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#罕见病

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Oct 13Tue
  1. biorxiv.org49

    Spatially resolved tumor-microenvironment architecture defines therapeutic response in unresectable hepatoblastoma

    Spatially organized tumor-microenvironment architecture distinguishes clinical outcomes in unresectable hepatoblastoma. Spatial transcriptomics (10x Visium, n = 11 tumors) and single-cell spatial imaging (NanoString CosMx, n = 3 tumors) on post-chemotherapy explants identified three architectures: relapse-prone tumors showed centralized, TME-dominated organization with SPP1+ TAMs, CAFs, hypoxia and MDK-LRP1 signaling, while non-relapse tumors showed compartmentalized tumor-immune interactions and preserved epithelial differentiation. Spatial architecture, not composition alone, may explain variable response beyond current risk stratification.

  2. doi.org40

    Treatment adherence and mental health in people with cystic fibrosis and advanced lung disease treated with elexacaftor/tezacaftor/ivacaftor

    Thirty-three people with cystic fibrosis and advanced lung disease maintained moderate-to-high adherence to elexacaftor/tezacaftor/ivacaftor after about 30 months, with overall adherence of 75.6%. At 36 months, sweat chloride had decreased by 57.4 mmol/L, ppFEV1 increased by 19.4%, and BMI increased by 1.6 kg/m2, with improved health-related quality of life across most CFQ-R domains. Concentration difficulties (25.8%) and insomnia (32.3%) persisted and were associated with anxiety.

Oct 12Mon
  1. Mult Scler41

    Autologous haematopoietic stem cell transplantation affects paramagnetic rim lesions in multiple sclerosis.

    Autologous haematopoietic stem cell transplantation was associated with a reduction in paramagnetic rim lesions, a marker of chronic inflammation that disease-modifying therapies barely affect. In 30 transplanted people with multiple sclerosis, PRL count decreased in 40% of PRL-positive cases scanned before and after AHSCT and in 57% of those scanned after only, with no new PRL appearing. Annualised PRL disappearance rates were -0.36 and -0.43, suggesting an effect on central nervous system microglia/macrophages.

  2. Sci Adv64

    SMCHD1 is a target for gene activation therapy to treat Prader-Willi syndrome.

    SMCHD1 represses the entire Prader-Willi syndrome locus in neural lineages in both mice and humans, making it a candidate target for activating the silenced maternal copy of the disease genes. Deleting Smchd1 after early development in vivo activated PWS genes in disease-relevant mouse tissues including hypothalamus and improved phenotypes in a PWS mouse model. Genome-wide SMCHD1 binding aside, this postearly targeting appeared safe, supporting gene activation therapy for the underlying cause of PWS rather than individual symptoms.

    Why it matters: It identifies a molecular target that activates the silenced maternal allele and improves disease phenotypes in a PWS mouse model.

Oct 11Sun
  1. biorxiv.org68

    Disrupted chromatin architecture blocks B lymphopoiesis in Down syndrome

    Three-dimensional genome architecture organizes human fetal haematopoiesis and explains the B-lineage defect in Down syndrome. Using ChromE-seq, a new single-cell assay jointly profiling chromatin conformation and transcription, the authors built a multimodal atlas of ~400,000 haematopoietic cells from disomic and trisomy 21 fetal liver. Trisomy 21 disproportionately disrupted B-lineage architecture, weakened an EBF1-centred regulatory circuit, and deleting a T21-sensitive EBF1 loop anchor reproduced the CLP-to-B-progenitor bottleneck seen in T21.

    Why it matters: Links 3D chromatin architecture to lineage priming and identifies an EBF1 circuit behind the trisomy 21 B-cell defect.

Oct 10Sat
  1. doi.org49

    JAK-inhibitor treatment induces rapid yet incomplete immune reconstitution in STAT1 gain-of-function

    JAK inhibitors produced rapid but incomplete immune reconstitution in two STAT1 gain-of-function patients carrying p.R321S and p.T385M mutations. Changes were seen as early as 1 week after treatment: T cells rebalanced toward a homeostatic status, TCR repertoire diversity increased quickly, and transcriptional dysregulation in monocytes improved, though defects such as natural killer deficiency persisted in one patient. The work defines both the therapeutic reach and the limits of JAK inhibition in STAT1 GOF.

