A review on Gaucher disease: therapeutic potential of ß-glucocerebrosidase-targeted mRNA/saRNA approach.

Gaucher disease (GD), a rare hereditary lysosomal storage disorder, occurs due to a deficiency in the enzyme ß-glucocerebrosidase (GCase). This deficiency leads to the buildup of substrate glucosylceramide (GlcCer) in macrophages, eventually resulting in various complications. Among its three types, GD2 is particularly severe with neurological involvements. Current treatments, such as enzyme replacement therapy (ERT), are not effective for GD2 and GD3 due to their inability to cross the blood-brain barrier (BBB). Other treatment approaches, such as gene or chaperone therapies are still in experimental stages. Additionally, GD treatments are costly and can have certain side effects. The successful use of messenger RNA (mRNA)-based vaccines for COVID-19 in 2020 has sparked interest in nucleic acid-based therapies. Remarkably, mRNA technology also offers a novel approach for protein replacement purposes. Additionally, self-amplifying RNA (saRNA) technology shows promise, potentially producing more protein at lower doses. This review aims to explore the potential of a cost-effective mRNA/saRNA-based approach for GD therapy. The use of GCase-mRNA/saRNA as a protein replacement therapy could offer a new and promising direction for improving the quality of life and extending the lifespan of individuals with GD.

siRNA-based approaches for castration-resistant prostate cancer therapy targeting the androgen receptor signaling pathway.

Androgen deprivation therapy is a common treatment method for metastatic prostate cancer through lowering androgen levels; however, this therapy frequently leads to the development of castration-resistant prostate cancer (CRPC). This is attributed to the activation of the androgen receptor (AR) signaling pathway. Current treatments targeting AR are often ineffective mostly due to AR gene overexpression and mutations, as well as the presence of splice variants that accelerate CRPC progression. Thus there is a critical need for more specific medication to treat CRPC. Small interfering RNAs have shown great potential as a targeted therapy. This review discusses prostate cancer progression and the role of AR signaling in CRPC, and proposes siRNA-based targeted therapy as a promising strategy for CRPC.

Design, evaluation, and immune simulation of potentially universal multi-epitope mpox vaccine candidate: focus on DNA vaccine.

Monkeypox (mpox) is a zoonotic infectious disease caused by the mpox virus. Mpox symptoms are similar to smallpox with less severity and lower mortality. As yet mpox virus is not characterized by as high transmissibility as some severe acute respiratory syndrome 2 (SARS-CoV-2) variants, still, it is spreading, especially among men who have sex with men (MSM). Thus, taking preventive measures, such as vaccination, is highly recommended. While the smallpox vaccine has demonstrated considerable efficacy against the mpox virus due to the antigenic similarities, the development of a universal anti-mpox vaccine remains a necessary pursuit. Recently, nucleic acid vaccines have garnered special attention owing to their numerous advantages compared to traditional vaccines. Importantly, DNA vaccines have certain advantages over mRNA vaccines. In this study, a potentially universal DNA vaccine candidate against mpox based on conserved epitopes was designed and its efficacy was evaluated via an immunoinformatics approach. The vaccine candidate demonstrated potent humoral and cellular immune responses in silico, indicating the potential efficacy in vivo and the need for further research.

Development of a Multi-Epitope Universal mRNA Vaccine Candidate for Monkeypox, Smallpox, and Vaccinia Viruses: Design and In Silico Analyses.

Notwithstanding the presence of a smallpox vaccine that is effective against monkeypox (mpox), developing a universal vaccine candidate against monkeypox virus (MPXV) is highly required as the mpox multi-country outbreak has increased global concern. MPXV, along with variola virus (VARV) and vaccinia virus (VACV), belongs to the Orthopoxvirus genus. Due to the genetic similarity of antigens in this study, we have designed a potentially universal mRNA vaccine based on conserved epitopes that are specific to these three viruses. In order to design a potentially universal mRNA vaccine, antigens A29, A30, A35, B6, and M1 were selected. The conserved sequences among the three viral species-MPXV, VACV, and VARV-were detected, and B and T cell epitopes containing the conserved elements were used for the design of the multi-epitope mRNA construct. Immunoinformatics analyses demonstrated the stability of the vaccine construct and optimal binding to MHC molecules. Humoral and cellular immune responses were induced by immune simulation analyses. Eventually, based on in silico analysis, the universal mRNA multi-epitope vaccine candidate designed in this study may have a potential protection against MPXV, VARV, and VACV that will contribute to the advancement of prevention strategies for unpredictable pandemics.

DKK1-targeting cholesterol-modified siRNA implication in hair growth regulation.

Despite advancements in medical research, androgenetic alopecia (AGA) remains a humankind problem that still needs to be overcome. To date, clinical practice lacks an ideal treatment for AGA. The Wnt/ß-catenin signaling pathway is evidenced to play a key role in hair regrowth, hence, modulating this signaling pathway for AGA therapy appears to be rational. One of the major inhibitors of the canonical Wnt/ß-catenin signaling pathway is dickkopf-related protein 1 (DKK1). In this report, we have selected a small interfering RNA (siRNA) targeting DKK1 in vitro via qPCR and then tested its efficacy in vivo on the depilated dorsal skin of the mice. The changes in hair growth in different groups were observed over time. Moreover, the visual observation of the hair growth and hematoxylin and eosin (HE) staining showed that DKK1-targeting siRNA reveals non-inferior results compared with the mice treated with the Food and Drug Administration (FDA)-approved, commercially available minoxidil (5%) topical solution that was used as a positive control. Both- positive control and DKK1-targeting siRNA groups demonstrated significantly superior results compared with the control group that received negative control siRNA. Consequently, siRNAs targeting DKK1 may promote hair growth regulation in the AGA population via potentially activating the Wnt/ß-catenin signaling pathway.