bims-curels 2023-03-19 papers

Issue of 2023‒03‒19
six papers selected by
Cure Mito Foundation

Schmerz. 2023 Mar 14.

[Clinical trials as a central part of patient-centered clinical research].

Karsten Gavenis, Orlando Guntinas-Lichius, Jan Löhler, Ralf Tostmann, Thomas Asendorf.

As the continuation and implementation of findings from basic (pre‑)clinical research, clinical trials make a significant contribution to medical research. They form the central building block of translational medicine and thus make a decisive contribution to bringing medical knowledge into general care. This helps to make possible a healthcare system that is aligned to the needs of patients and functions efficiently in the long term. Based on the specific objective, clinical trials must comply with national, but increasingly also with European and international regulatory requirements. In academia in particular, expertise in a variety of fields is required in order to make investigator-driven clinical trials a success. This expertise can be provided by a clinical trial center based within the institution conducting the trial.

Keywords: Biomedical translational science; Clinical trials as topic; Health care evaluation mechanisms; Patient-centered outcomes research; Quality assurance, health care

DOI: https://doi.org/10.1007/s00482-023-00712-x

Sci Rep. 2023 Mar 14. 13(1): 4193

Use of dual genomic sequencing to screen mitochondrial diseases in pediatrics: a retrospective analysis.

Teng-Hui Wu, Jing Peng, Li Yang, Yan-Hui Chen, Xiu-Lan Lu, Jiao-Tian Huang, Jie-Yu You, Wen-Xian Ou-Yang, Yue-Yu Sun, Yi-Nan Xue, Xiao Mao, Hui-Ming Yan, Rong-Na Ren, Jing Xie, Zhi-Heng Chen, Victor-Wei Zhang, Gui-Zhen Lyu, Fang He.

Mitochondrial diseases (MDs) were a large group multisystem disorders, attributable in part to the dual genomic control. The advent of massively sequencing has improved diagnostic rates and speed, and was increasingly being used as a first-line diagnostic test. Paediatric patients (aged < 18 years) who underwent dual genomic sequencing were enrolled in this retrospective multicentre study. We evaluated the mitochondrial disease criteria (MDC) and molecular diagnostic yield of dual genomic sequencing. Causative variants were identified in 177 out of 503 (35.2%) patients using dual genomic sequencing. Forty-six patients (9.1%) had mitochondria-related variants, including 25 patients with nuclear DNA (nDNA) variants, 15 with mitochondrial DNA (mtDNA) variants, and six with dual genomic variants (MT-ND6 and POLG; MT-ND5 and RARS2; MT-TL1 and NARS2; MT-CO2 and NDUFS1; MT-CYB and SMARCA2; and CHRNA4 and MT-CO3). Based on the MDC, 15.2% of the patients with mitochondria-related variants were classified as "unlikely to have mitochondrial disorder". Moreover, 4.5% of the patients with non-mitochondria-related variants and 1.43% with negative genetic tests, were classified as "probably having mitochondrial disorder". Dual genomic sequencing in suspected MDs provided a more comprehensive and accurate diagnosis for pediatric patients, especially for patients with dual genomic variants.

DOI: https://doi.org/10.1038/s41598-023-31134-5

Nucleic Acids Res. 2023 Mar 17. pii: gkad139. [Epub ahead of print]

Restoration of mitochondrial function through activation of hypomodified tRNAs with pathogenic mutations associated with mitochondrial diseases.

Ena Tomoda, Asuteka Nagao, Yuki Shirai, Kana Asano, Takeo Suzuki, Brendan J Battersby, Tsutomu Suzuki.

Mutations in mitochondrial (mt-)tRNAs frequently cause mitochondrial dysfunction. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), and myoclonus epilepsy associated with ragged red fibers (MERRF) are major clinical subgroups of mitochondrial diseases caused by pathogenic point mutations in tRNA genes encoded in mtDNA. We previously reported a severe reduction in the frequency of 5-taurinomethyluridine (τm5U) and its 2-thiouridine derivative (τm5s2U) in the anticodons of mutant mt-tRNAs isolated from the cells of patients with MELAS and MERRF, respectively. The hypomodified tRNAs fail to decode cognate codons efficiently, resulting in defective translation of respiratory chain proteins in mitochondria. To restore the mitochondrial activity of MELAS patient cells, we overexpressed MTO1, a τm5U-modifying enzyme, in patient-derived myoblasts. We used a newly developed primer extension method and showed that MTO1 overexpression almost completely restored the τm5U modification of the MELAS mutant mt-tRNALeu(UUR). An increase in mitochondrial protein synthesis and oxygen consumption rate suggested that the mitochondrial function of MELAS patient cells can be activated by restoring the τm5U of the mutant tRNA. In addition, we confirmed that MTO1 expression restored the τm5s2U of the mutant mt-tRNALys in MERRF patient cells. These findings pave the way for epitranscriptomic therapies for mitochondrial diseases.

DOI: https://doi.org/10.1093/nar/gkad139

Yi Chuan. 2023 Jan 20. 45(1): 42-51

Advances in the application of induced pluripotent stem cells in pediatric diseases.

Zhi-Chen Tian, Xiao-Juan Yin.

