Genetic Tuning: The Next Frontier of Genetic Medicine

Genetic medicine is getting a major tune-up. Recent advancements in genomics, bioinformatics and molecular biology are laying the foundation for a new era in precision genetic medicine – in which cellular and genomic information about disease will be incorporated into clinical care.

The scientific and medical communities have taken significant steps toward this vision, but critical gaps remain before patients receive the level of integrated care they deserve. Specifically, genetic medicine requires tools with more control over the level and duration of gene expression and the ability to target and regulate more than one gene at a time. Only then can we treat highly prevalent, complex diseases and develop cell therapies with more significant clinical benefit.

In this article, we describe genetic tuning, which is also known as epigenome editing – a powerful and sophisticated therapeutic approach that allows for unprecedented levels of control over gene regulation. We explain how genetic tuning differs from gene editing and other modalities of genetic medicine and describe how the ability to fine-tune genes will transform precision medicine.

What is genetic tuning?

Almost every cell in the human body contains the same set of 46 chromosomes and an identical collection of DNA sequences which together comprise the genome of that individual. Yet different cell types clearly possess diverse gene regulation patterns. This, after all, is what differentiates nerve cells from blood cells, muscle cells from bone cells.

Simply put, the epigenome is a system of reversible marks that lies outside or atop the DNA-based genome (hence, “epi-genome”). It regulates DNA structure and function, creating a diverse array of cell types from a single, genetic template.

Genetic tuning works in concert with this natural epigenetic machinery, by controlling which regions of the DNA are open for active use (via the processes of transcription into RNA) and which regions are packaged away and inaccessible. By selectively activating or repressing gene transcription, it is possible to shift the functional state of cells in therapeutically beneficial directions.

How is genetic tuning unique?

The unique distinctions of genetic tuning can best be understood in comparison to other modalities, such as nuclease-based gene editing. While genetic tuning and nuclease-based gene editing rely on similar enzymes to hone in on target DNA, the two approaches work quite differently once they arrive at the target sequence site.

Gene editing does almost exactly what you would expect from the name: it cuts, removes or replaces specific sections of DNA (ranging from individual nucleotide bases to entire genes) in order to knock out faulty or mutated genes, editing or replacing them completely. Gene editing can be highly successful in creating binary on-off switching and silencing in specific genes. But it struggles where more nuanced changes to expression are required.

Genetic tuning takes a more subtle approach, effectively replacing the switch with a dial.

By regulating the epigenome through a selection of enhancer sequences and effector proteins, genetic tuning can direct a wide spectrum of effects on gene expression – from transient activation to sustained repression.

This allows developers to fine-tune RNA output within a desired window of therapeutic effect, avoiding the perils of harmful over- or under-expression. And because genetic tuning is a “no-cut” mechanism, it can do all of this with no risk of damage to the underlying DNA.

How do these differences relate to precision medicine?

Gene editing has already shown great potential for diseases that wholesale gene excision or replacement treats, such as Leber congenital amaurosis and sickle cell anemia.

But many highly prevalent conditions are caused by a complex web of distinct genes and transcriptional interactions. These conditions require a multiplexing approach – targeting multiple genes or regulatory sites simultaneously to achieve a useful outcome.

This can, of course, be attempted with gene editing. But every cut compounds the risk of DNA damage, improper DNA repair and harmful chromosome translocations.

Because it does not cut DNA at all, genetic tuning eliminates the risk of introducing harmful genomic instability via multiple, double-stranded DNA breaks. This gives genetic tuning unprecedented multiplexing capabilities, dramatically expanding the reach of precision medicine into more complex, multigenic diseases.

Genetic tuning also holds the potential to enhance and expand the impact of existing cell and gene therapies. Cell and gene therapies are powerful therapeutics that use biology itself as medicine. In the case of cell therapies, such as CAR-T cell and immunotherapies, living cells are modified and (re)introduced for therapeutic effect. In gene therapy, the expression or genetic components of cells are altered, either in vivo or ex vivo, to correct genetic diseases.

Genetic tuning could help produce new cell therapies via multiplexed gene regulation, and by controlling the differentiation of desired cell types. This could relieve a key bottleneck in cell therapy manufacturing, in which production pipelines require several sequential edits – each lowering the quality of the resultant cell product.

The future is here

These innovations are not rapidly approaching – they are already on our doorstep.
At the American Society of Gene and Cell Therapy conference 2023, data was presented that indicated genetic tuning can be employed to achieve durable suppression of a therapeutically relevant gene (PCSK9) in non-human primates – with just a single dose of an epi-editing agent. Although the epi-editor itself was only present for a few days, the repressive effect has persisted in the test subject for more than 11 months and is still ongoing. Since then, the enhanced, tumor-killing effect of tuning multiple epigenetic sites simultaneously in T cells has also been demonstrated, along with breakthrough preclinical data supporting a potentially curative approach to treating chronic Hepatitis B virus (HBV) infection.

These, and other examples from the field, demonstrate that genetic tuning is moving rapidly toward practical, clinical application. With its unparalleled capacity for multiplexing and fine control of gene networks, genetic tuning is set to transform the development and application of cell and gene therapy. We can confidently look forward to a (very near) future where these transformative solutions find their way to the patients who need them most.

About the author:

Derek Jantz is chief scientific officer at Tune Therapeutics. A veteran entrepreneur with deep expertise in developing cell and gene therapeutics, Dr. Jantz was previously CSO at Precision Biosciences – a company he co-founded in 2006. There, he led the development of allogeneic CAR T and in vivo editing platforms and served on the board of directors.

He holds more than 50 patents relating to gene editing, gene therapy and cancer immunotherapy, and authored more than a dozen gene-editing publications. Dr Jantz has a PhD in biophysical chemistry from Johns Hopkins University School of Medicine and conducted his postdoctoral work at Duke University.