Our GalXC™ RNAi Platform
Our proprietary GalXC platform leverages a naturally occurring biologic process, ribonucleic acid interference, or RNAi, to create therapies that silence disease-causing genes. This platform enables Dicerna to identify and develop molecules that can effectively interfere with the RNAi processes that lead to defective or misregulated proteins that cause or contribute to disease.
How RNAi therapies work and their advantages
The DNA within each of us is essentially an “instruction manual” for building proteins that greatly affect our health. Messenger RNA (mRNA) carries these instructions from the DNA to sites in cells where proteins are made. During this biologic process, small interfering RNA (siRNA) molecules, such as GalXC, can induce the destruction of the mRNAs of targeted genes.
Because scientists can easily create synthetic siRNA that matches almost any mRNA, this RNAi-based approach to drug development can silence virtually any gene and has distinct advantages over more traditional therapeutic approaches, including:
- RNAi has an impact earlier in the disease-causing process. RNAi can be used to target any gene because it targets the mRNA that encodes the disease-driving protein. While some conventional therapies block the activity of proteins responsible for disease, RNAi therapies prevent these proteins from being created.
- RNAi is highly specific for the targeted gene because it uses a gene sequence match with the targeted gene and relies on naturally occurring cellular enzymes to mediate gene silencing. RNAi therapies are thought to be a potentially safer option than permanently editing DNA, which could have unknown, unwanted and irreversible consequences.
- RNAi therapies have the potential to reduce the treatment burden for patients. Their long duration of effect means they may be administered less frequently.
Our GalXC Platform
Dicerna scientists invented our GalXC RNAi technology platform to target specific genes and maximize pharmaceutical acceptability. We continue to expand the utility of our GalXC platform through a variety of modifications and chemistries.
We are using our proprietary GalXC technology to advance the development of next-generation RNAi-based therapies designed to silence disease-driving genes in the liver. Dicerna has continued to innovate and is exploring new applications of its RNAi technology with GalXC-Plus, extending our expertise in RNAi silencing to address new tissues and organs outside the liver, while retaining key pharmacological features from GalXC.
We believe our GalXC RNAi technology platform holds tremendous potential:
- Our GalXC molecules have been optimized for use in humans with respect to base sequences and chemical modifications to increase stability and mask them from mechanisms that recognize foreign nucleic acids to avoid inducing immune system stimulation.
- Our GalXC technologies are highly specific to the gene to which they are targeted due to the gene-sequence-based nature of our GalXC molecules interacting with their gene mRNA targets, enabling GalXC molecules to avoid direct off-target effects.
- Our GalXC technology enables convenient subcutaneous dosing.
- Our GalXC molecules have a long duration of action that can support infrequent dosing.
- Our GalXC molecules have demonstrated a high therapeutic index, exhibiting good tolerability in both preclinical and clinical studies, even at levels exceeding expected efficacious dose levels.
- Our GalXC molecules can be manufactured by existing, standard methods.
- Our GalXC RNAi therapies are fully reversible after cessation of treatment and can also be modulated by dose or intervals between administration, unlike gene therapy and gene editing.
Data from clinical and preclinical studies suggest that GalXC may offer several benefits, including:
- Potentially stronger potency than comparable RNAi therapies
- Highly specific binding to disease-causing targets
- Long duration of action
- An infrequent, subcutaneous dosing regimen, which can minimize treatment burden
- A high therapeutic index, which indicates broad applicability
For delivering to tissues outside the liver, Dicerna continues to innovate using modified structures, chemistries and conjugated moieties. Referred to as GalXC-Plus™, these proprietary technological advances extend our expertise in RNAi silencing to address new tissues and organs outside the liver, while retaining key pharmacological features from GalXC. In 2020, we first presented preclinical data demonstrating the potential application of our GalXC-Plus technology to the central nervous system, skeletal muscle and adipose tissue.
The RNAi revolution
Dicerna presents for the first time data on the application of its GalXC-Plus technology in multiple new tissue types.
Novo Nordisk and Dicerna announce a global licensing and research collaboration focused on cardiometabolic diseases.
Roche and Dicerna announce a global licensing and research collaboration focused on chronic hepatitis B virus infection.
Dicerna submits a clinical trial authorization (CTA) application to conduct a first-in-human Phase 1/2 study of belcesiran (DCR-A1AT).
Dicerna initiates first dosing in Phase 1 clinical trial of DCR-HBVS, now referred to as RG6346, for the treatment of chronic hepatitis B virus infection.
Alexion Pharmaceuticals and Dicerna announce a collaboration to create RNAi therapies for complement-mediated diseases.
Eli Lilly and Dicerna announce a global licensing and research collaboration focused on creating new medicines in cardiometabolic disease, neurodegenerative diseases and pain.
FDA approves first RNAi therapy.
Dicerna initiates PHYOX™ Phase 1 clinical trial of its lead clinical candidate, nedosiran, in patients with primary hyperoxaluria type 1 (PH1) and type 2 (PH2)
Boehringer Ingelheim and Dicerna announce research collaboration and license agreement to develop novel GalXC RNAi therapies for chronic liver diseases, beginning with nonalcoholic steatohepatitis (NASH).
Dicerna first applies GalXC, our proprietary, next-generation, RNAi technology platform to target LDHA in preclinical models of primary hyperoxaluria.
Dicerna receives a U.S. patent for its Dicer Substrate™ technology.
The City of Hope (COH) grants Dicerna exclusive worldwide license for Dicer substrate short interfering RNA (DsiRNA).
First foundational patent applications describing a new RNAi platform, GalXC, are filed. Additional patent applications filed in 2009 and 2010.
Fire and Mello receive the Nobel Prize for their discovery of RNAi.
Andrew Fire and Craig Mello publish their discovery of RNAi in Nature.