Publications

High-density lipoprotein (HDL) is an enigmatic member of the plasma lipid and lipoprotein transport system, best known for its ability to promote the reverse cholesterol efflux and the unloading of excess cholesterol from peripheral tissues. More recently, data in experimental mice and humans suggest that HDL may play important novel roles in other physiological processes associated with various metabolic disorders. Important parameters in the HDL functions are its apolipoprotein and lipid content, further reinforcing the principle that HDL structure defines its functionality. Thus, based on current evidence, low levels of HDL-cholesterol (HDL-C) or dysfunctional HDL particles contribute to the development of metabolic diseases such as morbid obesity, type 2 diabetes mellitus, and nonalcoholic fatty liver disease. Interestingly, low levels of HDL-C and dysfunctional HDL particles are observed in patients with multiple myeloma and other types of cancer. Therefore, adjusting HDL-C levels within the optimal range and improving HDL particle functionality is expected to benefit such pathological conditions. The failure of previous clinical trials testing various HDL-C-raising pharmaceuticals does not preclude a significant role for HDL in the treatment of atherosclerosis and related metabolic disorders. Those trials were designed on the principle of “the more the better”, ignoring the U-shape relationship between HDL-C levels and morbidity and mortality. Thus, many of these pharmaceuticals should be retested in appropriately designed clinical trials. Novel gene-editing-based pharmaceuticals aiming at altering the apolipoprotein composition of HDL are expected to revolutionize the treatment strategies, improving the functionality of dysfunctional HDL.

No abstract available

Gene therapy has become a promising treatment for inherited retinal dystrophies (IRDs), but understanding the genetic mechanisms involved is essential for its success. Various approaches, such as gene augmentation and DNA/RNA-based therapies, have shown effectiveness in some clinical trials. However, gene augmentation is not effective for some dominant mutations and genome editing produces off-target effects. Here, we review safer and viable alternatives that are being evaluated in preclinical models and clinical trials to address this challenge. We propose a novel perspective based on protein-targeting therapies, which although promising, remain unexplored. We suggest that frameshift variants, which produce novel epitopes, may allow for the development of mutant protein targeting agents for selective protein degradation. This approach could be useful for dominant variants, where gene replacement is ineffective. By examining these approaches, we aim to guide more targeted and effective gene therapies for IRDs, offering potential treatments where current methods fall short.

Despite exhaustive studies, researchers have made little progress in the field of adoptive cellular therapies for relapsed/refractory acute myeloid leukemia (AML), unlike the notable uptake for B cell malignancies. Various single antigen-targeting chimeric antigen receptor (CAR) T cell Phase I trials have been established worldwide and have recruited approximately 100 patients. The high heterogeneity at the genetic and molecular levels within and between AML patients resembles a black hole: a great gravitational field that sucks in everything. One must consider the fact that only around 30% of patients show a response; there are, however, consequential off-tumor effects. It is obvious that a new point of view is needed to achieve more promising results. This review first introduces the unique therapeutic challenges of not only CAR T cells but also other adoptive cellular therapies in AML. Next, recent single-cell sequencing data for AML to assess somatically acquired alterations at the DNA, epigenetic, RNA, and protein levels are discussed to give a perspective on cellular heterogeneity, intercellular hierarchies, and the cellular ecosystem. Finally, promising novel strategies are summarized, including more sophisticated next-generation CAR T, TCR-T, and CAR NK therapies; the approaches with which to tailor the microenvironment and target neoantigens; and allogeneic approaches.

No abstract available