Publications by authors named "Yuanhua Cai"

7 Publications

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Platelet-targeted hyperfunctional FIX gene therapy for hemophilia B mice even with preexisting anti-FIX immunity.

Blood Adv 2021 Mar;5(5):1224-1238

Blood Research Institute, Versiti Wisconsin, Milwaukee, WI.

Gene therapy may lead to a cure for hemophilia B (HB) if it is successful. Data from clinical trials using adeno-associated virus (AAV)-mediated liver-targeted FIX gene therapy are very encouraging. However, this protocol can be applied only to adults who do not have liver disease or anti-AAV antibodies, which occur in 30% to 50% of individuals. Thus, developing a protocol that can be applied to all HB patients is desired. Our previous studies have demonstrated that lentivirus-mediated platelet-specific FIX (2bF9) gene therapy can rescue bleeding diathesis and induce immune tolerance in FIXnull mice, but FIX expression was only ∼2% to 3% in whole blood. To improve the efficacy, we used a codon-optimized hyperfunctional FIX-Padua (2bCoF9R338L) to replace the 2bF9 cassette, resulting in 70% to 122% (35.08-60.77 mU/108 platelets) activity levels in 2bCoF9R338L-transduced FIXnull mice. Importantly, sustained hyperfunctional platelet-FIX expression was achieved in all 2bCoF9R338L-transduced highly immunized recipients with activity levels of 18.00 ± 9.11 and 9.36 ± 12.23 mU/108 platelets in the groups treated with 11 Gy and 6.6 Gy, respectively. The anti-FIX antibody titers declined with time, and immune tolerance was established after 2bCoF9R338L gene therapy. We found that incorporating the proteasome inhibitor bortezomib into preconditioning can help eliminate anti-FIX antibodies. The bleeding phenotype in 2bCoF9R338L-transduced recipients was completely rescued in a tail bleeding test and a needle-induced knee joint injury model once inhibitors dropped to undetectable. The hemostatic efficacy in 2bCoF9R338L-transduced recipients was further confirmed by ROTEM and thrombin generation assay (TGA). Together, our studies suggest that 2bCoF9R338L gene therapy can be a promising protocol for all HB patients, including patients with inhibitors.
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http://dx.doi.org/10.1182/bloodadvances.2020004071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948262PMC
March 2021

Platelet-Targeted FVIII Gene Therapy Restores Hemostasis and Induces Immune Tolerance for Hemophilia A.

Front Immunol 2020 12;11:964. Epub 2020 Jun 12.

Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, United States.

Platelets are small anucleated blood components primarily described as playing a fundamental role in hemostasis and thrombosis. Over the last decades, increasing evidence has demonstrated the role of platelets in modulating inflammatory reactions and immune responses. Platelets harbor several specialized organelles: granules, endosomes, lysosomes, and mitochondria that can synthesize proteins with pre-stored mRNAs when needed. While the functions of platelets in the immune response are well-recognized, little is known about the potential role of platelets in immune tolerance. Recent studies demonstrate that platelet-specific FVIII gene therapy can restore hemostasis and induce immune tolerance in hemophilia A mice, even mice with preexisting anti-FVIII immunity. Here, we review the potential mechanisms by which platelet-targeted FVIII gene therapy restores hemostasis in the presence of anti-FVIII inhibitory antibodies and induces immune tolerance in hemophilia A.
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http://dx.doi.org/10.3389/fimmu.2020.00964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303294PMC
March 2021

Induction of activated T follicular helper cells is critical for anti-FVIII inhibitor development in hemophilia A mice.

Blood Adv 2019 10;3(20):3099-3110

Blood Research Institute, Versiti, Milwaukee, WI.

