RNA Therapeutics

Advances in RNA Therapeutics and Limitations

There has been high level of recent interest in gene modulation with RNA based technologies (mRNA, gene editing, etc). Delivery Systems for RNA (typically viral or lipid based) are essential because RNA can cause strong immune/cytokine responses and are highly susceptible to degradation. Most delivery systems accumulate in the liver after IV (systemic) administration, cause toxicity and there are no good strategies for disseminated diseases like cancer.

The current RNA therapeutic applications are therefore limited to vaccines (local IM injection), ex vivo gene manipulation/editing (CAR-T, sickle cell), local delivery (eye) or liver-based diseases. Effective extra-hepatic targeting (e.g., for solid tumors) remains a major stumbling block in the development of RNA therapeutics.

Limitations of Cancer Therapy Today

The root cause of most cancers – i.e., Alterations/mutations in Tumor Suppressor Genes (TSGs) and Oncogenes (OGs) often cannot be directly targeted (only ancillary and secondary targets resulting from these gene alterations may be targetable). Currently available approaches in targeted therapy most often result in build-up of resistance over time due to development of alternate and redundant biological signaling pathways and cause ultimate failure of the treatment.

Aanastra’s Approach for the Future of RNA-based Cancer Treatment

Restoring, replacing or removal of the culprit genes as a strategy to treat cancers remains an untapped area due to delivery technology limitations. Aanastra’s approach to targeting TSGs and OGs can provide a major advance in treatment of cancer.

Our focus in cancer is based on a unique two-pronged approach: in vivo TUMOR SUPPRESSOR RESCUE™

(TSG-RESCUE™ , TSG-RESQ™) and in vivo ONCOGENE EDITING™ (ONCOEDIT™). These approaches have been validated by numerous studies in therapeutic cancer models including lung cancer, colorectal cancer, pancreatic cancer and osteosarcoma against targets like P53, BRCA1 and KRAS.

Our focus in other genetic diseases has been validated by studies in therapeutic models including reversal of hemophilia A (Factor VIII) and hypercholesterolemia (PCSK9) using our technology.

Therapeutic mRNA

mRNA are a promising new class of therapeutic molecules with the potential to treat a wide variety of diseases, which cannot be addressed with other technologies. mRNAs have highly similar compositions, generated with four different building blocks, but with a unique sequence order to encode a variety of different proteins.

In the last decade, therapeutic mRNA has become an efficient alternative to DNA. mRNA are easier to use and allow the fast development of therapies that are widely applicable for the treatment of many diseases (cancer, infectious diseases, rare diseases). Delivery of specific mRNA into cells can direct the production of specific proteins with the desired biological effects. This is not possible with other drug approaches.

CRISPR gene editing

Clustered, Regularly Interspaced, Short Palindromic Repeats “CRISPR” is an adaptive immune defense mechanism present in bacteria to degrade foreign genetic material, which is integrated into the CRISPR locus. The CRISPR/Cas9 system uses a combination of 2 types of molecules: a nuclease (the gene editor) and a guide RNA (which helps the nuclease find the right place to edit). CRISPR/Cas9 edits genes by precisely cutting DNA, and then letting natural DNA repair processes to take over. DNA damage is repaired by cellular DNA repair mechanisms, via either the non-homologous end joining DNA repair pathway (NHEJ), which leads to insertions or deletions creating errors, or the homology-directed repair (HDR) pathway, which can be used to recombine selected markers at specific sites in the genome.

CRISPR/CAS9 gene editing technology has the potential to revise, delete, and replace almost any gene in human cells in highly targeted manner. Hence, advances in this technology will help us to develop specific drugs for people with a wide variety of diseases.