Many Shades of Grey: Nuanced Treatments for Genetic Disease

The following article is an opinion piece written by Charles Gersbach. The views and opinions expressed in this article are those of the author and do not necessarily reflect the official position of Technology Networks.

For decades now, we have all seen news articles proclaiming the “beginning of the end” of genetic disease. Such stories have accompanied every major milestone in genetic research for the last 35 years – from the discovery of the genetic basis of cystic fibrosis in 1989, through the Human Genome Project in the 1990s, to the more recent arrival of CRISPR for precision gene editing.

In support of this view, the gene therapy field has made impressive progress in the treatment of single-gene disorders such as sickle cell disease and Hemophilia A. There are now well over 100 companies actively developing and testing gene therapies for a broad range of cancers, autoimmune diseases and neurological disorders.

Yet human biology remains painfully complex, and it is fair to say we have not yet seen the dramatic full-scale revolution in medicine that has so long been the promise of genetic therapeutics.  

Then again – perhaps the best is yet to come.

Strengths and limitations

Nuclease-based gene editing was – and still is – an incredible scientific breakthrough. It essentially gives scientists a pair of molecular scissors, allowing us to cut, edit and replace targeted genes with a degree of specificity that could scarcely be imagined by 20^th century genetic engineers. This mechanism has unlocked new potential in many fields, including medical diagnostics, agriculture and biofuel production.

But on a practical level, the therapeutic impact of gene editing has thus far been limited to single-gene disorders with fairly simple, straightforward mechanisms. Wherever the sole cause of disease can be addressed by manipulation of a single genomic target – as is the case with sickle cell disease – why not try to edit or remove that sequence?

Unfortunately, the most prevalent diseases in modern populations – including most autoimmune disorders, cardiovascular diseases and neurodegenerative conditions – are not caused by DNA mutations in simple, single-gene systems. In fact, many do not involve changes to gene sequence at all. Rather, they result from changes to gene output (or gene expression) in otherwise healthy genes. And more often than not, these expression changes involve not one gene, but multiple genes – acting within complex, interdependent networks.

So, if we are to fully realize the potential of genetic medicine, we need more nuanced tools that can modulate or fine-tune gene expression. Enter epi-genome editing, and the concept of genetic tuning.

Switches vs dimmers

Gene editing treats the genome like a series of light switches, where beneficial genes that were turned off by mutation can be corrected and reilluminated, or active, disease-causing genes can be edited so they are permanently turned off.

But the vast majority of human biology is actually controlled by a complex set of dimmer switches, with different genes expressed in distinct cell types, with varying degrees of intensity across the span of our lives. This places a practical limit on how many diseases we can target and treat with this binary, on/off approach.

By contrast, genetic tuning targets the more subtle “dimmer switches” of the epigenome – producing gradients of output and effect that can be fine-tuned as desired. In effect, it leverages the epigenome to regulate the production (or transcription) of RNA molecules, which in turn dictate the balance and activity of proteins within the cell.

Genetic tuning does this via a series of reversible chemical marks on top of the DNA that nature has evolved to dictate RNA expression. These marks and tags effectively control which genes are open and accessible for transcription, and which are inaccessible and packaged away. Orchestrating these naturally occurring conductors of gene expression can therefore shift the functional states of cells and rebalance gene expression towards health.

This represents a huge advance in the application of genetic medicine, as it allows for fine-graded levels of transcriptional change, as opposed to all-or-nothing gene knockouts or the forced overexpression of specific genes – both of which can cause their own problems.

With this newfound precision and flexibility, we can turn our attention to treating common and complex diseases that require expression shifts within narrow therapeutic windows, or the coordinated tuning of multiple genes at once.

Where we stand

The feasibility and effectiveness of genetic tuning have already been shown in several distinct settings, including early clinical trials. In academic research, epigenetic editing primes CAR T-cell therapies for successful tumor-clearing, and epigenetically upregulating the expression of tumor-associated antigens is used in mice to craft personalized mammary cancer treatments. Others are using the power of the epigenome to tackle the obesity epidemic, diabetes and infectious diseases.

CRISPR Technology: How Far Have We Come?

This infographic explores the history, breakthroughs and future directions of CRISPR-Cas systems, highlighting their transformative role in gene editing and personalized medicine
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Across the spectrum of human health genetic tuning is moving rapidly toward practical application. And thanks to the CRISPR gene editing goldrush, many shared components of the epi-editing workflow are already in place – such as precision DNA-binding proteins, rapid RNA manufacturing methods and targeted lipid nanoparticles (LNPs) for delivering epi-editing constructs to cells and tissues.

Based on the rapid pace of the genetic medicine industry, we anticipate genetic tuning will have a transformative impact on the clinic in the immediate future.

A new future for genetic medicine

As we transition into a world where gene tuning becomes commonplace, we can look forward to a near future where we can regulate the expression of multiple genes simultaneously. This capacity for multi-gene targeting – known in gene therapy as multiplexing – will be critical to successfully treating complex yet common diseases such as Alzheimer's and Parkinson's disease.

Multiplexing opens the door to controlling not just single protein levels, but the identity and behavior of an entire cell. Early experiments have already shown that by turning the right dials at the right times, we may be able to partially reprogram cells into a more functional and vibrant form of themselves – reviving or replacing cells lost to cancer, fibrosis, or degenerative brain disease.

While genetic medicine has made substantial technical progress, the path from promising lab results to widespread clinical application remains challenging. To push forward, we must systematically address the lingering limitations of delivery technology and our understanding of complex genetic networks.

Nevertheless, the expanding repertoire described here shows that we are driving steadily toward more versatile and effective genetic therapies for previously untreatable conditions – which can only be good news for patients.