The past twenty years have seen an explosion of interest in the structure and function of RNA and DNA. While some 80% of the human genome is transcribed into RNA, just ~3% of those transcripts code for protein sequences. Here, we discuss our group’s efforts to target RNA and DNA with drug-like small molecules using a small-molecule microarray (SMM) screening platform and the molecular basis for these interactions.

SMA is an inherited disease that leads to loss of motor function and ambulation, and a reduced life expectancy. We have been working to develop orally-administrated, systemically-distributed small molecules to increase levels of functional SMN protein. Herein, we describe the discovery risdiplam that focused on thorough pharmacology, DMPK and safety characterization and optimization. This compound is completing pivotal clinical trials and is a promising medicine for the treatment of patients in all ages and stages of SMA.

Modulation of enzymes that modify RNA (epitranscriptomics) is gaining interest in drug discovery. Gotham Therapeutics and ZoBio are developing inhibitors of YTHDF2, a multifunctional protein that selectively recognized 6 methyl-adenosine in mRNA thereby regulates protein expression. Results from fragment screening and hit evolution campaign will be presented.

Many rare inherited metabolic disorders are caused by deficiency of essential intracellular proteins (e.g. enzymes, transporters) responsible for maintaining proper homeostasis. Conventional protein replacement (e.g. enzyme replacement therapy or ERT) and gene therapy-based approaches are not an option for treating these disorders due to drug-delivery and efficacy/safety considerations. To develop new treatments for these diseases, we encapsulated nucleoside-modified, codon-optimized mRNAs, encoding these genes in lipid nanoparticles. Preclinical data demonstrating the efficacy and safety of our mRNA-LNP therapy for several rare metabolic disorders will be presented.

Our Neurochemistry Laboratory is advancing the therapeutic development of selective and potent alpha-synuclein (asyn), amyloid precursor protein (APP) and Prion protein (PrP) translation modulators. We discuss here the efficacy of key small molecules that alter translation rates of these disease associated proteins by the use of advantageous 5’UTR-directed repressor /reporters of the transcripts for their mRNAs (SNCA-mRNA, APP mRNA, PrP mRNA).  Our goal is to develop RNA directed molecules as neurotrophins for future treatments of Parkinson’s disease, as well as, neurodegenerative diseases that impair memory and cognition.

Recently, keen interest has been expressed at scientific symposia and in the scientific literature regarding RNA as a potential drug target in various diseases. Most of the efforts in targeting mRNA have focused on small drug molecules, since larger molecules often have difficulty in penetrating tumor cells. CharlestonPharma has developed a panel of human IgG1antibodies that bind to the nucleonin transporter on tumor cells in order to gain intracellular access. Once inside the tumor cell, the antibodies interfere with the stabilization of certain oncogenic mRNAs by nucleolin.

TANGO uses antisense oligonucleotides (ASOs) to prevent naturally occurring, non-productive splicing, and increase productive mRNA and fully functional protein. We identified non-productive events in > 50% protein-coding genes. ASOs targeting these events lead to increased mRNA and protein in a dose-dependent manner. TANGO-ASO treatment of Dravet syndrome mice lead to protein restoration to near normal levels, significant reversal of the survival phenotype, decreased seizure frequency and increased numbers of seizure-free mice. 

Anima Biotech is advancing Translation Control Therapeutics, the first platform for the discovery of small molecule drugs that selectively control mRNA translation. Using patented technology that causes ribosomes to emit light pulses as they assemble proteins, we screen for drug candidates that decrease or increase translation with selectivity towards mRNAs, tissues, cells or pathways. We advance an internal pipeline of programs across therapeutic areas and in strategic collaboration with Lilly.

Treatment of pancreatic ductal adenocarcinoma (PDAC) remains a clinical challenge. We discovered that miR-15a suppresses Wee1, Chk1, Yap-1, and BMI-1, causing cell cycle arrest and inhibiting cell proliferation. We developed a miRNA-based platform by replacing uracil (U) in the guide strand with 5-fluorouracil (5-FU). In vivo we showed the therapeutic power of 5-FU-miR-15a alone or in combination with gemcitabine with near complete elimination of PDAC lung metastatic tumor growth.