Oct 9Fri
  1. biorxiv.org40

    Coordinated alterations in SWI/SNF chromatin remodeling complex, mRNA splicing and mRNA methylation as hallmarks of salivary gland adenoid cystic carcinoma (SACC)

    Spatial transcriptomics of salivary gland adenoid cystic carcinoma points to coordinated disruption of epigenetic regulation as a contributor to the disease. The SWI/SNF chromatin remodeling complex, the NineTeen Complex, and the m6A RNA methylation complex were shown to interact directly, and immunohistochemistry on 48 tumor samples showed altered abundance of METTL3, METTL14, WTAP, PRP19, CDC5L and PLRG1 proteins. BRM directly regulates genes encoding subunits of these complexes and some EMT marker genes, and re-analysis revealed broad alterations in transcript usage and splicing events.

Oct 7Wed
  1. biorxiv.org47

    Disconnect Between Succinate, Succinyl-CoA, and Histone Succinylation in Cells and Gastrointestinal Stromal Tumors with Succinate Dehydrogenase Deficiency

    Succinate dehydrogenase (SDH) deficiency raises succinyl-CoA in multiple models, but histone succinylation does not increase, and lysine malonylation and glutarylation instead decrease. Liquid chromatography high resolution mass spectrometry across the NCI-60 panel, SDH-deficient and SDH-competent models, and GIST patient tumors showed no correlation between succinate to fumarate ratio and succinyl-CoA, and no rise in succinyl-CoA or desuccinylase expression in bulk tumors. Pharmacological desuccinylase inhibition showed very weak or no selective effect on SDH-deficient cell viability, challenging proposed succinylation-based therapeutic targeting.

Oct 5Mon
  1. Mol Cell65

    ZNFX1, an immunoregulatory RNA helicase and E3 ubiquitin ligase, assembles into pleiomorphic polymers.

    Cryo-EM structures of RNA-bound and RNA-free ZNFX1 reveal how a regulatory insertion auto-inhibits the helicase-associated ATPase by occluding the RNA-binding groove. ZNFX1 acts as a bi-catalytic E3 ubiquitin ligase through an RNF213-like RZ finger and a newly identified Miz-like domain, with ubiquitin chains enhancing E3 activity. Patient mutations show the helicase/ATPase, E3 ligase, and connecting zinc-finger stalk are all required for function, and polymer assembly drives trans-auto-ubiquitylation controlling ZNFX1 stability.

    Why it matters: Defines the structural mechanism linking an innate-immunity RNA helicase to ubiquitin signaling and patient mutations.

Oct 3Sat
  1. medrxiv.org53

    Lanreotide for Advanced Pheochromocytoma and Paraganglioma: Results of a Multicenter Phase II Trial

    Lanreotide depot/autogel 120 mg every 4 weeks showed antiproliferative activity in 18 patients with advanced or metastatic pheochromocytomas and paragangliomas, most of them (78%) carrying SDHx mutations. Disease stabilization occurred in 11 of 13 patients (85%) at about 1 year, with two partial responses and a median tumor growth rate of 0.00124/day (doubling time 559 days), consistent with a median PFS of at least 2 years. Treatment was well tolerated, with no discontinuations due to toxicity. The findings support somatostatin analogues as an option for SSTR-positive PPGL before escalating to more aggressive treatments.

Oct 2Fri
  1. Nature72

    Human genetics implicates a BACH2-NRF2 axis in fetal haemoglobin activation.

    A multi-ancestry genome-wide association study of fetal haemoglobin (HbF) levels in 28,279 individuals identified 91 conditionally independent associations across 12 genomic regions. The high-HbF-linked variant rs1010474-C reduces BACH2 expression, and perturbing or inhibiting BACH2 raises HbF: BACH2 restrains γ-globin activation, while its loss enhances NRF2 occupancy at the γ-globin genes, independently of BCL11A. Editing the overlapping BACH2 and NRF2 promoter motifs can selectively activate or repress γ-globin, pointing to a new targetable axis for HbF induction.

    Why it matters: Identifies BACH2-NRF2 as a BCL11A-independent, genetically supported mechanism for activating fetal haemoglobin.

  2. Cell68

    Condensates of the chromatin regulator ANKRD11 restrict hypertranscribed genes to safeguard development.

    The chromatin regulator ANKRD11 forms biomolecular condensates, via charge-block-patterned intrinsically disordered regions, that sequester elongation factors away from RNA polymerase II and restrict transcription of highly transcribed genes. A two-tiered genetic screen identified a network of such regulators enriched for developmental disorder genes. Ankrd11 loss in mice caused aberrant developmental gene activation, disrupted organogenesis and embryonic lethality, and KBG patient cells showed defective condensate formation with overactivation of hypertranscribed genes.

