Oral Delivery of Nucleic Acid Therapies for Local and Systemic Action.

Nucleic acid (NA) therapy has gained importance over the past decade due to its high degree of selectivity and minimal toxic effects over conventional drugs. Currently, intravenous (IV) or intramuscular (IM) formulations constitute majority of the marketed formulations containing nucleic acids. However, oral administration is traditionally preferred due to ease of administration as well as higher patient compliance. To leverage the benefits of oral delivery for NA therapy, the NA of interest must be delivered to the target site avoiding all degrading and inhibiting factors during its transition through the gastrointestinal tract. The oral route presents myriad of challenges to NA delivery, making formulation development challenging. Researchers in the last few decades have formulated various delivery systems to overcome such challenges and several reviews summarize and discuss these strategies in detail. However, there is a need to differentiate between the approaches based on target so that in future, delivery strategies can be developed according to the goal of the study and for efficient delivery to the desired site. The goal of this review is to summarize the mechanisms for target specific delivery, list and discuss the formulation strategies used for oral delivery of NA therapies and delineate the similarities and differences between local and systemic targeting oral delivery systems and current challenges.

Metabolic Rewiring by Loss of Sirt5 Promotes Kras-Induced Pancreatic Cancer Progression.

BACKGROUND & AIMS: SIRT5 plays pleiotropic roles via post-translational modifications, serving as a tumor suppressor, or an oncogene, in different tumors. However, the role SIRT5 plays in the initiation and progression of pancreatic ductal adenocarcinoma (PDAC) remains unknown. METHODS: Published datasets and tissue arrays with SIRT5 staining were used to investigate the clinical relevance of SIRT5 in PDAC. Furthermore, to define the role of SIRT5 in the carcinogenesis of PDAC, we generated autochthonous mouse models with conditional Sirt5 knockout. Moreover, to examine the mechanistic role of SIRT5 in PDAC carcinogenesis, SIRT5 was knocked down in PDAC cell lines and organoids, followed by metabolomics and proteomics studies. A novel SIRT5 activator was used for therapeutic studies in organoids and patient-derived xenografts. RESULTS: SIRT5 expression negatively regulated tumor cell proliferation and correlated with a favorable prognosis in patients with PDAC. Genetic ablation of Sirt5 in PDAC mouse models promoted acinar-to-ductal metaplasia, precursor lesions, and pancreatic tumorigenesis, resulting in poor survival. Mechanistically, SIRT5 loss enhanced glutamine and glutathione metabolism via acetylation-mediated activation of GOT1. A selective SIRT5 activator, MC3138, phenocopied the effects of SIRT5 overexpression and exhibited antitumor effects on human PDAC cells. MC3138 also diminished nucleotide pools, sensitizing human PDAC cell lines, organoids, and patient-derived xenografts to gemcitabine. CONCLUSIONS: Collectively, we identify SIRT5 as a key tumor suppressor in PDAC, whose loss promotes tumorigenesis through increased noncanonic use of glutamine via GOT1, and that SIRT5 activation is a novel therapeutic strategy to target PDAC.

Beyond Lipids: Exploring Advances in Polymeric Gene Delivery in the Lipid Nanoparticles Era.

The recent success of gene therapy during the COVID-19 pandemic has underscored the importance of effective and safe delivery systems. Complementing lipid-based delivery systems, polymers present a promising alternative for gene delivery. Significant advances have been made in the recent past, with multiple clinical trials progressing beyond phase I and several companies actively working on polymeric delivery systems which provides assurance that polymeric carriers can soon achieve clinical translation. The massive advantage of structural tunability and vast chemical space of polymers is being actively leveraged to mitigate shortcomings of traditional polycationic polymers and improve the translatability of delivery systems. Tailored polymeric approaches for diverse nucleic acids and for specific subcellular targets are now being designed to improve therapeutic efficacy. This review describes the recent advances in polymer design for improved gene delivery by polyplexes and covalent polymer-nucleic acid conjugates. The review also offers a brief note on novel computational techniques for improved polymer design. The review concludes with an overview of the current state of polymeric gene therapies in the clinic as well as future directions on their translation to the clinic.

Advances in Lipid-Based Codelivery Systems for Cancer and Inflammatory Diseases.

Combination therapy targeting multiple therapeutic targets is a favorable strategy to achieve better therapeutic outcomes in cancer and inflammatory diseases. Codelivery is a subfield of drug delivery that aims to achieve combined delivery of diverse therapeutic cargoes within the same delivery system, thereby ensuring delivery to the same site and providing an opportunity to tailor the release kinetics as desired. Among the wide range of materials being investigated in the design of codelivery systems, lipids have stood out on account of their low toxicity, biocompatibility, and ease of formulation scale-up. This review highlights the advances of the last decade in lipid-based codelivery systems focusing on the codelivery of drug-drug, drug-nucleic acid, nucleic acid-nucleic acid, and protein therapeutic-based combinations for targeted therapy in cancer and inflammatory diseases.