The development of neutralizing anti-FVIII antibodies (inhibitors) is a major complication of FVIII protein replacement therapy in patients with hemophilia A (HA). Although multiple lines of evidence indicate that the immune response against FVIII is CD4 T-cell-dependent and many FVIII-derived CD4 epitopes have already been discovered, the role of T follicular helper (TFH) cells in FVIII inhibitor development is unknown. TFH cells, a newly identified subset of CD4 T cells, are characterized by expression of the B-cell follicle-homing receptor CXCR5 and PD-1. In this study, we show for the first time that IV FVIII immunization induces activation and accumulation and/or expansion of PD-1+CXCR5+ TFH cells in the spleen of FVIII-deficient (FVIIInull) mice. FVIII inhibitor-producing mice showed increased germinal center (GC) formation and increased GC TFH cells in response to FVIII immunization. Emergence of TFH cells correlated with titers of anti-FVIII inhibitors. Rechallenge with FVIII antigen elicited recall responses of TFH cells. In vitro FVIII restimulation resulted in antigen-specific proliferation of splenic CD4+ T cells from FVIII-primed FVIIInull mice, and the proliferating cells expressed the TFH hallmark transcription factor BCL6. CXCR5+/+ TFH-cell-specific deletion impaired anti-FVIII inhibitor production, confirming the essential role of CXCR5+/+ TFH cells for the generation of FVIII-neutralizing antibodies. Together, our results demonstrate that the induction of activated TFH cells in FVIIInull mice is critical for FVIII inhibitor development, suggesting that inhibition of FVIII-specific TFH-cell activation may be a promising strategy for preventing anti-FVIII inhibitor formation in patients with HA.
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http://dx.doi.org/10.1182/bloodadvances.2019000650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849959PMC
October 2019

Nongenotoxic antibody-drug conjugate conditioning enables safe and effective platelet gene therapy of hemophilia A mice.

Blood Adv 2019 09;3(18):2700-2711

Blood Research Institute, Versiti Wisconsin, Milwaukee, WI.

Gene therapy offers the potential to cure hemophilia A (HA). We have shown that hematopoietic stem cell (HSC)-based platelet-specific factor VIII (FVIII) (2bF8) gene therapy can produce therapeutic protein and induce antigen-specific immune tolerance in HA mice, even in the presence of inhibitory antibodies. For HSC-based gene therapy, traditional preconditioning using cytotoxic chemotherapy or total body irradiation (TBI) has been required. The potential toxicity associated with TBI or chemotherapy is a deterrent that may prevent patients with HA, a nonmalignant disease, from agreeing to such a protocol. Here, we describe targeted nongenotoxic preconditioning for 2bF8 gene therapy utilizing a hematopoietic cell-specific antibody-drug conjugate (ADC), which consists of saporin conjugated to CD45.2- and CD117-targeting antibodies. We found that a combination of CD45.2- and CD117-targeting ADC preconditioning was effective for engrafting 2bF8-transduced HSCs and was favorable for platelet lineage reconstitution. Two thirds of HA mice that received 2bF8 lentivirus-transduced HSCs under (CD45.2+CD117)-targeting ADC conditioning maintained sustained therapeutic levels of platelet FVIII expression. When CD8-targeting ADC was supplemented, chimerism and platelet FVIII expression were significantly increased, with long-term sustained platelet FVIII expression in all primary and secondary recipients. Importantly, immune tolerance was induced and hemostasis was restored in a tail-bleeding test, and joint bleeding also was effectively prevented in a needle-induced knee joint injury model in HA mice after 2bF8 gene therapy. In summary, we show for the first time efficient engraftment of gene-modified HSCs without genotoxic conditioning. The combined cocktail ADC-mediated hematopoietic cell-targeted nongenotoxic preconditioning that we developed is highly effective and favorable for platelet-specific gene therapy in HA mice.
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http://dx.doi.org/10.1182/bloodadvances.2019000516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759737PMC
September 2019

Risk Factors of Gastric Cancer in High-Risk Region of China: A Population-Based Case-control Study

Asian Pac J Cancer Prev 2019 Mar 26;20(3):775-781. Epub 2019 Mar 26.

Fujian Xianyou Hospital, Putian, China.

Background: The reason for the high incidence of gastric cancer (GC) in Xianyou County of China was largely unknown. We aimed to explore the potential sociodemographic risk factors and their associations to GC. Methods: A population-based case-control study was conducted during March 2013 and April 2016 in Xianyou County. All newly diagnosed patients of GC were recruited as cases, while controls were selected by matching for cases’ sex, age (± 3 years) and the place of residence. Results: A total of 523 GC cases and 523 matched healthy controls were included in the final analysis with mean age of 66.27±8.81 years for cases and 66.31±8.83 years for controls, respectively. Participants with low socioeconomic status were observed with higher GC risk compared to those in high socioeconomic status (adjusted OR=2.10, 95% CI: 1.13-3.89). Compared to those regularly drink green tea, patients did not have this dietary habit had nearly 3-fold increased GC risk (adjusted OR=2.91, 95% CI: 1.38-6.13). Other dietary habit, including consumption of hard food, omission of breakfast, consumption of pickled vegetables 30 years ago, overeating were all associated with increased risk of GC. Interaction effect were found. Patients in low socioeconomic status and skipped breakfast had 10-fold higher risk of GC compared to reference group in high socioeconomic status and eat breakfast regularly (OR=10.71, 95% CI: 5.19-22.10). Furthermore, patients in low socioeconomic status and consumed pickled vegetable 30 years ago had 6-fold higher risk of GC compared to those in high socioeconomic status but did not intake pickled vegetables 30 years ago (OR=6.11, 95% CI: 3.87-9.66). Conclusion: High incidence of GC risk in Xianyou County might be partly attributed to various sociodemographic factors. Specific prevention effort could be target on population in low socioeconomic status combined with habit of breakfast omission or intake of pickled vegetables.
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http://dx.doi.org/10.31557/APJCP.2019.20.3.775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825772PMC
March 2019

