bims-tyki2d 2026-06-28 papers

Issue of 2026–06–28
five papers selected by
Zoya Panahloo, UCB

Biomed Pharmacother. 2026 Jun 26. pii: S0753-3322(26)00735-3. [Epub ahead of print]201 119699

Clinical development in primary mitochondrial diseases at a translational inflection point: Lessons, mechanisms, and emerging therapeutic strategies.

Li-Tzu Wang, Han-Ying Jhuang.

Clinical development for primary mitochondrial diseases (PMDs) has spanned more than two decades, yet therapeutic success remains limited. In this Review, we provide a comprehensive, pharmacology-focused analysis of the PMD clinical trial landscape and identify key mechanistic and translational determinants underlying recent progress. A systematic survey of ClinicalTrials.gov covering January 2010 to April 2026 identified 159 registered studies across PMD subtypes after deduplication, including 110 interventional trials. Progress has been constrained by marked genetic and phenotypic heterogeneity, small and geographically dispersed patient populations, and the lack of validated pharmacodynamic and disease-specific endpoints. Consequently, several well-designed late-stage trials have yielded negative or inconclusive outcomes, and regulatory approvals have historically been scarce. Recent advances, however, indicate a shift in trajectory. Four therapies have achieved regulatory authorization, including idebenone for Leber hereditary optic neuropathy, taurine for MELAS, and recent FDA approvals of doxecitine and doxribtimine (Kygevvi) for thymidine kinase 2 deficiency and elamipretide (FORZINITY) for Barth syndrome. These successes share a convergent translational framework integrating mechanism-based pharmacology, genotype-driven patient selection, and biologically aligned endpoints. Clinical activity has also accelerated, with approximately half of PMD interventional trials initiated since 2020 and 50 studies currently active or recruiting. Emerging strategies include NAD⁺ augmentation, soluble guanylate cyclase stimulation, mTOR modulation, gene therapies, and heteroplasmy-targeting approaches. Collectively, these advances mark an emerging inflection point and suggest a path toward greater regulatory success in the coming decade.

Keywords: Clinical trials; Gene therapy; Leber hereditary optic neuropathy; MELAS; Primary mitochondrial disease; Translational medicine; Trial design

DOI: https://doi.org/10.1016/j.biopha.2026.119699

Orphanet J Rare Dis. 2026 Jun 24.

Implementation of a medical genomics program for rare diseases in Uruguay.

Camila Simoes, María Fernanda Domínguez, Soledad Rodriguez, Mariana Moraes, María Paula Frade, Mariana Brandes, Martín Graña, Lucía Sosa, Santiago Fontenla, Alejandra Tapié, Nicolás Dell'Oca, Olaf Riess, José Tort, Hugo Naya, Víctor Raggio, Lucia Spangenberg.

BACKGROUND: Rare diseases (RDs) affect an estimated 7% of the global population and comprise ~7,000 heterogeneous conditions, most of which have a genetic etiology. Despite their collective burden, RDs pose major diagnostic challenges, often resulting in prolonged diagnostic odysseys with substantial clinical, emotional, and economic consequences. Next generation sequencing technologies such as whole exome (WES) and whole genome sequencing (WGS) have transformed RD diagnostics in high-resource settings. In contrast, the use of such technologies in Latin America remains uneven due to structural, regulatory, and economic constraints. In addition, the underrepresentation of admixed populations in genomic databases further complicates variant interpretation, reducing the diagnostic yield. In this context, we created the first genomic medicine program for rare diseases in Uruguay to address these challenges by implementing next-generation sequencing (NGS) strategies for diagnosis.
MATERIAL AND METHODS: Whole exome sequencing (WES) and whole genome sequencing (WGS) were performed on a cohort of 203 patients with suspected RD belonging to the Uruguayan public healthcare system. Variant prioritization was conducted using established bioinformatics pipelines integrating population frequency filtering, inheritance models, functional impact, and phenotype-driven clinical interpretation. Implementation of population-aware variant interpretation strategies was critical in this admixed population, helping to reduce false-positive findings arising from the underrepresentation of Latin American populations in global reference databases. This framework was built through sustained collaboration between academic institutions and healthcare providers, with a strong emphasis on local capacity building in clinical genetics, molecular diagnostics, and bioinformatics.
RESULTS: To date, we have analyzed a total of 203 patients: 172 using WES, 29 using WGS, and 11 using mitochondrial DNA sequencing (9 of whom were also analyzed by WES). The overall diagnostic yield was 48% for WES and 31% for WGS. The program significantly shortened diagnostic trajectories and enabled actionable clinical insights in a substantial proportion of cases.
CONCLUSIONS: Our experience shows that comprehensive genomic diagnostics for RDs can be successfully carried out in emerging genomic medicine settings through integrated workflows and sustained investment in human capital. This initiative represents a scalable model for other low income countries seeking to incorporate genomic medicine into public healthcare systems and highlights the importance of regional genomic data to improve diagnostic accuracy and equity.

