Chemotherapy

Chemotherapy is a type of therapeutics involving strong chemicals meant to kill rogue cells in your body. Chemotherapy is often attributed to cancer treatment, but actually it describes any kind of therapeutics that involve a chemical. One of the major reasons which render chemotherapy largely unsuccessful, is our inability to direct such molecules to a particular type of cell, such as a diseased cell. This leads to high cytotoxicity, detrimental to the neighbouring healthy cells and which tend to significantly reduce the lifespan of a patient.

On the other hand, targeted drug delivery to diseased cells reduces bystander cell toxicity and can be used to transport poorly permeable drugs, such as nucleic acid based therapeutic molecules. Extensive scientific evidence accumulated in the past years has emphasised the dysregulation of gene expression in various pathological conditions. These include cancer, inflammatory disorders, deficiency syndromes and neurodegenerative diseases. Therefore, the ability to manipulate gene expressions either by overexpression of modified messenger RNAs (mmRNA), or by short interfering RNAs (siRNA) rendering a gene silent in any desired cell or tissues, holds great potential for therapeutic interventions. However, mRNA molecule mediated desired gene expression is hindered due to technological challenges such as, ability to successfully transcribe in-vitro mRNA in large amounts, instability in-vivo and immunogenicity. Furthermore the major challenge in RNA based therapies lies in targeting the RNA molecules effectively to desired cell types.

A recent study at Tel Aviv university, Israel by the Dan Peer group focuses on this issue of developing a targeted mmRNA or siRNA molecule to desired cells or tissues. Inflammatory diseases and cancer are multifactorial diseases and an optimal therapy must ensure the ability to engage different gene targets in distinct cell types. Cancer being highly heterogeneous, any attempt to target a particular receptor of a cancer cell will most likely fail and cause resistant cancer cells to flourish once deprived of the particular receptor protein. Therefore, a delivery platform that can be adjusted for each patient and target several receptors would be ideal. The strategy devised by the group, is to incorporate the mmRNA or siRNA molecules into lipid nanoparticles (LNP) and coat the LNPs with high affinity monoclonal antibodies (mAb) for any particular cell-specific receptor, thereby ensuring high cell or tissue specificity. To resolve the issue of inefficient mAb association with LNPs, the mAbs are non-covalently attached to LNPs via a recombinant protein (anchored secondary scFv enabling targeting, ASSET). ASSET is a membrane anchored lipoprotein incorporated into LNPs and interacts with Ab Fc domain.

Compared to a targeted chemotherapeutic drug, a recombinant protein widely used as a therapeutic agent today, requires multiple injections to maintain desired protein concentrations in a therapeutic window. In addition it entails high cost and long purification processes which limits their production by pharmaceutical industries. Taken together, the use of recombinant proteins as therapeutic agents is limited owing to technological limitations and calls for a suitable, safe alternative. Indeed, the targeted chemotherapeutic approach provides a flexible platform that delivers mmRNA or siRNA to modulate gene expressions in targeted cell populations and thus bears immense therapeutic potential.

Figure 1. Schematic illustration of the versatility of the targeting platform. Adapted from Kedmi et.al., Nature Nanotechnology, 2018.

Figure 2. (a) Schematic illustration of ASSET incorporation into LNPs. 1) target cell membrane, 2) targeted cell surface receptor, 3) encapsulated siRNA, 4) LNP, 5) ASSET anchored in the LNP. (b) The ASSET expression vector. Adapted from Kedmi et.al., Nature Nanotechnology, 2018