Our Technology

Our Technology

GalXC™ Technology Platform: RNAi in Action

 

What is GalXC™?

Dicerna invented the RNAi technology platform called GalXCTM, which is a proprietary technology platform that advances the development of next-generation RNA interference (RNAi) based therapies designed to silence disease-driving genes in the liver.

How does it work?

GalXC harnesses the power of the natural RNAi pathway, a pathway within cells whose purpose is to silence genes. In this biological process, the double-stranded RNA molecules trigger the potent and specific destruction of messenger RNAs (mRNAs) of disease-driving genes. Dicerna’s investigational drugs are designed to silence or “knock down” the expression of a targeted gene in a way that is highly selective, specific, precise and reversible.

GalXC-based therapies are processed by the Dicer enzyme, which is the natural initiation point for RNAi within the human cell.

We invented the RNAi technology platform called GalXCTM, which 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-based therapies are processed by the Dicer enzyme, which is the natural initiation point for RNAi within the human cell. By using the Dicer enzyme as the entry point into the RNAi, we seek to optimize the activity of the RNAi pathway so that it operates in the most specific and potent fashion. Compounds produced via GalXC are intended to be broadly applicable across multiple therapeutic areas, including rare diseases, viral infectious diseases, chronic liver diseases, and cardiovascular diseases.

GalXC Mechanism of Action

What makes GalXC different?

Our GalXC molecules are structured to be processed by the enzyme Dicer, the initiation point for RNAi in the human cell cytoplasm. Unlike earlier generation RNAi molecules, which mimic the output product of Dicer processing, all our DsiRNAs, including GalXC molecules, enter the RNAi pathway prior to Dicer processing. By using the Dicer enzyme as the entry point into the RNAi, we seek to optimize the activity of the RNAi pathway so that it operates in the most specific and potent fashion.

Moreover, the GalXC RNAi platform does not involve lipid nanoparticles (LNPs) or other formulation components that facilitate drug delivery, simplifying the platform and eliminating any requirement for functional excipients. Instead, our GalXC molecules are stabilized by chemical modifications and utilize a four base sequence known as a tetraloop, where each base is conjugated to a simple sugar, N-acetylgalactosamine (GalNAc), that is specifically recognized by a receptor on the surface of hepatocyte liver cells. The tetraloop configuration, which is unique to Dicerna’s GalXC compounds, interfaces effectively with the RNAi machinery, allowing flexible and efficient conjugation to the targeting ligands, and stabilizing the RNAi duplex to enable effective delivery of our GalXC RNAi-inducing molecules directly to the liver.

 

 

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.

 

How will GalXC be used?

The GalXC RNAi technology platform is particularly well-suited for subcutaneous delivery of RNAi therapies to the liver, as hepatocytes have a cell surface membrane receptor for the GalNAc sugars that are attached to GalXC compounds. This leads to effective internalization and access to the RNAi machinery within hepatocytes.

Compounds produced via GalXC are intended to be broadly applicable across multiple therapeutic areas, including rare diseases, viral infectious diseases, chronic liver diseases, and cardiovascular diseases.

Dr. Douglas Fambrough, president and chief executive officer, and Bob Brown, chief scientific officer and senior vice president of research and development, provide an overview of Dicerna’s GalXC technology and how it is differentiated.