Our objective is to achieve an efficient and targeted delivery of miRNA analogs to human adipocytes. An optimized efficiency/safety profile of our new chemical entities relies on the specific delivery to human adipocytes (the target tissue) of enough copies of a miRNA analog to produce a potent but safe thermogenic effect. Hence the trademarked name of our Company, AptamiR™, that combines the word apta (from the Latin verb aptare “fit together”) with the microRNA abbreviation miR.
AptamiR is currently validating various novel combinations of several components (a miRNA analog, a carrier/delivery system and a targeting agent) described below for achieving an efficient and targeted delivery of microRNA modulators to human adipocytes:
Lipid Conjugates: The first method shown to improve the in vivo delivery of miRNA analogs was 3’ conjugation with cholesterol. We are taking advantage of the fact that the adipocyte membrane is rich in receptors and transporters for fatty acids to conjugate our miRNA candidates with distinct fatty acids that are actively transported across the adipocyte membrane.
Lipid Nanoparticles: Lipid nanoparticles (LNPs) are used for the protection and delivery of small molecules and more recently oligonucleotides like siRNAs. Both systemic and localized deliveries of a therapeutic load have been achieved by LNPs.
Polymer Nanoparticles: Polymer-based nanoparticles, produced in relatively homogeneous size up to 100 nm, can deliver a variety of cargo molecules, including small molecules, siRNAs and anti-miRNAs. We are concentrating on positively charged particles that can electrostatically bind to oligonucleotides, protect them from degradation and facilitate their intra-cellular delivery.
Exosomes: Exosomes are cell-derived vesicles with a diameter between 30 and 100 nm, which were long-considered as “cellular trash cans”. Recently, exosomes were shown to have important roles in inter-cellular signaling as well as transport of proteins and miRNAs. They also show promise as drug delivery vehicles, as they can evade the immune system, and directly fuse with the membrane of a target cell, allowing for delivery of microRNA modulators directly into the cytoplasm, bypassing the endosomes.
Aptamers: Aptamers are oligonucleotides that are 30-100 nucleotides long that can fold into three-dimensional shapes and bind with very high affinity and specificity to ligands such as proteins, much like antibodies. Aptamers have been shown to promote the uptake of cargo molecules, including oligonucleotides like microRNA modulators, into specific cell types. This can be achieved through direct conjugation of the aptamer to the microRNA modulator, or when inserted at the surface of carriers like a lipid nanoparticle, polymer nanoparticle or an exosome carrying the microRNA.