  3. nature.com61

    Reactivation of the embryonic ζ-globin gene ameliorates severe forms of α-thalassemia

    Reactivating the embryonic ζ-globin gene can ameliorate severe forms of α-thalassemia. Liu et al. identify cis-regulatory elements that silence ζ-globin in definitive erythroid cells, and gene-editing strategies targeting them restore ζ-globin expression to therapeutically relevant levels in mouse and human disease models. The work points to a new genome-editing approach for severe α-thalassemia.

    Why it matters: It identifies cis-regulatory silencers of ζ-globin and shows gene editing can reactivate it in disease models.

Oct 1Thu
  1. nature.com63

    Human genetics implicates a BACH2–NRF2 axis in fetal haemoglobin activation

    A multi-ancestry GWAS of fetal haemoglobin (HbF) levels in 28,279 individuals across European, African and Asian cohorts identified 91 conditionally independent signals at 12 loci, including BACH2 as a new regulator. BACH2 restrains NRF2-mediated transcriptional activation of the γ-globin genes HBG1 and HBG2, defining a BACH2–NRF2 axis in HbF regulation. The finding adds a genetically nominated activator pathway to the known repressors and suggests therapeutic targets for sickle cell disease and β-thalassaemia.

    Why it matters: It nominates a new genetically validated activator, BACH2, of fetal haemoglobin, opening therapeutic avenues for haemoglobin disorders.

  2. nature.com56

    Restoring hearing in people with a rare form of deafness

    A gene therapy delivering a functional OTOF gene to inner-ear hair cells improved hearing in around 80% of participants within 24 weeks in the CHORD clinical trial, which enrolled 24 participants aged between 10 months and 16 years with OTOF-associated hearing impairment. Each participant received Otarmeni as a one-time infusion, either in one ear or in both ears. In April, Otarmeni became the first gene therapy for hearing loss approved by the US Food and Drug Administration.

Sep 30Wed
  1. medrxiv.org51

    Somatic and Germline Telomere Biology in Sarcoma: Telomere Maintenance Is Acquired at Liposarcoma Dedifferentiation, and Genetically Longer Telomeres Are Associated With Liposarcoma Risk

    Telomere maintenance in sarcoma is histology-specific, with telomerase activation and ATRX/DAXX loss mutually exclusive across 11,792 patients in AACR Project GENIE. Dedifferentiated liposarcoma acquired telomere maintenance at dedifferentiation (28.0% vs 8.7% in well-differentiated liposarcoma), mainly through focal TERT amplification, and such alterations predicted shorter overall survival (HR 2.04). Mendelian randomization in FinnGen linked genetically longer telomeres to liposarcoma risk (OR per SD 4.10).

Sep 23Wed
  1. medrxiv.org50

    Mammography utilization and male breast cancer in BRCA1/2 carriers

    Mammography use among males with pathogenic BRCA1/2 variants is low: only 19% of 810 BRCA+ males had a documented mammogram, and just 16% of 562 age-eligible males completed one. No male breast cancer was detected in 97 screening mammograms, while symptom-driven mammograms found MBC in 29% of 59 BRCA+ versus 21% of 228 BRCA- males (p=0.219). Nearly all MBC in both groups was diagnosed after symptoms, often at advanced stages, with 55% of 22 BRCA+ tumors node positive.

    Why it matters: Quantifies very low screening mammography uptake in BRCA+ males despite elevated hereditary breast cancer risk.

Sep 15Tue
  1. Sci Adv64

    Engineering suppressor tRNAs for effective treatment of Duchenne muscular dystrophy.

    Engineered UAA suppressor tRNAs, delivered systemically with optimized AAV vectors and RNA polymerase III promoters, restored full-length dystrophin and recovered muscle strength and motor function in mice with nonsense mutations, at lower doses than AAV microdystrophin therapies. No adverse toxicology appeared, and proteome-wide analysis showed reversion of molecular pathophysiology. The approach targets the roughly 15% of DMD patients with nonsense mutations.

    Why it matters: First platform shown to restore full-length dystrophin rather than a truncated version, at lower doses than microdystrophin.

  2. Nat Med63

    Citywide implementation of a rapid whole-genome sequencing program for critically ill pediatric patients.

    A citywide rapid whole-genome sequencing program in Dubai intensive care units diagnosed 53% of 100 critically ill pediatric patients, with a median turnaround of 3.4 days and a yield of 80% in consanguineous families. Compared with matched historical standard genetic testing, rWGS cut diagnostic time from 38 to 3.4 days, raised yield from 30% to 53%, and changed clinical management in 53% versus 18% of patients. The results support making rWGS routine in neonatal and pediatric intensive care.

    Why it matters: Shows citywide rWGS in intensive care outperforms standard testing on yield, speed and management.

Sep 8Tue
  1. Nature76

    Non-genotoxic transplantation and in vivo selection through epitope editing.

