Gene therapy for polygenic or complex diseases.

Gene therapy utilizes nucleic acid drugs to treat diseases, encompassing gene supplementation, gene replacement, gene silencing, and gene editing. It represents a distinct therapeutic approach from traditional medications and introduces novel strategies for genetic disorders. Over the past two decades, significant advancements have been made in the field of gene therapy, leading to the approval of various gene therapy drugs. Gene therapy was initially employed for treating genetic diseases and cancers, particularly monogenic conditions classified as orphan diseases due to their low prevalence rates; however, polygenic or complex diseases exhibit higher incidence rates within populations. Extensive research on the etiology of polygenic diseases has unveiled new therapeutic targets that offer fresh opportunities for their treatment. Building upon the progress achieved in gene therapy for monogenic diseases and cancers, extending its application to polygenic or complex diseases would enable targeting a broader range of patient populations. This review aims to discuss the strategies of gene therapy, methods of gene editing (mainly CRISPR-CAS9), and carriers utilized in gene therapy, and highlight the applications of gene therapy in polygenic or complex diseases focused on applications that have either entered clinical stages or are currently undergoing clinical trials.

Genetic factors, risk prediction and AI application of thrombotic diseases.

In thrombotic diseases, coagulation, anticoagulation, and fibrinolysis are three key physiological processes that interact to maintain blood in an appropriate state within blood vessels. When these processes become imbalanced, such as excessive coagulation or reduced anticoagulant function, it can lead to the formation of blood clots. Genetic factors play a significant role in the onset of thrombotic diseases and exhibit regional and ethnic variations. The decision of whether to initiate prophylactic anticoagulant therapy is a matter that clinicians must carefully consider, leading to the development of various thrombotic risk assessment scales in clinical practice. Given the considerable heterogeneity in clinical diagnosis and treatment, researchers are exploring the application of artificial intelligence in medicine, including disease prediction, diagnosis, treatment, prevention, and patient management. This paper reviews the research progress on various genetic factors involved in thrombotic diseases, analyzes the advantages and disadvantages of commonly used thrombotic risk assessment scales and the characteristics of ideal scoring scales, and explores the application of artificial intelligence in the medical field, along with its future prospects.

Associations of blood pressure in the third trimester and risk of venous thromboembolism postpartum.

Studies on the associations of blood pressure (BP) and the risk of venous thromboembolism (VTE) had been performed neither among pregnant women nor in Chinese population. This study included participants of pregnant women from a retrospective multicenter cohort, between May 2020 and April 2023. Systolic BP (SBP) and diastolic BP (DBP) of the participants were measured in the third trimester. The incidences of VTE (including deep venous thrombosis and/or pulmonary embolism) at 42 days postpartum were followed. With regards to SBP, pregnant women in the Q1 (≤114 mmHg), Q2 (115-122 mmHg), and Q4 group (≥131 mmHg) had increased risk of VTE than those in Q3 group (123-130 mmHg), with ORs 4.48 [1.69, 11.85], 3.52 [1.30, 9.59], and 3.17 [1.12, 8.99], respectively. Compared with pregnant women with the Q4 of DBP (≥85 mmHg), women of Q1 (≤71 mmHg) were found to have elevated risk of VTE (OR 2.73 [1.25, 5.96]). A one standard deviation decrease of DBP (9 mmHg) was related with 37% elevated risk of VTE (OR 1.37 [1.05, 1.79]). This study demonstrated a U-shaped association of SBP in the third trimester and VTE postpartum and inverse association of DBP in the third trimester and VTE postpartum.

Nuclear Matrix-associated Protein SMAR1 Attenuated Acute Graft-versus-host Disease by Targeting JAK-STAT Signaling in CD4 + T Cells.

BACKGROUND: Acute graft-versus-host disease (aGVHD) mediated by alloreactive T cells remains a serious and life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT). The contribution of the different CD4 + T helper cell subtypes to the pathogenesis and regulation of aGVHD is a central point in current research. The specialized effector subsets of T cells that differentiate from naive T cells into mature cells are closely related to scaffold/matrix-associated region-1-binding protein (SMAR1). However, the role of SMAR1 in aGVHD is unclear. METHODS: Peripheral blood was collected from the patients with or without aGVHD after allo-HCT. The differences in CD4 + T cells transduced with the SMAR1 lentivirus vector and empty vector were analyzed. A humanized aGVHD mouse model was constructed to evaluate the function of SMAR1 in aGVHD. RESULTS: The expression of SMAR1 was significantly reduced in the CD4 + T cells from aGVHD patients and related to the occurrence of aGVHD. SMAR1 overexpression in human CD4 + T cells regulated CD4 + T-cell subsets differentiation and inflammatory cytokines secretion and inhibited the Janus kinase/signal transducer and activator of transcription pathway. Moreover, SMAR1 changed chromatin accessibility landscapes and affected the binding motifs of key transcription factors regulating T cells. Additionally, upregulation of SMAR1 expression in CD4 + T cells improved the survival and pathology in a humanized aGVHD mouse model. CONCLUSIONS: Our results showed that upregulation of SMAR1 regulated the CD4 + T-cell subpopulation and cytokines secretion and improved survival in a humanized aGVHD mouse model by alleviating inflammation. This study provides a promising therapeutic target for aGVHD.

Season of delivery and risk of venous thromboembolism during hospitalization among pregnant women.

