10.1186/s13023-023-02667-9
ZFA (Stuttgart). 2022 ;98(5): 178-183

[Patient and Public Involvement in Family Medicine Research].

für die AG Partizipation der Initiative Deutscher Forschungspraxennetze – DESAM-ForNet

  Patient and Public Involvement (PPI) has gained importance in Germany and is also increasingly implemented in research in family medicine. Internationally, diverse frameworks give recommendations on how to successfully design and implement PPI in specific contexts. However, it is crucial to share experiences on PPI in specific settings such as family medicine in order to learn from each other. Thus, this article provides an overview of PPI concepts in the practice-based research networks (PBRNs) of the Initiative of German Practice-Based Research Networks - DESAM-ForNet. In the PBRNs patients and the public are involved in the research process by repeated group meetings in "public forums" (BayFoNet), "round tables" (FoPraNet-BW) or "patient advisory boards" (HAFO.NRW, RESPoNsE, SaxoForN) with a special focus on the planning and dissemination phase of projects. The most successful recruitment strategies so far have encompassed individual patient contacts of family physicians, postings/posters, local self-help organizations and standardized patient programs. Evaluation of PPI is currently being designed in most PBRNS. Overall, the PBRN-specific PPI concepts represent diverse possibilities to create long-term collaborative partnerships with patients and the public. These exemplary concepts are meant to encourage the further development and implementation of adapted PPI-concepts in family medicine research.

Keywords:  family medicine; participation; patient and public involvement; practice-based research networks

DOI:  https://doi.org/10.53180/zfa.2022.0178-0183
Mol Ther Methods Clin Dev. 2023 Jun 08. 29 513-521

Medicaid coverage practices for approved gene and cell therapies: Existing barriers and proposed policy solutions.

Jeremy Allen, Diane Berry, Francesca Cook, Ashley Hume, Rayne Rouce, Anirudh Srirangam, Jennifer Wellman, Caitlin McCombs.

  The current Medicaid system is ill equipped to handle the anticipated approvals of new gene and cell therapy products. These advanced therapies tend to be single-dose, potentially durable options for a variety of indications spanning oncology, rare disease, and more. The up-front cost of these therapies contrasts with chronic care treatment, which may incur cost over the life of a patient. The cost of these innovative treatments, along with the anticipated larger patient pools, can limit patient access as Medicaid programs operate on limited or fixed budgets. Given the value of these therapies for diseases that may have large Medicaid populations, the system will need to grapple with the existing barriers to access to ensure equitable patient care. This review focuses on one such barrier, discrepancies between product indications and state Medicaid and Medicaid Managed Care Organization coverage policies, and it proposes federal policy solutions to this barrier to better accommodate the exponential growth of the gene and cell therapy pipeline.

Keywords:  CMS; Medicaid; cell therapy; coverage to label; development pipeline; gene therapy; patient experience; payment policy; time to treatment; value-based payment

DOI:  https://doi.org/10.1016/j.omtm.2023.05.015
Front Mol Biosci. 2023 ;10 1120376

Metabolomics of infectious diseases in the era of personalized medicine.

Mahbuba Rahman, Herb E Schellhorn.

  Infectious diseases continue to be a major cause of morbidity and mortality worldwide. Diseases cause perturbation of the host's immune system provoking a response that involves genes, proteins and metabolites. While genes are regulated by epigenetic or other host factors, proteins can undergo post-translational modification to enable/modify function. As a result, it is difficult to correlate the disease phenotype based solely on genetic and proteomic information only. Metabolites, however, can provide direct information on the biochemical activity during diseased state. Therefore, metabolites may, potentially, represent a phenotypic signature of a diseased state. Measuring and assessing metabolites in large scale falls under the omics technology known as "metabolomics". Comprehensive and/or specific metabolic profiling in biological fluids can be used as biomarkers of disease diagnosis. In addition, metabolomics together with genomics can be used to differentiate patients with differential treatment response and development of host targeted therapy instead of pathogen targeted therapy where pathogens are more prone to mutation and lead to antimicrobial resistance. Thus, metabolomics can be used for patient stratification, personalized drug formulation and disease control and management. Currently, several therapeutics and in vitro diagnostics kits have been approved by US Food and Drug Administration (FDA) for personalized treatment and diagnosis of infectious diseases. However, the actual number of therapeutics or diagnostics kits required for tailored treatment is limited as metabolomics and personalized medicine require the involvement of personnel from multidisciplinary fields ranging from technological development, bioscience, bioinformatics, biostatistics, clinicians, and biotechnology companies. Given the significance of metabolomics, in this review, we discussed different aspects of metabolomics particularly potentials of metabolomics as diagnostic biomarkers and use of small molecules for host targeted treatment for infectious diseases, and their scopes and challenges in personalized medicine.

Keywords:  biomarkers; infectious diseases; metabolomics; multidisciplinary field; personalized medicine

DOI:  https://doi.org/10.3389/fmolb.2023.1120376
J Pediatr. 2023 Jun 02. pii: S0022-3476(23)00385-2. [Epub ahead of print] 113537

Genomics Research with Undiagnosed Children: Ethical Challenges at the Boundaries of Research and Clinical Care.