    Epitope editing of KIT lets transplanted haematopoietic stem/progenitor cells escape anti-KIT monoclonal antibodies, enabling non-genotoxic in vivo conditioning and selection. Adenine base editing or prime editing introduced the KIT mutations together with BCL11A erythroid enhancer disruption to induce fetal haemoglobin for sickle cell disease and β-thalassaemia. Edited haematopoietic cells progressively enriched under anti-KIT selective pressure without clonal selection, allowing chemotherapy- and radiotherapy-free haematopoietic replacement.

    Why it matters: Replaces genotoxic transplant conditioning with antibody-based selection of edited HSPCs.

Sep 1Tue
  1. N Engl J Med78

    Eplontersen for Transthyretin Amyloid Cardiomyopathy.

    Eplontersen, an antisense oligonucleotide that reduces hepatic transthyretin production, did not reduce cardiovascular death or recurrent cardiovascular events in transthyretin amyloid cardiomyopathy. In the phase 3 CARDIO-TTRansform trial, 1432 patients received subcutaneous eplontersen 45 mg or placebo every 4 weeks for 140 weeks; the primary composite occurred at a rate ratio of 0.89 (95% CI, 0.73 to 1.09; P = 0.28). The finding leaves no demonstrated outcome benefit for eplontersen on top of standard treatment in ATTR-CM.

    Why it matters: Negative phase 3 result for eplontersen in 1432 patients with ATTR-CM at 140 weeks.

Aug 31Mon
  1. Science66

    Nonviral delivery of chemically modified tRNA rescues nonsense mutations in cystic fibrosis.

    Chemically modified suppressor tRNAs delivered by tailored lipid nanoparticles rescued nonsense mutations in cystic fibrosis. Adding N1-methyladenosine to sup-tRNAs improved premature termination codon readthrough, tRNA aminoacylation, functional persistence, and reduced innate immune activation. The LNP-delivered sup-tRNAs restored CFTR expression and function in bronchial epithelial cells, mouse models, and patient-derived organoids.

    Why it matters: Combines chemical tRNA modification with pulmonary LNP delivery to address the main barriers to sup-tRNA therapy.

  2. JAMA56

    Gene Silencer Therapy in Transthyretin Amyloid Cardiomyopathy: A Meta-Analysis of Outcomes Trials.

    Pooled analysis of the phase 3 trials HELIOS-B and CARDIO-TTRansform (2086 patients with ATTR-CM) found TTR gene-silencing therapy cut the composite of all-cause mortality and recurrent cardiovascular events by 20% (RR, 0.80; 95% CI, 0.69-0.94), reduced all-cause death (HR, 0.74; 95% CI, 0.61-0.91), and preserved 6-minute walk distance (+22.2 m vs placebo). Benefit was significant in patients not on baseline TTR stabilizers (RR, 0.69) but not in those already receiving stabilizer therapy (RR, 0.97). The findings support TTR gene silencing for ATTR-CM and clarify how background stabilizer use shapes the treatment effect.

    Why it matters: It quantifies the overall effect of TTR gene silencers in ATTR-CM and shows benefit depends on baseline stabilizer use.

Aug 27Thu
  1. nature.com44

    Scaling rapid whole-genome sequencing for critical pediatric care in the Middle East

    A rapid whole-genome sequencing program called Little Falcon was implemented at scale for critically ill pediatric patients in Dubai, supporting improved diagnosis and management. The work demonstrates the clinical utility of rWGS in populations of Middle Eastern and Asian ancestries. It extends evidence for rapid genome sequencing in pediatric critical care beyond previously studied populations.

Aug 26Wed
  1. Cell66

    DDIAS shields single-stranded DNA in mitosis and promotes vertebrate brain development.

    DDIAS acts as a mitosis-specific DNA damage response protein, functioning as a phosphorylation-dependent effector of the TOPBP1-CIP2A complex that shields single-stranded DNA from aberrant nucleolytic processing during chromosome segregation, with a pronounced effect in BRCA1-/BRCA2-deficient cells. Biallelic inactivating DDIAS mutations were identified in patients with a severe neurodevelopmental disorder, and human cerebral organoids and zebrafish models show DDIAS limits DNA damage specifically in neural progenitor cells.

    Why it matters: Links a mitotic DNA protection pathway to patient mutations and a conserved role in vertebrate brain development.

Aug 25Tue
  1. Cell60

    Lymphatic vessels invade bone in disease but are absent in health and regeneration.

