By Yizhou Dong
It is estimated more than 10,000 human diseases are caused by genetic disorders. Many of these diseases are fatal, and currently there are no effective treatments. Infectious diseases like Hepatitis B affect over 350 million people worldwide. Cancer has overtaken heart diseases as the leading cause of death. Consequently, new therapeutic strategies are in urgent demand.
To address these challenges, we integrate pharmaceutics, pharmaceutical chemistry, biomedical engineering, materials formulation, and animal studies to design novel therapeutic medicines and uncover their mechanisms of actions. The ultimate goal is to translate our scientific results and technological inventions into more effective treatments that will lead to more fulfilling lives for human patients.
Recently, my team invented new lipid-like nanoparticles (TT-LLNs) through an orthogonal array design (Fig 1), which demonstrates improved delivery efficiency of mRNA encoding luciferase in vitro by over 350-fold with significantly reduced experimental volume. O-TT3 LLNs, a lead material, is able to restore the human factor IX (hFIX) level to normal physiological values in FIX-knockout mice. Consequently, these mRNA-based nanomaterials merit further development for treating genetic disorders such as hemophilia.
In addition, we investigated the effects of chemically modified nucleotides on mRNA translation. We synthesized a library of mRNAs using chemically modified nucleotides. We incorporated substitution of single modifications and combinations of modifications. 5moU modifications significantly increased stability of eGFP mRNA. More importantly, we identified N1-methylpseudouridine, 5-methoxyuridine, and pseudouridine as promising nucleotides for mRNA modifications, which offered new insights on chemically modified mRNAs.
Fig 1. Illustration of material development for mRNA delivery.
With the support of the New Investigator Grant from the AAPS Foundation, we aim to develop new types of biomaterials for genome engineering. With results obtained, we will further advance these novel platforms of therapeutics for human clinical trials in the future. More importantly, the success of this work will have broad impacts on drug delivery and therapeutic applications.