Role of gene therapy in sickle cell disease.

BACKGROUND: Gene therapy is an emerging treatment for sickle cell disease that works by replacing a defective gene with a healthy gene, allowing the body to produce normal red blood cells. This form of treatment has shown promising results in clinical trials, and is a promising alternative to traditional treatments. Gene therapy involves introducing a healthy gene into the body to replace a defective gene. The new gene can be delivered using a viral vector, which is a modified virus that carries the gene. The vector, carrying the healthy gene, is injected into the bloodstream. The healthy gene then enters the patient's cells and begins to produce normal hemoglobin, the protein in red blood cells that carries oxygen throughout the body. METHODOLOGY: We conducted an all-language literature search on Medline, Cochrane, Embase, and Google Scholar until December 2022. The following search strings and Medical Subject Heading (MeSH) terms were used: "Sickle Cell," "Gene Therapy" and "Stem Cell Transplantation". We explored the literature on Sickle Cell Disease for its epidemiology, etiopathogenesis, the role of various treatment modalities and the risk-benefit ratio of gene therapy over conventional stem cell transplant. RESULTS: Gene therapy can reduce or eliminate painful episodes, prevent organ damage, and raise the quality of life for those living with the disease. Additionally, gene therapy may reduce the need for blood transfusions and other traditional treatments. Gene therapy has the potential to improve the lives of those living with sickle cell disease, as well as reduce the burden of the disease on society.

Toll-like receptor 2 deficiency hyperactivates the FoxO1 transcription factor and induces aging-associated cardiac dysfunction in mice.

Toll-like receptors (TLRs) are a family of pattern-recognition receptors involved in innate immunity. Previous studies have shown that TLR2 inhibition protects the heart from acute stress, including myocardial infarction and doxorubicin-induced cardiotoxicity in animal models. However, the role of TLR2 in the development of aging-associated heart failure is not known. In this work, we studied aging-associated changes in structure and function of TLR2-deficient mice hearts. Whereas young TLR2-KO mice did not develop marked cardiac dysfunction, 8- and 12-month-old TLR2-KO mice exhibited spontaneous adverse cardiac remodeling and cardiac dysfunction in an age-dependent manner. The hearts of the 8-month-old TLR2-KO mice had increased fibrosis, cell death, and reactivation of fetal genes. Moreover, TLR2-KO hearts displayed reduced infiltration by macrophages, increased numbers of myofibroblasts and atrophic cardiomyocytes, and higher levels of the atrophy-related ubiquitin ligases MuRF-1 and atrogin-1. Mechanistically, TLR2 deficiency impaired the PI3K/Akt signaling pathway, leading to hyperactivation of the transcription factor Forkhead box protein O1 (FoxO1) and, in turn, to elevated expression of FoxO target genes involved in the regulation of muscle wasting and cell death. AS1842856-mediated chemical inhibition of FoxO1 reduced the expression of the atrophy-related ubiquitin ligases and significantly reversed the adverse cardiac remodeling while improving the contractile functions in the TLR2-KO mice. Interestingly, TLR2 levels decreased in hearts of older mice, and the activation of TLR1/2 signaling improved cardiac functions in these mice. These findings suggest that TLR2 signaling is essential for protecting the heart against aging-associated adverse remodeling and contractile dysfunction in mice.