    Lymphatic vessels are absent from bone during homeostasis and do not contribute to bone regeneration after injury, according to Prox1-based genetic tracing and a dual-recombinase LEC-specific labeling system. LECs are found only in connective tissues such as the periosteum surrounding bone. In mouse models of generalized lymphatic anomaly and Gorham-Stout disease, hyperplastic LECs breach the periosteum and invade bone tissue.

    Why it matters: It contradicts a prior report that lymphatic vessels populate normal bone and aid regeneration.

Aug 24Mon
  1. nature.com43

    Post-Exposure Prophylaxis with a monoclonal antibody cocktail Following Bundibugyo Ebolavirus Exposure in Adults and Children

    Emergency-use post-exposure prophylaxis with the monoclonal antibody cocktail MBP134 was well tolerated in an adult and four children with high- to intermediate-risk exposure to Bundibugyo ebolavirus, with no evidence of Bundibugyo virus disease in this case series. The findings support future evaluation of MBP134 as post-exposure prophylaxis for outbreaks.

Aug 20Thu
  1. Nature78

    An Icelandic pangenome reference.

    An Icelandic pangenome reference (HPRC-ICE), built by adding 698 Icelandic haplotypes to the HPRC pangenome, reduces reference bias in short-read mapping. Mapping reads from 57,630 Icelanders with the new Weaver tool called 98.96 million variants, a 6.17% increase over a linear reference, and uncovered variants in low-mappability regions, including a GBA1 SNP associated with early onset Parkinson's disease, replicated in 429,193 UK Biobank participants, and a CBS SNP pathogenic for homocystinuria.

    Why it matters: Shows pangenome mapping recovers clinically relevant variants missed by linear references, at population scale.

  2. Nat Med69

    Large-scale whole-genome sequencing reveals the landscape and health implications of de novo mutations.

    Whole-genome sequencing of 24,030 individuals from 7,851 parent-offspring families identified 390,924 de novo single-nucleotide variants, showing that paternal and maternal aging have distinct mutational patterns, with maternal DNM accumulation accelerating at advanced ages. ART procedures had age-independent effects: ICSI raised paternal dnSNVs and ovarian stimulation raised maternal dnSNVs. In vitro embryo manipulation increased early post-zygotic mosaic mutations, particularly C>A substitutions linked to delayed neurocognitive development at 1 year.

    Why it matters: Quantifies how parental age and specific ART procedures shape de novo mutations and offspring outcomes in a large family cohort.

Aug 18Tue
  1. Sci Immunol68

    Fusion of IgG antibodies to albumin inhibits transport across the placenta.

    Fusing IgG antibodies to albumin markedly reduced transplacental transport in mice and in an ex vivo human placental perfusion system, while preserving the FcRn-conferred prolonged plasma half-life. Fab fragments fused to engineered albumin with enhanced FcRn binding showed minimal fetal exposure. In a mouse model of fetal and neonatal alloimmune thrombocytopenia, albumin fusion of an anti-human platelet antigen IgG reduced fetal antibody transfer and attenuated thrombocytopenia in offspring.

    Why it matters: It offers an engineering route to antibody therapies that limit fetal exposure during pregnancy without sacrificing half-life.

  2. Sci Adv47

    Mito-TEMPO improves survival rates in npc1-knockout zebrafish by reducing oxidative stress and enhancing mitophagy via Sod2.

    Mito-TEMPO, a mitochondria-targeted antioxidant acting on SOD, increased survival rates and ameliorated cholesterol accumulation and liver function impairment in early-stage npc1-knockout zebrafish. npc1 deficiency correlated with reduced Sod2 expression, excessive oxidative stress, mitochondrial dysfunction, and defective mitophagy; treatment attenuated oxidative stress and promoted PINK1/Parkin-dependent mitophagic flux through SOD2 enhancement. The work supports Mito-TEMPO as a potential therapy and SOD2 as a possible target for Niemann-Pick type C disease.

Aug 14Fri
  1. Sci Immunol69

    An autoinflammatory CDC42 variant M45L demonstrates the mechanism of pyrin inflammasome activation.

    The CDC42 M45L variant causes a previously unrecognized autoinflammatory condition by activating the pyrin inflammasome. CDC42 binds the PYD and B30.2 domains of pyrin, and M45L greatly enhances the B30.2 interaction, with methionine-45 sitting in a hydrophobic cleft of the B30.2 domain; all affected individuals showed highly elevated circulating IL-18. Blocking IL-1 was therapeutically effective in this CDC42 M45L endotype, supporting a model in which CDC42 nucleates pyrin to liberate the PYD for inflammasome activation.

    Why it matters: It defines a new autoinflammatory endotype with a mechanistic explanation and an effective IL-1-blocking treatment.

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