Improved Cardiac Function in Postischemic Rats Using an Optimized Cardiac Reprogramming Cocktail Delivered in a Single Novel Adeno-Associated Virus

Circulation, Ahead of Print. BACKGROUND:Cardiac reprogramming is a technique to directly convert nonmyocytes into myocardial cells using genes or small molecules. This intervention provides functional benefit to the rodent heart when delivered at the time of myocardial infarction or activated transgenically up to 4 weeks after myocardial infarction. Yet, several hurdles have prevented the advancement of cardiac reprogramming for clinical use.METHODS:Through a combination of screening and rational design, we identified a cardiac reprogramming cocktail that can be encoded in a single adeno-associated virus. We also created a novel adeno-associated virus capsid that can transduce cardiac fibroblasts more efficiently than available parental serotypes by mutating posttranslationally modified capsid residues. Because a constitutive promoter was needed to drive high expression of these cell fate–altering reprogramming factors, we included binding sites to a cardiomyocyte-restricted microRNA within the 3’ untranslated region of the expression cassette that limits expression to nonmyocytes. After optimizing this expression cassette to reprogram human cardiac fibroblasts into induced cardiomyocyte-like cells in vitro, we also tested the ability of this capsid/cassette combination to confer functional benefit in acute mouse myocardial infarction and chronic rat myocardial infarction models.RESULTS:We demonstrated sustained, dose-dependent improvement in cardiac function when treating a rat model 2 weeks after myocardial infarction, showing that cardiac reprogramming, when delivered in a single, clinically relevant adeno-associated virus vector, can support functional improvement in the postremodeled heart. This benefit was not observed with GFP (green fluorescent protein) or a hepatocyte reprogramming cocktail and was achieved even in the presence of immunosuppression, supporting myocyte formation as the underlying mechanism.CONCLUSIONS:Collectively, these results advance the application of cardiac reprogramming gene therapy as a viable therapeutic approach to treat chronic heart failure resulting from ischemic injury.

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Agosto 2023

Cracking the host functional network involved in hepatitis B virus cccDNA biology

Hepatitis B virus (HBV) causes chronic infection in at least 250 million people worldwide, resulting in approximately 850 000 deaths annually. Chronic carriers are at risk of developing severe liver disease including decompensated cirrhosis and hepatocellular carcinoma (HCC). HBV infection can be prevented with a highly effective prophylactic vaccine. Viraemia can be suppressed with nucleos/tide analogues targeting the HBV polymerase, but standard-of-care therapy rarely leads to a cure leaving patients requiring lifelong therapy to prevent relapse of viral replication. Furthermore, even on treatment patients remain at a residual risk of developing HCC. Development of treatments resulting in a functional cure has been hampered by our incomplete understanding of HBV persistence and the difficulty of targeting pharmacologically essential steps in the viral replicative cycle.1 HBV is a partially double-stranded DNA virus of the Hepadnaviridae family, which has a complex replication cycle and is intricately intertwined with the host cell DNA…

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Agosto 2023

Cost-effectiveness of tenofovir prophylaxis during pregnancy for the elimination of mother-to-child transmission of the hepatitis B virus: real-world analysis from Thailand

Objective
Despite implementing hepatitis B immunoglobulin (HBIG) and vaccination, data suggest it would not be sufficient to reach the elimination targets. Tenofovir disoproxil fumarate (TDF) has been added to the Thai national standards of care for prevention of transmission of the hepatitis B virus during birth. To optimise national strategies in Thailand, we assessed TDF’s effectiveness for prevention of mother-to-child transmission and conducted cost-effectiveness analyses of different TDF-based strategies.

Research design and methods
We retrospectively reviewed medical records of mother and infant pairs whose mothers were positive for hepatitis B e-antigen (HBeAg) and received TDF to prevent maternal transmission of viral hepatitis B during 2018–2020. Based on the available data on transmission rate, we also applied a decision tree to estimate the cost-effectiveness of different TDF-based strategies to eligible mothers. These included: (1) HBIG for all hepatitis B virus (HBV) exposed infants; (2) HBIG for only infants of HBeAg-positive mothers (‘HBIG for e-positive’) and (3) without HBIG to infants (‘HBIG-free’). The incremental cost-effectiveness ratio between the different strategies and baseline intervention without TDF was calculated. The one-way sensitivity analysis was used to adjust prevalence of HBeAg-positive mothers, cost of HBIG, cost of TDF and transmission rate.

Results
Of 223 infants enrolled, 212 (95.0%) received HBIG, while 11 (5.0%) did not. None of the infants had chronic HBV infection. The most cost-saving intervention was ‘HBIG-free’ followed by ‘HBIG for e-positive’. The one-way sensitivity demonstrated that the results were reasonably robust to changes. The cost-saving was greater with a higher hepatitis B virus surface antigen (HBsAg) prevalence. The HBIG-free strategy remained best at 0%–1.4% transmission rates, meeting the additional target for eliminations.

Conclusion
The study is the first cost-effectiveness analyses to provide evidence supporting an HBIG-free strategy in an antiviral era. This approach should be considered to prevent mother-to-child transmission in resource-constrained settings, particularly in countries with a high HBsAg prevalence.

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Luglio 2023