VXX-401, a novel anti-PCSK9 vaccine, reduces LDL-C in cynomolgus monkeys.

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of disease burden in the world and is highly correlated with chronic elevations of LDL-C. LDL-C-lowering drugs, such as statins or monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9), are known to reduce the risk of cardiovascular diseases; however, statins are associated with limited efficacy and poor adherence to treatment, whereas PCSK9 inhibitors are only prescribed to a "high-risk" patient population or those who have failed other therapies. Based on the proven efficacy and safety profile of existing monoclonal antibodies, we have developed a peptide-based vaccine against PCSK9, VXX-401, as an alternative option to treat hypercholesterolemia and prevent ASCVD. VXX-401 is designed to trigger a safe humoral immune response against PCSK9, resulting in the production of endogenous antibodies and a subsequent 30-40% reduction in blood LDL-C. In this article, VXX-401 demonstrates robust immunogenicity and sustained serum LDL-C-lowering effects in nonhuman primates. In addition, antibodies induced by VXX-401 bind to human PCSK9 with high affinity and block the inhibitory effect of PCSK9 on LDL-C uptake in a hepatic cell model. A repeat-dose toxicity study conducted in nonhuman primates under good laboratory practices toxicity indicated a suitable safety and tolerability profile, with injection site reactions being the main findings. As a promising safe and effective LDL-C-lowering therapy, VXX-401 may represent a broadly accessible and convenient option to treat hypercholesterolemia and prevent ASCVD.

The effects of histone deacetylase inhibitors on glioblastoma-derived stem cells.

Glioblastoma multiforme (GBM) is the most malignant brain tumor with limited effective treatment options. Cancer stem cells (CSCs), a subpopulation of cancer cells with stem cell properties found in GBMs, have been shown to be extremely resistant to radiation and chemotherapeutic agents and have the ability to readily reform tumors. Therefore, the development of therapeutic agents targeting CSCs is extremely important. In this study, we isolated glioblastoma-derived stem cells (GDSCs) from GBM tissue removed from patients during surgery and analyzed their gene expression using quantitative real-time PCR and immunocytochemistry. We examined the effects of histone deacetylase inhibitors trichostatin A (TSA) and valproic acid (VPA) on the proliferation and gene expression profiles of GDSCs. The GDSCs expressed significantly higher levels of both neural and embryonic stem cell markers compared to GBM cells expanded in conventional monolayer cultures. Treatment of GDSCs with histone deacetylase inhibitors, TSA and VPA, significantly reduced proliferation rates of the cells and expression of the stem cell markers, indicating differentiation of the cells. Since differentiation into GBM makes them susceptible to the conventional cancer treatments, we posit that use of histone deacetylase inhibitors may increase efficacy of the conventional cancer treatments for eliminating GDSCs.