Epigenetic editing – the power of CRISPR without cutting DNA

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Epic Bio is an epigenetic editing company, leveraging the power of CRISPR without cutting DNA.

The company’s proprietary Gene Expression Modulation System (GEMS) includes the smallest Cas protein known to work in human cells. This enables in vivo or ex vivo delivery via a single viral vector. 

Epic’s lead program, EPI-321, is in IND-enabling studies for the treatment of facioscapulohumeral muscular dystrophy (FSHD). Additional programs seek to address alpha-1 antitrypsin deficiency (A1AD), heterozygous familial hypercholesterolemia (HeFH), and other indications. 

This week, we discuss epigenetic editing, why it’s reversible, and how it can treat FSHD and other conditions. Our guest is Epic Bio founder, Dr Stanley Qi, one of the original inventors of CRISPR.

About Epic Bio

The company, which was formed in 2019, is based on Qi’s work in developing better technologies and tools to modify and control the human genome beyond gene editing. 

“We’ve been very much focused on thinking how we could use these technologies to treat disease. And we have particular focus on the human epigenome, such as the epigenetic editing,” Qi said.

What is epigenetic editing?

CRISPR has been around for about a decade, with CRISPR treatments starting to be available to patients. However, Qi has found a different path.

“We’ve been working on this very different spectrum of the CRISPR, which is we do not focus on gene editing. CRISPR allows us to cut the DNA and modify the sequence on that particular site of the DNA. However, since day one, our inspiration is less about this cutting ability.”

Qi said that CRISPR acts like precise scissors, but Epic Bio is more inspired by the precision than the scissors. He added that this has led to two inventions. Beyond the gene editing applications enabled by the nuclease CRISPR–Cas9 and CRISPR–Cas12a, the invention of the nuclease-dead Cas molecules (dCas9 and dCas12a) offers a platform for the precise control of genome function without gene editing.

As an RNA-guided DNA binding platform, dCas9 was first repurposed to regulate transcription. Cas9 is a large, multi-domain protein. However, early work showed silencing the two endonuclease domains (the HNH domain that cleaves the target DNA strand, and the RuvC domain that cleaves the non-target DNA strand) in Cas9 via point mutations resulted in a nuclease-dead dCas9 that could bind to DNA. 

Using dCas9 to repress gene expression is called CRISPR interference (CRISPRi).

What is the Gene Expression Modulation System?

Qi said the core of the company’s technology to precisely modify human genetics, relies on two components. The first is a precision molecule. 

“We invented a molecule which is only a third of the size of Cas9, which makes it much easier to deliver into the cells or into the body. And the second component, which is a piece of protein, is actually an enzyme that either comes from natural human proteins or is being engineered to further improve the activity,” Qi said. 

“This enzyme will modify the chemistry on the DNA or histones associated with DNA. So, we can influence how the genes are turned on or turned off. We call it gene expression modulation because we can turn on or switch off gene expression.”

“What excites me most is it expands the scope of gene editing to treat more disease beyond simply editing the DNA sequence.”

Dr Stanley Qi, founder, Epic Bio

How is the process reversible?

Qi said that the process they are using is reversible. 

“If we think about the gene editing, we talk about modifying the gene sequence, such as by converting a single base pair, A to a G, for example, or disrupting a gene by deleting a fragment from this gene. And all these modifications are considered irreversible. 

“Being irreversible bears a big risk: if these irreversible modifications occur outside of your general interest on another site, which we call off-target, if such a thing happens, it will be very hard to remedy that. Epigenetics, by intrinsic design, either from nature or from our technology, is reversible. Because think about the chemistry on the DNA. It’s all being introduced and erased. For every single modification, like a DNA methylation, there is a writer. Meanwhile, there is an eraser. And it’s kind of like a whiteboard.”

Advancing treatments

Qi said he believes epigenetic editing is the next pillar of gene editing and gene therapy. 

“What excites me most is it expands the scope of gene editing to treat more disease beyond simply editing the DNA sequence. While gene editing can only address a smaller population of patients, can we use epigenetic editing technologies to dramatically broaden it?”

Qi cited cystic fibrosis as an example. It’s a disease caused by one gene, but there are more than 2,000 possible mutations spread across the gene, he explained. He noted that it would be necessary to develop a different modality for each mutation. In turn, this would causes issues related to clinical trials and cost.

“When we think about that, if we can use epigenetic editing, we can make it mutation agnostic, saying sure, there are a few hundred patients for each mutation, but there are 2,000 mutations, but it’s caused by one single gene. What about we use epigenetic editing to either reactivating the gene function or silencing the gene function? Then we don’t need to develop so many different modalities for individual mutations. We can design one modality targeting a region common to all the people and let this, our enzyme, the epigenetic enzyme, introduce the chemistry.” 

Treating more conditions

Qi added that the scope for epigenetic editing is huge. He said the first part of the company’s strategy is to prove the technology is safe, and that it works. The first disease the company is working on is facioscapulohumeral muscular dystrophy (FSHD). 

The goal is to tackle more conditions as the technology becomes proven. Qi said Epic Bio is both a platform technology company and also a gene therapy company

“We are providing a broad technology based on epigenetic editing. We have a pipeline for protein engineering and screening, and we also have artificial intelligence discovery pipelines in the company to discover and engineer and optimize all these epigenome editing molecules. And these technologies are probably useful even beyond the gene therapy field, for example, cancer treatments.”

To learn more about this topic:

Here are some links to more articles on the subject of epigenetics and epigenetic editing.

Explore other topics: CRISPRepigeneticsGene editing

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