Keywords: Exome sequencing; Genetic diagnostic; Genome sequencing; Medical genomics; Rare diseases

DOI: https://doi.org/10.1186/s13023-026-04387-2

Ned Tijdschr Geneeskd. 2026 May 26. pii: D8907. [Epub ahead of print]170

[The rise of genetic therapies: urgent moral and societal questions].

Kris E Leeuwenberg, Karlien Mul, Bart P van de Warrenburg, Gert Olthuis.

Genetic therapies offer long-awaited hope for patients with rare genetic diseases and are emerging as cancer treatment as well. While these innovations appear promising, they are also extremely expensive and raise concerns about how they fit into an already overburdened healthcare system. What are the societal implications when these treatments become available? And how can we guide their adoption in the Dutch healthcare system in an ethically responsible manner? We describe the emerging landscape of genetic therapies, and specifically examine the ethical concerns surrounding their implementation within the Dutch healthcare system. From this reflection, we seek to offer direction on how to approach these new biomedical developments in a way that preserves the fundamental values of solidarity and justice. This is particularly important, given how rapidly developments in this field are progressing.

Hum Genet. 2026 Jun 26. pii: 54. [Epub ahead of print]145(1):

AI in variant analysis: fast track to genetic diagnoses.

Elizabeth J Wilk, Sasha Taluri, Timothy C Howton, Anthony B Crumley, Michal Mrug, Brittany N Lasseigne.

While falling costs have expanded access to genomic sequencing, clinical utility is frequently hindered by the challenge of interpreting complex genetic data. Variant analysis for rare disease patients especially requires significant time and expertise, creating a bottleneck that delays diagnostics. Although advances in genetic variant classification have improved diagnostic precision, they have also increased the identification of variants of uncertain significance (VUSs), widening the interpretation gap between data generation and clinical actionability. The high prevalence of VUSs can lead to false reassurance or psychological distress by misinterpretting inconclusive results. We propose that artificial intelligence (AI) is a critical clinical decision-support tool for bridging this gap, offering a scalable framework to optimize variant interpretation and shorten the diagnostic odyssey. While reclassification ultimately requires biological evidence that AI cannot replace, these tools serve as essential aggregators and prioritizers, especially as guidelines transition toward the upcoming quantitative ACMG v4 framework. We advocate integrating AI throughout the genetic diagnostic workflow-from initial phenotyping to variant prioritization-to facilitate data-driven, personalized treatment. We outline current AI-assisted approaches and discuss anticipated challenges in this pursuit, such as privacy, training data bias and quality, model explainability, and the necessity of a total product life cycle for validation. To address these challenges, we provide recommendations for "human-in-the-loop" design and intuitive workflow integration to ensure AI tools meet the highest standards of precision, reproducibility, and transparency to maximize adoption. By standardizing AI across the variant analysis pipeline, we can fast-track the path to genetic diagnoses, effectively bridging the interpretation gap and enabling rapid delivery of personalized medical interventions.

DOI: https://doi.org/10.1007/s00439-026-02847-0

Arch Med Res. 2026 Jun 22. pii: S0188-4409(26)00077-9. [Epub ahead of print]57(8): 103454

Access to Medicines for Rare Diseases in Brazil.

Catia Veronica Dos Santos Oliveira, Claudia Garcia Serpa Osorio-de-Castro, Vera Lúcia Edais Pepe.

Brazil is a continental country with socioeconomic inequities, hampering access to essential goods and services, including health care. Brazil's Unified Health System (SUS) is a universal, publicly funded health system, warranting free access to health care, including medicines. Significant advances followed the creation of SUS, the implementation of the National Medicines Policy (PNM) and the National Pharmaceutical Services Policy (PNAF) between 1990 and 2000, such as country-wise organization and management of pharmaceutical services and provision of high-cost medicines, a segment including most medicines for rare diseases. The National Policy for Comprehensive Care for Individuals with Rare Diseases has fostered discussion and action on comprehensive care for individuals with rare conditions. However, insufficient funding, setbacks in provision, shortages and the pressures of innovation, patents and prices of medicines have burdened access initiatives. The paper presents the Brazilian scenario and discusses the main pathways for access to medicines for rare diseases in the country, beginning by a comprehensive description of administrative routes, as marketing authorization and incorporation into the health system, which constitute the more straightforward and norm-adherent paths. However, the alternative pathway, litigation for access, guaranteed by the Brazilian Constitution that upholds the right to health, has consolidated itself in the last 20 years, taking an enormous toll on expenditures and appropriate use of medicines. To overcome these challenges and expand access to drugs for rare diseases Brazil must ensure robust evidence-based use for adequate indications, monitoring and managed entry of new medicines and ethical allocation of resources.

Keywords: Access to medicines; Brazil; Drugs for rare diseases; Health policy; Rare Diseases; Unified Health System

DOI: https://doi.org/10.1016/j.arcmed.2026.103454