Advances of adeno-associated virus applied in gene therapy to hemophilia from bench work to the clinical use

Hemophilia A and B are diseases caused by a single gene deficiency and are thus suitable for gene therapy.In recent clinical research,adeno-associated virus(AAV)was employed by several teams in the treatment of hemophilia A and B,and the outcomes were encouraging.In this review,we summarized the most recent research on the mechanism and application of AAV in the treatment of hemophilia,trying to analyze the advantages of AAV gene therapy and the main challenges in its clinical use.We also summarized the clinical trials involving hemophilia,especially those employing AAV gene therapy to treat hemophilia A and B,some of which have already been completed and some that are still ongoing.From the reports of the completed clinical trials,we tried to determine the correlations among AAV dose,AAV serotype,immune response,and gene expression time.Finally,taking into account the most recent studies investigating AAV capsid modification,transgene optimization,and AAV chaperones,we summarized the direction of basic research and clinical applications of AAV in the future.

Efficacy and safety of human umbilical cord-derived mesenchymal stem cells in the treatment of refractory immune thrombocytopenia:a prospective,single arm,phase I trial

Patients with refractory immune thrombocytopenia(ITP)frequently encounter substantial bleeding risks and demonstrate limited responsiveness to existing therapies.Umbilical cord-derived mesenchymal stem cells(UC-MSCs)present a promising alternative,capitalizing on their low immunogenicity and potent immunomodulatory effects for treating diverse autoimmune disorders.This prospective phase I trial enrolled eighteen eligible patients to explore the safety and efficacy of UC-MSCs in treating refractory ITP.The research design included administering UC-MSCs at escalating doses of 0.5×10^(6)cells/kg,1.0×10^(6)cells/kg,and 2.0×10^(6)cells/kg weekly for four consecutive weeks across three cohorts during the dose-escalation phase,followed by a dose of 2.0×10^(6)cells/kg weekly for the dose-expansion phase.Adverse events,platelet counts,and changes in peripheral blood immunity were monitored and recorded throughout the administration and follow-up period.Ultimately,12(with an addition of three patients in the 2.0×10^(6)cells/kg group due to dose-limiting toxicity)and six patients were enrolled in the dose-escalation and dose-expansion phase,respectively.Thirteen patients(13/18,72.2%)experienced one or more treatment emergent adverse events.Serious adverse events occurred in four patients(4/18,22.2%),including gastrointestinal hemorrhage(2/4),profuse menstruation(1/4),and acute myocardial infarction(1/4).The response rates were 41.7%in the dose-escalation phase(5/12,two received 1.0×10^(6)cells/kg per week,and three received 2.0×10^(6)cells/kg per week)and 50.0%(3/6)in the dose-expansion phase.The overall response rate was 44.4%(8/18)among all enrolled patients.To sum up,UC-MSCs are effective and well tolerated in treating refractory ITP(ClinicalTrials.gov ID:NCT04014166).

Sex-specific impact on disease outcome and the mutational landscape in essential thrombocythemia:A retrospective cohort study

To the Editor:Male sex has been confirmed to be an independent risk factor for survival in patients with essential thrombocythemia(ET).[1,2]Sexual dimorphism significantly contributes to patient heterogeneity,and adopting a sex-informed perspective has emerged as a pioneering paradigm in the field of precision medicine.Investigating the spectrum of sex disparities among patients diagnosed with ET holds substantial scientific justification.Furthermore,sex influences the presentation,disease phenotypes,symptom expression,and clinical outcomes of classical Philadelphia chromosome-negative myeloproliferative neoplasm(MPN).[3,4]The objective of our study was to comprehensively elucidate the impact of sex on ET by exploring disease genotype and phenotype as well as clinical outcomes.

HDAC inhibitors improve CRISPR-mediated HDR editing efficiency in iPSCs

Genome-edited human induced pluripotent stem cells(iPSCs)hold great promise for therapeutic applications.However,low editing efficiency has hampered the applications of CRISPR-Cas9 technology in creating knockout and homology-directed repair(HDR)-edited iPSC lines,particularly for silent genes.This is partially due to chromatin compaction,inevitably limiting Cas9 access to the target DNA.Among the six HDAC inhibitors we examined,vorinostat,or suberoylanilide hydroxamic acid(SAHA),led to the highest HDR efficiency at both open and closed loci,with acceptable toxicity.HDAC inhibitors equally increased non-homologous end joining(NHEJ)editing efficiencies(~50%)at both open and closed loci,due to the considerable HDAC inhibitor-mediated increase in Cas9 and sgRNA expression.However,we observed more substantial HDR efficiency improvement at closed loci relative to open chromatin(2.8 vs.1.7-fold change).These studies provide a new strategy for HDRediting of silent genes in iPSCs.