Our Technology

Our GalXCTM Technology Platform: Enhancing the Utility of DsiRNA-EX Molecules

Delivering DsiRNAs to the Liver.

GalXCTM is a proprietary technology platform that advances the development of next-generation RNAi-based therapies designed to silence disease-driving genes in the liver.

GalXC enables subcutaneous delivery of Dicerna’s RNAi therapies to hepatocytes in the liver and may offer several distinct benefits, as shown in animal models. These potential benefits include:

  • potency that is on par with or better than comparable platforms
  • exquisite specificity to gene targets
  • long duration of action versus other modalities
  • simple, infrequent dosing regimen

For delivery to the liver, we attach N-acetylgalactosamine (GalNAc) sugars to one or more points on GalXC compounds, yielding multiple effective and proprietary conjugate delivery configurations. These molecules specifically bind to highly expressed asialoglycoprotein (ASGPR) receptors on the target cells, leading to internalization and access to the RNAi machinery within the cells. GalXC allows us to screen and optimize therapeutic leads with greater efficiency, and to apply them to a wide variety of gene targets associated with liver-related diseases.

GalNAc has been used as a liver-targeting delivery vehicle since the early 1990s. We invented the DsiRNA-EX molecular structures and started developing the GalXC structures in 2008. With GalXC, our proprietary implementation of the GalNAc technology, the GalNAc sugar molecules are chemically conjugated to specific bases on the DsiRNA-EX RNA duplexes in a configuration that is unique to Dicerna. GalXC compounds have been our core focus since 2013.

Many of our conjugates produced via GalXC technology incorporate a folded motif known as a tetraloop in the extended region. The tetraloop configuration, which is unique to Dicerna’s GalXC compounds, interfaces effectively with the RNAi machinery. The GalXC platform allows flexible and efficient conjugation to the targeting ligands, and stabilizes the RNAi duplex to enable effective delivery of our GalXC RNAi-inducing molecules directly to the liver.

 

Dicerna’s Proprietary GalXC Configuration Interfaces Effectively with the RNAi Machinery

Dicerna

Our unique, proprietary tetraloops incorporate specific design principles (e.g., sequence and chemistry features) accumulated from our research data, relevant literature and 3D modeling to maximize their efficiency and optimization. Our data suggest that in the tetraloop format, the Dicer protein presents the RISC machinery with a pre-formed Guide Strand:

Dicerna 2

 

GalXC Technology Platform: Potential Therapeutic Applications

As Dicerna reported during its 2016 Investor Day presentation, subcutaneously delivered GalXC compounds silenced 12 different disease targets in animal models, highlighting the long duration of action, infrequent dosing and tolerability of GalXC-based compounds. Use of the GalXC platform yielded gene silencing of greater than 90% for multiple genes in non-human primates (NHPs) after a single dose. In an NHP model of an undisclosed rare disease gene target, a single 3 mg/kg dose achieved a maximum gene silencing of 94%, with an average gene silencing of approximately 88%. Another single 3 mg/kg dose NHP study resulted in an average of 97% silencing of an undisclosed rare disease gene target.

Future Directions for the GalXC Technology Platform

Our GalXC compounds incorporate our unique, proprietary tetraloop technology and are broadly applicable across multiple therapeutic areas, including rare diseases, chronic liver diseases, cardiovascular disease, and viral infectious diseases. These compounds may be used to develop additional therapeutic agents targeting other cell types in the future.

GalXC Mechanism of Action