bims-tyki2d 2025-11-23 papers

Issue of 2025–11–23
four papers selected by
Zoya Panahloo, UCB

Adv Ther. 2025 Nov 21.

Study Designs and Crafting Endpoints for Gene Therapy Development Programs in Rare Disease: A Narrative Review.

on behalf of the Rare Disease Clinical Outcome Assessment Consortium

Gene therapies are emerging as a promising strategy for the treatment of rare genetic diseases, for which treatment options are often limited and do not address the underlying disease mechanisms. However, there are significant challenges for gene therapy programs, including defining a suitable first-in-human cohort and selecting endpoints with appropriate variability, sensitivity, reliability, and clinical meaningfulness; a systematic framework for the assessment and approval of these treatments is lacking. In this review, we share insights from 12 clinical development programs that culminated in recent approvals of gene therapies for rare genetic diseases (2016-2023). These approvals highlight useful strategies for navigating the unique challenges of gene therapy trials, including early and frequent engagement with regulatory bodies, incorporating the patient voice, selecting meaningful clinical outcome assessments and suitable controls, and leveraging well-matched real-world data to understand long-term efficacy, durability, and safety. By systematically documenting and analyzing detailed examples in this review, it becomes possible to derive data-driven solutions that can inform the design of future studies. Such solutions may diverge from prior assumptions or preconceptions but can provide a more evidence-based foundation for improving trial efficiency, and ultimately accelerate the development of urgently needed therapies for patients with rare genetic diseases.

Keywords: Clinical development; Clinical outcome assessments; Clinical trials; Endpoints; Gene therapy; Genetic disorders; Marketing authorization; Rare diseases; Regulatory approval; Study design

DOI: https://doi.org/10.1007/s12325-025-03385-3

Front Neurosci. 2025 ;19 1696899

NMPhenogen: a comprehensive database for genotype-phenotype correlation in neuromuscular genetic disorders.

Usha Manjunath, Venkatesh R, Sacheta Sudhendra Kulkarni, Harshatha N Reddy, Anupama Anil, Rakesh Kumar Mishra, Gayatri Rangarajan Iyer.

Neuromuscular genetic disorders (NMGDs) are genetically and clinically diverse group of inherited diseases that affect approximately 1 in 1,000 people worldwide with a calculated prevalence of 37 per 10,000 in the general population. These disorders arise from a variety of genetic changes such as insertions, deletions, duplications and expansions of repeats in more than 747 nuclear and mitochondrial genes critical for the function of peripheral nerves, motor neurons, neuromuscular junctions or skeletal muscles, leading to progressive weakness and degeneration of muscles. Major subtypes include muscular dystrophies, congenital myopathies, motor neuron diseases, peripheral neuropathies, and mitochondrial myopathies. Clinical presentation of NMGDs is highly variable in the age of onset, severity and pattern of muscle involvement, often leading to prolonged and complex diagnostic process. Conventional diagnostic methods have relied on clinical history, physical examination and invasive procedures like muscle biopsy. But the development of next-generation sequencing (NGS) has transformed diagnostics by enabling comprehensive analysis of NMGD-related genes. Despite this advancement, interpreting the numerous variants identified by NGS remains challenging. The guidelines of the American College of Medical Genetics and Genomics (ACMG) offer a standardized approach to variant classification as pathogenic, likely pathogenic, variant of uncertain significance, likely benign and benign. However, this requires the integration of complex evidence from population data, computational predictions, and functional assays. The major challenge is the robust correlation of genotypic information with the huge phenotypic range of NMGDs which is a task complicated by the unavailability of population-specific genetic databases. To address these issues, we have developed NMPhenogen (https://gi-lab-tigs.github.io/Homepage/), a new database designed to enhance the diagnosis and understanding of NMGDs. NMPhenogen is a centralized repository for data related to NMGD-associated genes and variants along with their clinical presentations. It includes two primary modules: NMPhenoscore, which enhances disease-phenotype correlations, and a Variant classifier, which facilitates standardized variant classification based on published guidelines. This combined resource aims to streamline the diagnostic process, support clinical decision-making, and eventually contribute to improving patient care and genetic counseling.

Keywords: ACMG; NMGD; NMPhenoscore; disease prioritization; neuromuscular disorders; variant classification; variant classifier; variant interpretation tool

DOI: https://doi.org/10.3389/fnins.2025.1696899

J Mol Neurosci. 2025 Nov 19. 75(4): 154

Hypocitrullinemia as an Early Diagnostic Biomarker for MT-ATP6 Mitochondrial Diseases.

Yingxue Li, Dongjuan Wang, Maobin Zhou, Haoxuan Sun, Siqi Hong, Li Jiang, Yi Guo.

MT-ATP6 mitochondrial diseases are a group of disorders inherited from the maternal lineage caused by pathogenic variants in the MT-ATP6 gene, which encodes the a subunit of mitochondrial complex V (ATP synthase) in the electron transport chain. In this study, statistical analysis of 69 mitochondrial disease patients with complete blood metabolic screening at our center demonstrated that hypocitrullinemia exhibited 58% sensitivity (7/12) and 100% specificity (57/57) for diagnosing MT-ATP6 mitochondrial diseases. For detecting the m.8993T > G variant, the diagnostic sensitivity reached 78% (7/9) with maintained 100% specificity (60/60). Among the 7 patients with hypocitrullinemia, one had mtDNA large segment deletion syndrome involving MT-ATP6, and the other 6 had MT-ATP6 mitochondrial diseases due to the m.8993T > G variant. Hypocitrullinemia was initially detected in 3 patients during newborn screening and persisted in follow-up evaluations. A literature review identified 42 cases with MT-ATP6 variants exhibiting hypocitrullinemia, of whom 21 were diagnosed with decreased citrulline during newborn screening. We propose that hypocitrullinemia may serve as an early, characteristic serum biomarker for MT-ATP6 mitochondrial diseases, particularly aiding in the early diagnosis of the m.8993T > G variant. It also exhibits high specificity for diagnosing MT-ATP6 mitochondrial diseases and the m.8993T > G variant. Timely interventions, such as proactive diagnosis of pathogenic variants and administration of mitochondrial cofactors and citrulline, can mitigate the risk of decompensation and improve long-term prognosis.

Keywords: MT-ATP6 ; Biomarker; Hypocitrullinemia; Leigh syndrome; m.8993T > G

DOI: https://doi.org/10.1007/s12031-025-02440-6

BMB Rep. 2025 Nov 20. pii: 6418. [Epub ahead of print]

Mitochondrial transplantation restores mitochondrial content and function in SSBP1-related mitochondrial DNA depletion syndrome.

Dohee Kim, Seo-Eun Lee, JuHyuen Cha, Jun Ho Lee, Young Cheol Kang, Sang-Yeon Lee.

This study examined therapeutic potential of mitochondrial transplantation using PN-101, a mitochondria preparation derived from human umbilical cord mesenchymal stem cells (UCMSCs), to address SSBP1-related mitochondrial DNA (mtDNA) depletion syndrome. Patient-derived fibroblasts harboring a heterozygous SSBP1 mutation (c.272G＞A:p.Arg91Gln) were treated with PN-101. Its successful uptake and integration into these cells were confirmed. Subsequent analyses revealed that PN-101 treatment significantly increased mtDNA copy numbers in a time- and dose-dependent manner, elevated the expression of key oxidative phosphorylation proteins, and enhanced overall mitochondrial bioenergetics. Taken together, these results provide strong evidence that mitochondrial transplantation holds promise as a therapeutic strategy for primary mitochondrial diseases, including those involving SSBP1 mutations.