CAMP4’s RNA-based Therapy Shows Promise in Preclinical Studies
Note: This story was updated Feb. 7, 2022, to clarify that CAMP4 will continue preclinical studies for its lead candidate. Also, CAMP4 licensed the antisense oligonucleotides from OPKO Health, not the RNA Actuating Platform, which was developed in-house.
CAMP4 Therapeutics‘ investigational RNA-based therapy — called CMP-SCN (CO-3527) — increased the expression of the SCN1A gene, which is deficient in most patients with Dravet syndrome, in both human and non-human primate cells, and reduced seizure frequency and duration in a mouse model of the disease, according to data presented at the recent American Epilepsy Society (AES) Annual Meeting.
Gene expression is the process by which information in a gene is synthesized to create a protein.
“These data collectively validate our disease-modifying strategy for Dravet, which, we believe, will be therapeutically impactful,” David Bumcrot, PhD, chief scientific officer of CAMP4, said in a press release.
CAMP4 will continue to test its lead candidate in preclinical studies and soon expects to file an investigational new drug (IND) application in the U.S. to conduct its first in-human studies.
“Based on these data, CAMP4 will pursue clinical development for CMP-SCN with the expectation of filing an Investigational New Drug Application with the U.S. Food and Drug Administration by the end of 2022,” Bumcrot said.
The results were presented in a scientific poster titled “SCN1A upregulation via antisense oligonucleotides targeting SCN1A-NAT as a novel therapeutic strategy for Dravet syndrome.”
Dravet syndrome is a genetic disorder mostly caused by mutations in the SCN1A gene, which contains the instructions for a protein called NaV1.1. These mutations lead to the impaired production of NaV1.1, causing an overactivation of the nervous system and the development of seizures. Most patients with Dravet have frequent and lasting seizures.
The information coded in genes, before being translated into a protein, is first converted into a messenger RNA or mRNA — the molecule generated from DNA that serves as a template for protein production.
However, cells possess several other classes of RNA molecules, including regulatory RNAs — such as those called natural antisense transcripts, or NATs — that control gene activity in a precise and tunable manner. Specifically, NATs interact with specific mRNAs to increase or decrease protein production.
CAMP4’s RNA Actuating Platform designs antisense oligonucleotides (ASOs) — short pieces of DNA or RNA — to target these NATs to change the activity of a gene, but in a controlled manner to prevent toxicity.
In this case, the CMP-SCN ASO, which was licensed from OPKO Health, was designed to target the NAT associated with the SCN1A gene (SCN1A-NAT), to increase its protein production.
Researchers from CAMP4 and the University of Miami Health System conducted lab (in vitro) studies with a human neuroblastoma cell line as well as with mouse hippocampal nerve cells. They confirmed that treatment with CMP-SCN led to an increase in SCN1A gene expression and restored neuronal function. Of note, the hippocampus is a brain region important for learning and memory, and is also part of the limbic system, which is associated with the functions of feeling and reacting.
Importantly, and according to the press release, CMP-SCN is able to target SCN1A-NAT that is stably expressed from birth to adulthood, supporting its therapeutic effect irrespective of a patient’s age.
In a mouse model of Dravet syndrome, treatment with CMP-SCN led to an increase by 25% in the activity of the SCN1A gene. This was accompanied by a marked reduction — around 70% — of seizure frequency and duration.
“The data at AES show that CMP-SCN resulted in increased SCN1A mRNA expression both in vitro and in vivo. In a mouse disease model, treatment with a SCN1A NAT-targeting ASO led to an increase in SCN1A expression by 25%, which was accompanied by an approximately 70% decrease in the number, frequency, amplitude and duration of seizures,” said Bumcrot.
The findings were reproduced in non-human primates, where CMP-SCN also led to an increase in both SCN1A mRNA and SCN1A protein levels across four brain regions — the ependyma, temporal cortex, medulla, and the hippocampus.
The ependyma is involved in the production of the cerebrospinal fluid or CSF, which surrounds the brain and spinal cord, and serves as a reservoir for neuroregeneration. The temporal cortex is involved in the processing of sensory information, such as sounds. The medulla plays a role in regulating involuntary (autonomic) nervous system functions, which allows for unconscious bodily functions like breathing or digesting food.
“In CAMP4’s recent non-human primate study, a low dose of CMP- SCN increased SCN1A protein expression 1.5-2 fold across multiple regions of the brain,” Bumcrot said.
“Our selection of the specific regRNA target and precise ASO design are intended to enable the development of a potent, programmable and durable therapy for this devastating early-childhood epilepsy and we now have the evidence supporting this approach and facilitating progression to IND-enabling studies,” he added.