Undiagnosed Diseases Network

OBJECTIVE: To explore the perspectives of parents of undiagnosed children enrolled in genomic diagnosis research regarding their motivations for enrolling their children, their understanding of the potential burdens and benefits, and the extent to which their experiences ultimately aligned with or diverged from their original expectations.STUDY DESIGN: In-depth interviews were conducted with parents, audio-recorded and transcribed. A structured codebook was applied to each transcript, after which iterative memoing was used to identify themes.
RESULTS: Fifty-four parents participated, including 17 (31.5%) whose child received a diagnosis through research. Themes describing parents' expectations and experiences of genomic diagnosis research included: 1) the extent to which parents' motivations for participation focused on their hope that it would directly benefit their child; 2) the ways in which parents' frustrations regarding the research process confused the dual clinical and research goals of their participation; and 3) the limited clinical benefits parents ultimately experienced for their children.
CONCLUSION: Our results suggest that parents of undiagnosed children seeking enrollment in genomic diagnosis research are at risk of a form of therapeutic misconception - in this case, diagnostic misconception. These findings indicate the need to examine the processes and procedures associated with this research in order to appropriately communicate and balance the potential burdens and benefits of study participation.

DOI: https://doi.org/10.1016/j.jpeds.2023.113537
JAMA Netw Open. 2023 06 01. 6(6): e2316383

Partnering With Patients, Caregivers, and Clinicians to Determine Research Priorities for Concussion.

Canadian Traumatic Brain Injury Research Consortium

Importance: Identifying research priorities of patients with concussion, their caregivers, and their clinicians is important to ensure future concussion research reflects the needs of those who will benefit from the research.Objective: To prioritize concussion research questions from the perspectives of patients, caregivers, and clinicians.
Design, Setting, and Participants: This cross-sectional survey study used the standardized James Lind Alliance priority-setting partnership methods (2 online cross-sectional surveys and 1 virtual consensus workshop using modified Delphi and nominal group techniques). Data were collected between October 1, 2020, and May 26, 2022, from people with lived concussion experience (patients and caregivers) and clinicians who treat concussion throughout Canada.
Exposures: The first survey collected unanswered questions about concussion that were compiled into summary questions and checked against research evidence to ensure they were unanswered. A second priority-setting survey generated a short list of questions, and 24 participants attended a final priority-setting workshop to decide on the top 10 research questions.
Main Outcomes and Measures: Top 10 concussion research questions.
Results: The first survey had 249 respondents (159 [64%] who identified as female; mean [SD] age, 45.1 [16.3] years), including 145 with lived experience and 104 clinicians. A total of 1761 concussion research questions and comments were collected and 1515 (86%) were considered in scope. These were combined into 88 summary questions, of which 5 were considered answered following evidence review, 14 were further combined to form new summary questions, and 10 were removed for being submitted by only 1 or 2 respondents. The 59 unanswered questions were circulated in a second survey, which had 989 respondents (764 [77%] who identified as female; mean [SD] age, 43.0 [4.2] years), including 654 people who identified as having lived experience and 327 who identified as clinicians (excluding 8 who did not record type of participant). This resulted in 17 questions short-listed for the final workshop. The top 10 concussion research questions were decided by consensus at the workshop. The main research question themes focused on early and accurate concussion diagnosis, effective symptom management, and prediction of poor outcomes.
Conclusions and Relevance: This priority-setting partnership identified the top 10 patient-oriented research questions in concussion. These questions can be used to provide direction to the concussion research community and help prioritize funding for research that matters most to patients living with concussion and those who care for them.

DOI: https://doi.org/10.1001/jamanetworkopen.2023.16383
Pharmaceut Med. 2023 Jun 07.

The Cost of Biotech Innovation: Exploring Research and Development Costs of Cell and Gene Therapies.

Marco T Sabatini, Mark Chalmers.

BACKGROUND: Clinical development paradigms for cell and gene therapies appear to be different to those of more conventional treatments: therefore, it is informative to explore this from the perspective of investments required to bring a new cell and/or gene therapy to the market. While there are a number of studies in the literature analyzing clinical-stage R&D costs for novel therapeutics, these are 'modality-agnostic' and thus do not elucidate costs specifically for the emerging class of cell and gene therapies.OBJECTIVES: The objective of this study was to understand the research and development (R&D) costs associated with the clinical development of new cell and gene therapy assets METHODS: As part of our analysis of clinical-stage R&D costs for cell and gene therapies, we focused our efforts on cell and gene therapy assets recently approved by the US Food and Drug Administration (FDA) or expected to receive FDA approval by the end of 2024. A total of 25 therapies were identified for the study, 11 of which had sufficient level of detail for our clinical-stage R&D costing study. We calculated the clinical-stage R&D costs to bring a new cell and/or gene therapy to the market following a three-step approach, starting with (1) calculation of the out-of-pocket investment reported in US SEC reports; (2) we adjusted these figures for the risk of failure by applying a clinical trial phase-dependent attrition risk rate; (3) we accounted for the cost of capital of 10.5%.
RESULTS: After accounting for R&D attrition rate (i.e., costs of failed programs) and applying a cost of capital at 10.5%, we estimate that the clinical-stage R&D investment required to bring a new cell and/or gene therapy to market is US$1943 M (95% CI US$1395 M, US$2490 M).
CONCLUSION: This knowledge can inform financial planning for biopharma companies looking to enter the space and inform policy makers within the context of the commercialization and pricing of such therapies.

DOI: https://doi.org/10.1007/s40290-023-00480-0