The optimal diagnosis and treatment of pediatric diseases depend on more adequate understanding of pathophysiology. The advent of induced pluripotent stem cells (iPSCs) has provided new strategies for the research and therapy of pediatric diseases. iPSCs are pluripotent stem cells induced by reprogramming of mature cells. Now they can be induced from many types of somatic cells (such as fibroblasts, peripheral blood mononuclear cells and urine cells).With the improvement of various reprogramming methods, its generation procedure is more and more optimized, and the use of small molecules to induce iPSCs is one of the research focus now. Due to their ability to differentiate into a variety of cells, combined with the development of gene editing technology, iPSCs have been increasingly favored in the modeling of diseases and cell therapy, especially hereditary diseases, and have achieved some success in clinical treatment. But before they can be widely used in clinical treatment, there are still some problems to be solved, such as tumorigenicity, immunogenicity and heterogeneity. This article reviewed the source of iPSCs, reprogramming technology, applications of iPSCs in common childhood diseases, current problems and prospects, in order to deepen the understanding of iPSCs and provide reference for in-depth research in field of exploring mechanisms of diseases and therapy of diseases.

Keywords: cell therapy; disease modeling; induced pluripotent stem cells; reprogramming

DOI: https://doi.org/10.16288/j.yczz.22-245

Res Sq. 2023 Feb 27. pii: rs.3.rs-2612547. [Epub ahead of print]

Inflammatory and interferon gene expression signatures in patients with mitochondrial disease.

Emily Warren, Eliza M Gordon-Lipkin, Foo Cheung, Jinguo Chen, Amrita Mukherjee, Richard Apps, John S Tsang, Jillian Jetmore, Shannon Kruk, Yuanjiu Lei, A Phillip West, Peter J McGuire.

Background: People with mitochondrial disease (MtD) are susceptible to metabolic decompensation and neurological symptom progression in response to an infection. Increasing evidence suggests that mitochondrial dysfunction may cause chronic inflammation, which may promote hyperresponsiveness to pathogens and neurodegeneration. Methods: We collected whole blood from a cohort of MtD patients and healthy controls and performed RNAseq to examine transcriptomic differences. We performed GSEA analyses to compare our findings against existing studies to identify commonly dysregulated pathways. Results: Gene sets involved in inflammatory signaling, including type I interferons, interleukin-1β and antiviral responses, are enriched in MtD patients compared to controls. Monocyte and dendritic cell gene clusters are also enriched in MtD patients, while T cell and B cell gene sets are negatively enriched. The enrichment of antiviral response corresponds with an independent set of MELAS patients, and two mouse models of mtDNA dysfunction. Conclusions: Through the convergence of our results, we demonstrate translational evidence of systemic peripheral inflammation arising from MtD, predominantly through antiviral response gene sets. This provides key evidence linking mitochondrial dysfunction to inflammation, which may contribute to the pathogenesis of primary MtD and other chronic inflammatory disorders associated with mitochondrial dysfunction.

DOI: https://doi.org/10.21203/rs.3.rs-2612547/v1

J Med Internet Res. 2023 Mar 14. 25 e39262

Direct-to-Consumer Recruitment Methods via Traditional and Social Media to Aid in Research Accrual for Clinical Trials for Rare Diseases: Comparative Analysis Study.

Janelle Applequist, Cristina Burroughs, Peter A Merkel, Marc Rothenberg, Bruce Trapnell, Robert Desnick, Mustafa Sahin, Jeffrey Krischer.

BACKGROUND: Recruitment into clinical trials is a challenging process, with as many as 40% of studies failing to meet their target sample sizes. The principles of direct-to-consumer (DTC) advertising rely upon novel marketing strategies. The ability to reach expansive audiences in the web-based realm presents a unique opportunity for researchers to overcome various barriers to enrollment in clinical trials. Research has investigated the use of individual web-based platforms to aid in recruitment and accrual into trials; however, a gap in the literature exists, whereby multiple mass communication platforms have yet to be investigated across a range of clinical trials.OBJECTIVE: There is a need to better understand how individual factors combine to collectively influence trial recruitment. We aimed to test whether DTC recruitment of potentially eligible study participants via social media platforms (eg, Facebook [Meta Platforms Inc] and Twitter [Twitter Inc]) was an effective strategy or whether this acted as an enhancement to traditional (eg, email via contact registries) recruitment strategies through established clinical research sites.
METHODS: This study tested multiple DTC web-based recruitment efforts (Facebook, Twitter, email, and patient advocacy group [PAG] involvement) across 6 national and international research studies from 5 rare disease consortia. Targeted social media messaging, social media management software, and individual study websites with prescreening questions were used in the Protocol for Increasing Accrual Using Social Media (PRISM).
RESULTS: In total, 1465 PRISM website referrals occurred across all 6 studies. Organic (unpaid) Facebook posts (676/1465, 46.14%) and Rare Diseases Clinical Research Network patient contact registry emails (461/1465, 31.47%) represented the most successful forms of engagement. PRISM was successful in accumulating a 40.1% (136/339) lead generation (those who screened positive and consented to share their contact information to be contacted by a clinical site coordinator). Despite the large number of leads generated from PRISM recruitment efforts, the number of patients who were subsequently enrolled in studies was low. Across 6 studies, 3 participants were ultimately enrolled, meaning that 97.8% (133/136) of leads dropped off.
CONCLUSIONS: The results indicate that although accrual results were low, this is consistent with previously documented challenges of studying populations with rare diseases. Targeted messaging integrated throughout the recruitment process (eg, referral, lead, and accrual) remains an area for further research. Key elements to consider include structuring the communicative workflow in such a way that PAG involvement is central to the process, with clinical site coordinators actively involved after an individual consents to share their contact information. Customized approaches are needed for each population and research study, with observational studies best suited for social media recruitment. As evidenced by lead generation, results suggest that web-based recruitment efforts, coupled with targeted messaging and PAG partnerships, have the potential to supplement clinical trial accrual.

Keywords: clinical trial; clinical trial accrual; clinical trial recruitment; direct-to-consumer advertising; patient-centered research; rare diseases; research participant recruitment; research recruitment; social media recruitment; web-based recruitment

DOI: https://doi.org/10.2196/39262