How Can Genetic Tuning Expand the Reach of Genetic Medicine?
By Heidi Zhang, Ph.D., Tune Therapeutics
For many years now, the scientific community has shared a vision of precision genetic medicine: one in which the rapid and comprehensive mapping of cellular information helps clinicians to create more personalized and effective treatments. Recent advances in whole-genome sequencing, bioinformatics, and multi-omics have brought us ever closer to that goal. But much work remains before the advanced genome-level data produced in academic settings are routinely integrated into clinical treatments and care.
Despite an impressive rate of progress, the present iteration of precision medicine leaves many critical patient groups entirely unaddressed. Some of its current modalities and applications are life-changing for patients with a select few conditions — namely, those with single-point mutation pathologies. But countless patients with chronic and complex diseases remain underserved. The more researchers and clinicians learn about the complexities of disease biology, the more we understand that new approaches are required to expand the range of patients treatable via genetic medicine modalities.
Epigenome editing, or genetic tuning, is just such an approach. An innovative molecular technology that fine-tunes the expression of genes to a therapeutically appropriate dosage, genetic tuning effectively expands the reach of genetic medicine beyond the binary on-and-off switches of prior methods. Here, we describe how genetic tuning works and how it can revolutionize our approach to precision medicine.
How Does Genetic Tuning Differ From Gene Editing?
The first thing to understand about genetic tuning is that it works with an entirely different substrate than its predecessors. Where gene editing works principally with protein-encoding DNA, genetic tuning works with the epigenome, a system of reversible marks on top of the genome that regulates how that foundational DNA is used. If DNA encodes the recipe book of life, then the epigenome controls which recipes and ingredients are available for active use. In other words, it determines how much of each ingredient is used and when they go into the mix. By targeting the epigenome's natural regulation network, we can change the balance of the expression of individual genes, ultimately changing the functional biology of cells, tissues, and body systems.
Genetic tuning also employs very different mechanisms of action compared to prior modalities. Traditional gene editing is a powerful tool that uses nuclease proteins to slice through the backbone of a DNA strand like a pair of molecular scissors. This mechanism can be useful for some applications — excising harmful mutations or deactivating dangerously overexpressed genes. But cutting into DNA also activates the DNA damage-and-repair response, which can cause undesirable and sometimes catastrophic side effects.
By contrast, genetic tuning is an entirely "no-cut" approach, meaning that the epigenomic agents of genetic tuning do not cut, nick, or rearrange the coding sequence of targeted DNA in any way. Instead, they bind to DNA without cutting it and use epigenetic effector proteins to regulate gene expression via the more benign and reversible processes of methylation, demethylation, and chromatin remodeling. This effectively eliminates the risk of DNA damage and the unforeseen outcomes of DNA repair in targeted cells.
A third distinction of genetic tuning as a modality is its effective outputs. Viral gene delivery and gene editing have been used for decades to create binary on-and-off effects: inserting, deleting, or rewriting target genes to yield wholesale gene silencing or overexpression. But because it leverages epigenetic mechanisms and leaves endogenous gene sequences intact, genetic tuning can create more subtle gradations of functional output, turning specific genes up or down to differing extents, as desired. In a sense, this shifts genetic medicine from a binary, all-or-nothing modality to a more analog, controllable approach.
The Potential For Genetic Tuning To Revolutionize Genetic Medicine
So how might these unique attributes and outputs of genetic tuning translate into broader clinical reach and impact? Perhaps most obviously, it widens the net of treatable conditions — from typically rare diseases involving single-gene point mutations to more common, complex multigenic conditions. As the pioneers of nuclease-based gene editing have already demonstrated, it can be incredibly successful in conditions where individual genes require excision or replacement, like Leber congenital amaurosis and sickle cell anemia. But on a proportional scale of global disease prevalence, the vast majority of patients suffer from more complex and multifaceted diseases, which current precision medicine approaches cannot serve.
With new targets, new mechanisms, and greater capacity for control, genetic tuning is expanding the reach of gene therapy to target these more common and complex disease settings.
One pivotal attribute here lies in its powerful multiplexing capabilities. The etiology of many diseases, from cancer to heart disease, is a complex system of interconnected genes. Tackling these complex pathologies requires a strategy that can effectively target multiple genes or regulatory sequences simultaneously and without risking chromosome breaks or rearrangements. In data shared at the recent ASGCT conference, Tune scientists demonstrated the ability to do this with multiple genes involved in T cell function and proliferation.
Which brings us to the second path to impact: the enhancement of existing cell therapeutics. Cell therapies are powerful therapeutic applications that use engineered cells as biological drugs and have found great success in clinical oncology, notably in the form of CAR T cells. But producing precise, efficient, and functional cell therapies via gene editing has proven challenging, as cell therapies are highly complex and require the careful balance of multiple factors.
With its capacity for multiplexing genes and gene networks, genetic tuning could change all this. With new and unparalleled control over multiple gene outputs, cell therapy developers could fine-tune their biological therapeutics for enhanced functional performance, bringing cell therapies into a new clinical era.
Finally, genetic tuning has the potential to bridge the gap between cutting-edge knowledge in genomics and bioinformatics and the creation of effective precision medicines. As the scientific community moves forward in learning more about genetic and epigenetic function and dysregulation, we will naturally seek to translate that knowledge into more specific and effective therapies. But understanding the relationships between genome structure and cell behavior and function is an endlessly complex undertaking. Thus far, current approaches for studying genomic structure and function have proven insufficient. Here again, genetic tuning can help us reimagine what is possible. With the powerful functional screening tools it provides, we can use genetic tuning to comprehensively screen the form and function of any genomic region of interest. We can quickly identify the critical regulators of gene expression and use these as new targets in designing novel treatments.
Viewed in totality, we can see that genetic tuning has the potential to transform the entire field of precision genetic medicine — pushing the envelope on the diseases we consider treatable, empowering existing cell and gene therapies with greater accuracy and efficacy, translating cutting-edge academic knowledge into clinical potential, and ultimately improving patient outcomes.
About The Author:
Heidi Zhang, Ph.D., is the executive vice president and head of technical operations at Tune Therapeutics. She is a seasoned scientific executive who has led global teams across a range of biotech and pharma companies, including Juno Therapeutics, Genentech, Novartis, and Amgen. Prior to Tune, Zhang was the vice president of cell therapy product & analytical development at Bristol Myers-Squibb. She has led commercial launches of numerous lifesaving medicines, including recent cell therapies Abecma and Breyanzi.