Therapeutic Strategy

Active Targeted Delivery

In order to optimize the benefit-risk ratio and the PK/PD profile of our drug candidates, AptamiR is developing Generation 2.5 microRNA Oligonucleotide Therapeutics (ONTs) to achieve their active targeted delivery to Adipose Tissues and/or Ovarian Cancer Cells

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

Our New Generation 2.5 ONTs are designed:

  • To eliminate potential toxicities by replacing PS and LNA modifications by a PNA backbone
  • To maintain resistance to nucleases and proteases/peptidases
  • To conjugate the ONT to a fatty acid or a short peptide for enhanced targeted delivery to adipocytes or ovarian cancer cells of a greatly reduced effective dose with an extended duration of action
  • To avoid chirality
  • To limit protein binding

Active Targeted Delivery to Adipocytes

Selection of the Fatty Acid Translocase (FAT) transporter for active targeted delivery of microRNA ONTs to adipocytes:

  • The membrane transporter FAT/CD36/SCARB3 is the main route of uptake by adipose tissues of long-chain fatty acids as well as short peptides like Hexarelin, Prohibitin and Thrombospondin Peptide-1
  • 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
  • Altered expression of FAT has been linked to phenotypic features of the metabolic syndrome including insulin resistance and dyslipidemia
  • As the average obese male patient weighs around 200 lbs. with 40% being adipose tissue, there is a huge amount of FAT available at the surface of adipose tissues to transport inside the adipocytes our new generation 2.5 of miR-22-3p antagomirs coupled to a fatty acid or a peptide
  • Consequently, the effective dose of our generation 2.5 ONTs is significantly reduced with a greatly improved safety and PK/PD profile, especially the mean residence time inside the targeted cells

2-D Structure of FAT:

https://www.ncbi.nlm.nih.gov/pubmed/27090938                              

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 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:

We are currently focusing on two approaches for targeted delivery of ONTs to adipocytes:

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.

ONT-Lipid Conjugate

Peptide Conjugates: Short peptides have been shown to facilitate the delivery of ONTs 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.

ONT-Peptide Conjugate

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.

Active Targeted Delivery to Ovarian Cancer Cells and their Tumor Environment

Selection of the Folic Acid receptor alpha (FOLR1) for active targeted delivery of microRNA ONTs to primary Ovarian Cancer Cells

  • The Folic Acid Receptor Alpha (FOLR1) is highly expressed at the surface of Epithelial Ovarian Cancer Cells:

Approach used for targeted delivery of microRNAs ONTs to ovarian cancer cells:

Selection of the FAT transporter and the FABP4 lipid transporter for active targeted delivery of ONTs to the adipose-rich omentum microenvironment of metastatic Ovarian Cancers

  • Ovarian Cancers have a predilection for metastasis to the omentum, an extensive tissue layer on the surface of intra-peritoneal organs that is primarily composed of adipocytes
  • Shedding from the primary ovarian cancer cells and exosomes in the peritoneal cavity is a main aspect of Ovarian Cancer
  • Extracellular vesicles (exosomes also named oncosomes in the context of cancers) play a significant role in cell-to-cell communications and spreading of Ovarian Cancer from the primary tumor
  • The adipose-rich omentum microenvironment plays important roles in the progression and resistance to treatments of ovarian cancer:
  • The increased lipid cellular uptake by the membrane transporters Fatty Acid Translocase (FAT/CD36/SCARB3) and Fatty Acid-Binding Protein 4 (FABP4) is implicated in Ovarian Cancer metastasis
  • FABP4 is upregulated at the adipocyte-Ovarian Cancer cells interface and is a key determinant of metastatic potential of Ovarian Cancers
  • miRNAs exert various effects in the Ovarian Cancer microenvironment of endothelial cells, fibroblasts, macrophages and adipocytes
  • Lipid transporters have great potential for targeted and efficient delivery of small RNAs such as miRNA ONTs to the tumor microenvironment of Ovarian Cancers.

Therefore, to treat Ovarian Cancer we propose to couple our microRNA ONTs to:

  1. Folic Acid (“FolamiRs”) for active targeted and efficient delivery to primary Ovarian Cancer cells
  2. Fatty Acids (“AdipomiRs”) for active targeted and efficient delivery to the metastatic Ovarian Cancer microenvironment
  3. Short Peptides (“PeptidomiRs”) for active targeted and efficient delivery to the metastatic Ovarian Cancer microenvironment
  4. Lipid Nanoparticles (“LipomiRs”) for active targeted and efficient delivery to the metastatic Ovarian Cancer microenvironment