The world watched on in awe as teams successfully administered a personalized gene therapy to infant KJ Muldoon (“Baby KJ”). This extraordinary achievement reignited public and scientific excitement in and around genetic medicine by bringing life-changing therapies to patients with previously incurable rare conditions. This demonstrated the power of genetic medicines and their potential for rare diseases. The remarkable impact for Baby KJ also opens up the possibilities of the potential for genetic medicines to transform, not just rare diseases, but common diseases as well.
In this article, we will explore the common myths surrounding one specific therapeutic approach that could enable genetic medicines to address common diseases: epigenetic editing. By separating the facts from fiction, we will define epigenetic editing, clearly differentiate it from other modalities, and discuss why it’s uniquely positioned to expand the reach of genomic medicine.
Derek Jantz is the Chief Scientific Officer at Tune Therapeutics.
Tune Therapeutics
Myth: Epigenetic Editing is the Same as CRISPR
The confusion with CRISPR-based gene editing is the most prevalent myth surrounding epigenetic editing.
Let’s cut through the confusion once and for all. CRISPR acts like a molecular pair of scissors, locating and snipping directly into the genome. This approach can be incredibly powerful to make a permanent correction, like fixing a single base pair mutation. However, the pathology of the vast majority of diseases is more complex than that. When a more delicate and nuanced strategy is required, CRISPR simply isn’t the right tool for the job.
While epigenetic editing uses some of the same enzymes as CRISPR, it only uses CRISPR’s targeting capabilities to home in on specific genomic regions, with no cutting involved. The slicing component of CRISPR (or other DNA-binding domains) is entirely eliminated, leaving the DNA completely intact. Instead, epigenetic editing uses another set of enzymes to change the chemical modifications adorning the DNA. These changes impact how the DNA is read and interpreted, influencing RNA expression without changing the underlying DNA itself.
Altogether, this allows epigenetic editing to flex in several ways in which CRISPR falls short. First, it reduces the inherent risks of DNA damage by leaving the underlying genetic code unaltered. Second, epigenetic editing allows for safe multiplexing—changing the expression of several genes at once. The ability to modulate gene expression across multiple genes will be critical to addressing common diseases. Data has shown that multiplexing genes with gene editing can lead to potential safety concerns. Generating multiple cuts could increase the chance of chromosomal rearrangements and genetic instability, making multiplexing with gene editing a highly risky proposition.
Myth: Epigenetic Editing is Imprecise
Another common misconception concerns the precision of epigenetic editing. This misconception is easily cleared when looking at the machinery running the engine of epigenetic editing. As described above, epigenetic editing uses the same genomic GPS system as CRISPR to find its precise DNA target, giving it nucleotide-level precision. This results in small, targeted adjustments to specific genes or regulatory regions instead of genome-wide changes. In fact, the epigenetic system is the natural way biology regulates expression across the human body. Nature requires precise, tunable changes in gene expression across cell types for proper development and to respond to environmental changes. Epigenetic editing simply co-opts this precise, natural process for a therapeutic effect.
Myth: Epigenetic Editing is a Binary System
Most genes are not defined by their simple existence but rather by the level of their expression. The etiology of many genetic conditions isn’t simply the presence or absence of a single pathological gene, but the degree to which a gene produces (or fails to produce) RNA. That means the approach to treating such conditions should address the level of RNA expressed instead of merely the absence or presence of a gene.
CRISPR-based gene editing loses the nuance of expression level. In this system, genes are either clearly all the way on or all the way off, like flipping a light switch on or off; there is no room for in between. In reality, though, RNA expression is more like a dimmer switch with varying degrees of expression influencing biology.
Epigenetic editing has the precision and flexibility to work in the gray area often missed by CRISPR. Instead of cutting and pasting genes with a pair of molecular scissors, epigenetic editing can tweak the molecules decorating the DNA to shift RNA expression. This allows teams to control the dimmer switch and shift how “brightly” genes are expressed.
Myth: Epigenetic Editing is Only Useful for Rare Diseases
This one is clearly false, but understandable. Early research on epigenetic editing focused on rare or monogenic conditions. These indications often served as a proof of concept rather than reflecting the limit of the power of epigenetic editing.
As described, epigenetic editing can change the expression of several genes simultaneously, precisely regulating complex gene networks that are the crux of many common but surprisingly complex diseases. This simultaneously wide-reaching and fine-tuned control makes epigenetic editing uniquely promising for diseases like chronic hepatitis B, cardiovascular disease, and autoimmune diseases.
Epigenetic editing represents an exciting step for medical science. It’s working to bring the promise of personalized medicine from science fiction into scientific fact and medical reality. Its level of precision and nuance could be a game changer for treating diseases that haven’t responded to current therapies. As this technology advances through the clinic, it has the potential to shift how we approach disease treatment, ultimately leading to better health outcomes.
