Therapeutic Strategy

Delivery Platform

In order to optimize the benefit-risk ratio and the PK/PD profile of our drug candidates, AptamiR is developing our second generation of Oligonucleotide Therapeutic Agents to achieve their targeted delivery to adipose tissues. 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.

Selection of the Fatty Acid Translocase (FAT) transporter for targeted delivery. The membrane transporter FAT/CD36 is the main route of uptake of long-chain fatty acids by adipose tissues:

FAT 2D Structure

Altered expression of FAT has been linked to phenotypic features of the metabolic syndrome including insulin resistance and dyslipidemia. FAT is expressed in cells and tissues sensitive to metabolic dysfunctions, such as adipocytes, hepatocytes, skeletal and cardiac myocytes, pancreatic β-cells, kidney glomeruli and tubules cells, monocytes and macrophages

As a reference, the Asialoglycoprotein receptor 1 (ASGR1) has been targeted for preferred delivery of N-acetylgalactosamine-coupled ONTs to the liver (e.g. the now approved siRNA Inclisiran, Leqvio®). Comparison of the mRNA and protein expression levels for these 2 membrane transporters (www.proteinatlas.org) shows that RNA and protein expressions of FAT are very high in adipose tissues.:

As the average obese male patient weighs around 200lbs with 40% being adipose tissue, there is a huge amount of FAT available at the surface of adipose tissues to transport our second generation of miR-22-3p antagomir coupled to a fatty acid or a peptide targeting FAT. Consequently, the effective dose for our second generation of drugs should be much lower with a greatly improved PK/PD profile, especially mean residence time in cells.

We are currently focusing on two approaches:

Lipid Conjugates: We are taking advantage of the fact that the human 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 via the Fatty Acid Translocase (FAT) transporter.

Peptide Conjugates: Short peptides have been shown to facilitate the delivery of oligonucleotide therapeutic agents inside cells.  We are taking advantage of the fact that the Fatty Acid Translocase (FAT) transporter present in the adipocyte membrane can also transport peptides to conjugate our miRNA candidates to short peptides that are actively transported across the adipocyte membrane via the Fatty Acid Translocase (FAT) transporter.

The Adipocyte-Targeting Delivery platform developed by AptamiR could be used not only for oligonucleotides but also for small molecules, peptides, peptidomimetics, nutraceuticals and gene editing systems.