Prognostic value and susceptibility of BAX rs4645878 polymorphism in cancer: A systematic review and meta-analysis.

Medicine (Baltimore) 2018 Jul;97(29):e11591

Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital, Fuzhou City Union Clinical Medical Colleges, Fujian Medical University Department of hematology, Fujian Fuzhou Children's Hospital, Fuzhou, Fujian Province, PR China.

Background: BCL-2 Associated X (BAX) is an important modulator of apoptosis. The associations between BAX gene polymorphism and cancer susceptibility and prognosis in different ethnic groups and types of cancer have yielded controversial results. To reconcile the results, a systematic review followed by meta-analysis was performed to assess the associations.

Methods: A systematic search of Medline database (PubMed), EMBASE, China Biology Medicine disc, China National Knowledge Infrastructure, Wanfang databases for publications on BAX polymorphisms, and susceptibility and prognosis was carried out until July 2017. Retrieved 14 articles met the inclusions. Summary odds ratios (ORs) and hazard ratios (HRs) with their 95% confidence intervals (CIs) were harnessed to determine the strength of correlation between BAX polymorphisms and cancer susceptibility and prognosis, which were combined using fixed- or random-effects models as appropriate.

Results: A total of 12 trials involving 3321 cases and 3209 controls were included in our pooled analysis regarding the polymorphisms and the susceptibility of cancers. Overall, results of the present meta-analysis demonstrated that there was no significant association between BAX polymorphisms and susceptibility of cancers (OR = 1.052, 95% CI: 0.827-1.339, P = .679, A vs G). Even in a stratified analysis by ethnicity and the sources of control groups, the results were consistent. Four retrospective studies of 549 cases qualified for meta-analysis were identified to set forth the associations of the polymorphisms with cancer prognosis. Our results suggested that BAX gene polymorphisms were significantly associated with unfavorable prognosis (HR = 1.735, 95% CI: 1.368-2.202, P = .000, GG vs GA/AA).

Conclusion: There is no significant association between BAX gene polymorphism and cancer susceptibility, but it probably contributes to increased adverse prognosis to cancer.
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http://dx.doi.org/10.1097/MD.0000000000011591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6086507PMC
July 2018

Association of NFKB1 and NFKBIA gene polymorphisms with susceptibility of gastric cancer.

Tumour Biol 2017 Jul;39(7):1010428317717107

2 School of Public Health, Fujian Medical University, Fuzhou, China.

Xianyou county of Fujian province, located on the southeast coastal of China, has higher gastric cancer mortality. Chronic inflammation plays an important role in the occurrence of gastric cancer, in which the nuclear factor-κB signaling pathway of the inflammatory reaction begins and plays an important role in the amplification process. Studies have found that a single-nucleotide polymorphism of nuclear factor-κB signaling pathway molecules encoding genes is associated with gastric cancer, but the combined effect of the nuclear factor-κB signaling pathway gene has not been explained nor has been cardia and non-cardia gastric cancer risk factors and genetic susceptibility loci. New gastric cancer cases of the Fujian Xianyou Hospital were the research object. They were divided into cardia and non-cardia cancer in order to study a single-nucleotide polymorphism of the nuclear factor-κB signaling pathway important node molecules P50 and I kappa B encoding genes NFKB1 and NFKBIA by desorption ionization time of flight mass spectrometry analysis and by matrix-assisted laser mass spectrometry. The results showed that NFKB1 and NFKBIA single-nucleotide polymorphisms and gastric cancer are related and that the combined effects of polymorphisms in two genes and the NFKBIA gene monomer increased the risk of gastric cancer, and it was found that in different types of gastric cancer (the cardia and non-cardia cancer), susceptible polymorphism sites and combined effects are different.
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http://dx.doi.org/10.1177/1010428317717107DOI Listing
July 2017