Background: Seasons were found to be related to the occurrences of venous thromboembolism (VTE) in hospitalized patients. No previous study has explored whether seasons were associated with VTE risk in pregnant women. This study aimed to investigate the relationships between the season of delivery and VTE risk during hospitalization among pregnant women. Methods: This is a multi-center retrospective cohort study of pregnant women. Participants were those who delivered at seven designated sites in Hubei Province, China, during the period from January 2017 to December 2022. They were categorized according to their season/month of delivery. Information on new-onset VTE during hospitalization was followed. Results: Approximately 0.28% (104/37,778) of the pregnant women developed new-onset VTE during hospitalization for delivery. After adjustment, compared with participants in the spring group, participants in the summer, autumn, and winter groups had an increased risk of VTE during hospitalization. The ORs were 2.59 [1.30, 5.15], 2.83 [1.43, 5.60], and 2.35 [1.17, 4.75] for the summer, autumn, and winter groups, respectively. Pregnant women in the combined group (summer + autumn + winter) had an increased risk of VTE during hospitalization than those in the spring group (OR, 2.59 [1.39, 4.85]). By restricting the analyses among pregnant women without in vitro fertilization, gestational diabetes mellitus, and preterm, the results still remained robust. Compared with participants who delivered in March, April, and May, participants who delivered in June, July, September, November, December, and February had a higher risk of VTE during hospitalization. Conclusion: This study demonstrated that pregnant women who delivered in summer, autumn, and winter had an increased VTE risk during hospitalization compared with those who delivered in spring.

Tissue-type plasminogen activator (tPA) homozygous Tyr471His mutation associates with thromboembolic disease.

Tissue-type plasminogen activator (tPA) encoded by PLAT is a major mediator that promotes fibrinolysis and prevents thrombosis. Pathogenetic mutations in PLAT associated with venous thromboembolism have rarely been reported. Here, we report the first case of a homozygous point mutation c.1411T>C (p.Y471H) in PLAT leading to thromboembolic events and conduct related functional studies. The corresponding tPA mutant protein (tPA-Y471H) and wild-type tPA (tPA-WT) were synthesized in vitro, and mutant mice (PLATH/H mice) were constructed. The molecular docking and surface plasmon resonance results indicated that the mutation impeded the hydrogen-bonding interactions between the protease domain of tPA and the kringle 4 domain of plasminogen, and the binding affinity of tPA and plasminogen was significantly reduced with a difference of one order of magnitude. mRNA half-life assay showed that the half-life of tPA-Y471H was shortened. The inferior vena cava thrombosis model showed that the rate of venous thrombosis in PLATH/H mice was 80% compared with 53% in wild-type mice. Our data suggested a novel role for the protease domain of tPA in efficient plasminogen activation, and demonstrated that this tPA mutation could reduce the fibrinolysis function of the body and lead to an increased propensity for thrombosis.

Association between serum alkaline phosphatase levels in late pregnancy and the incidence of venous thromboembolism postpartum: a retrospective cohort study.

Background: Two previous studies found alkaline phosphatase (ALP) levels were related with the development of venous thromboembolism (VTE) in hospitalised patients. VTE is a leading cause of death during pregnancy and postpartum. No prior study has investigated the associations of ALP levels and VTE postpartum, and the related mechanisms remain unclear. This study aimed to investigate the associations between ALP levels and VTE postpartum, and to reveal the potential mechanisms. Methods: In this retrospective cohort study, we included pregnant women who planned to deliver at the Department of Obstetrics and Gynecology in the three designated hospitals in a multicentre cohort of pregnant women in Wuhan, China, during two recruitment periods of January 1, 2018 to December 31, 2019, and May 14, 2020 to March 25, 2022. A total of 10,044 participants with serum ALP and whole blood hemoglobin measurements in late pregnancy (median, 37 (35, 39) weeks) were enrolled. The participants' incidences of VTE (deep venous thrombosis and/or pulmonary embolism) postpartum were confirmed from the medical records. Pregnant women with new-onset VTE postpartum (within 6 weeks after delivery) were confirmed as VTE cases. Findings: Approximately 0.8% (79/10,044) of the pregnant women were diagnosed with VTE postpartum. In the unadjusted model, pregnant women with the lowest quintile of serum ALP levels (≤116 U/L) in late pregnancy had higher risk of VTE postpartum compared with those with the highest quintile (≥199 U/L) (OR, 2.83 [1.32, 6.05]). After adjusting for covariates of demographic, life style, birth outcomes, and other liver enzymes, pregnant women with the lowest quintile of serum ALP levels (≤116 U/L) in late pregnancy had increased risk of VTE postpartum compared with those with the highest quintile (≥199 U/L) (OR, 2.48 [1.14, 5.40]). A one standard deviation decrease of ln-transformed ALP levels were associated with elevated risk of VTE postpartum (OR, 1.29 [1.02, 1.62]). Significant negative associations of ALP with VTE were found in the unadjusted and adjusted models. The negative associations between ALP and VTE remained consistent in sensitivity analyses among participants with non-GDM, single pregnancy, non-preeclampsia, non-postpartum hemorrhage, non-extremely/very preterm and cesarean delivery. Decreased serum ALP levels significantly (P < 0.05) related to decreased hemoglobin, which was significantly (P < 0.05) related to increased risk of VTE postpartum. Decreased hemoglobin significantly (P < 0.05) mediated 7.59% of ALP-associated VTE postpartum. Interpretation: This study suggested that low serum ALP levels in late pregnancy were associated with increased risk of VTE postpartum, and the ALP-associated VTE risk may be partially mediated by hemoglobin, suggesting that serum ALP in late pregnancy could be a promising biomarker for the prediction of VTE postpartum. Funding: The National Natural Science Foundation of China, and the Program for HUST Academic Frontier Youth Team.