RNA aptamers specific for transmembrane p24 trafficking protein 6 and Clusterin for the targeted delivery of imaging reagents and RNA therapeutics to human β cells

Abstract

The ability to detect and target β cells in vivo can substantially refine how diabetes is studied and treated. However, the lack of specific probes still hampers a precise characterization of human β cell mass and the delivery of therapeutics in clinical settings. Here, we report the identification of two RNA aptamers that specifically and selectively recognize mouse and human β cells. The putative targets of the two aptamers are transmembrane p24 trafficking protein 6 (TMED6) and clusterin (CLUS). When given systemically in immune deficient mice, these aptamers recognize the human islet graft producing a fluorescent signal proportional to the number of human islets transplanted. These aptamers cross-react with endogenous mouse β cells and allow monitoring the rejection of mouse islet allografts. Finally, once conjugated to saRNA specific for X-linked inhibitor of apoptosis (XIAP), they can efficiently transfect non-dissociated human islets, prevent early graft loss, and improve the efficacy of human islet transplantation in immunodeficient in mice.

Non-coding RNAs in diabetes mellitus and diabetic cardiovascular disease

“…With the help of gene editing technology, it may also be possible to use gene therapy to restore the expression of abnormal ncRNAs in patients in the long term ( 170 ). A recent study developed a tool for RNA delivery that targets β-cells ( 171 ). In addition, various carriers, including liposomes and exosomes, have been found to be useful for delivering RNA ( 172 , 173 ).…”

Nanozyme as a rising star for metabolic disease management

“…Nevertheless, the current absence of specific probes hinders our ability to accurately measure the mass of human β cells and deliver effective treatments in clinical settings. Van et al have documented the discovery of two RNA aptamers, which selectively and specifically recognize mouse and human β cells by targeting transmembrane p24 trafficking protein 6 and clusterin [ 86 ]. Multiple investigations have showcased the effectiveness of utilizing exosomes, which have emerged as highly promising nano-carriers for delivering therapeutic agents like small interfering RNA, microRNAs, proteins, or chemical medicines to targeted cells [ 87 , 88 ].…”

“…Their distribution can be influenced by factors like blood flow, tissue permeability, and interactions with proteins or cells in the circulation [ 186 ]. Nanozymes can accumulate in specific tissues or organs, depending on their targeting strategies or the physiological characteristics of the target site [ 61 , 86 ]. Once inside the cell, nanozymes can be localized in different cellular compartments, such as endosomes, lysosomes, or cytoplasm, depending on the specific targeting or delivery strategy employed [ 104 ].…”

Aptamer-Based Targeted Delivery of Functional Nucleic Acids

“…In 2022, Van Simaeys et al reported the identification of two RNA aptamers that could bind to transmembrane p24 trafficking protein 6 and clusterin of mouse and human β cells. Similar to the design shown in Figure , aptamers 1-717 and 12-3773 were conjugated with XIAP saRNA to specifically mediate the expression of inflammatory cytokines, improving the efficacy of human islet transplantation in mice with immunodeficiency …”

“…In 2006, a small activating RNA (saRNA) was designed to activate gene transcription, emerging as a powerful tool for targeting various human cancers. , The C/EBPα (CCAAT/enhancer-binding-protein-alpha), , DPYSL3 (dihydropyrimidinase-related protein 3), and XIAP (X-linked inhibitor of apoptosis protein) genes have been investigated as targets by aptamer–saRNA chimeras for the targeted treatment of pancreatic cancer. Based on cell-SELEX technology, Yoon et al selected aptamers able to bind specifically to surface epitopes of human pancreatic adenocarcinoma, PANC-1.…”