New Gene Silencers Offer Hope for Hereditary Blood Disorders

According to a recent study, chemical tags previously thought of as genetic clutter are potent gene silencers; eliminating them could lead to safer treatments for hereditary blood disorders.

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In addition to providing a safer means of treating genetic diseases like sickle cell disease, a new version of CRISPR technology created at UNSW Sydney demonstrates that chemical tags on DNA, which are sometimes dismissed as little more than genetic cobwebs, actively mute genes.

Scientists have debated for decades whether methyl groups, small chemical clusters that build up on DNA, are the real source of gene suppression or just debris that builds up in the genome where genes are disabled.

However, in a recent study published in Nature Communications, researchers at the University of New South Wales, in collaboration with colleagues in the US at the St Jude Children’s Research Hospital, have demonstrated that deleting these tags can turn genes back on, proving that methylation is not only associated with silencing but also directly causes it.

We showed very clearly that if you brush the cobwebs off, the gene comes on, and when we added the methyl groups back to the genes, they turned off again. So, these compounds aren’t cobwebs – they are anchors.

Merlin Crossley, Study Lead Author and Professor, University of New South Wales

A Brief History of CRISPR

Clustered Regularly Interspaced Short Palindromic Repeats, or CRISPR, are the building blocks of gene-editing technology. This technology enables researchers to identify and alter damaged DNA segments frequently by substituting them with healthy ones.

It utilizes a naturally occurring technique, initially identified in bacteria fending off invading viruses by ‘snipping’ the viral DNA strands.

The first generation of CRISPR lab equipment operated this way, cutting DNA sequences to silence defective genes. The second generation enabled researchers to zoom in and repair specific letters in the genetic code. However, both procedures require cutting the genetic code, which carries the danger of unintended modifications that might lead to additional health issues.

However, the third generation, known as epigenetic editing, examines the surface of genes in the nucleus of all cells in the body. Instead of cutting DNA strands to delete or alter defective genes, this approach removes methyl groups from quiet or suppressed genes.

Sickle Cell Diseases

According to the researchers, epigenetic editing might be used to treat people suffering from Sickle Cell Disease, which is caused by genetic abnormalities that change the form and function of red blood cells, resulting in persistent discomfort, organ damage, and a shorter life span.

Crossley added, “Whenever you cut DNA, there’s a risk of cancer. And if you’re doing a gene therapy for a lifelong disease, that’s a bad kind of risk, but if we can do gene therapy that doesn’t involve snipping DNA strands, then we avoid these potential pitfalls.”

Instead of cutting, the new technique uses a modified CRISPR system to deliver enzymes that remove methyl groups from DNA, thus removing the brakes on silent genes. The fetal globin gene is essential for providing oxygenated blood to a developing fetus in utero, and the researchers believe that turning it back on after delivery might offer a simple workaround for the malfunctioning adult globin gene that causes Sickle Cell disease.

“You can think of the fetal globin gene as the training wheels on a kid’s bike. We believe we can get them working again in people who need new wheels,” added Merlin Crossley.

The Big Picture

So far, all efforts to accomplish this have been conducted in a lab on human cells in a test tube at UNSW and Memphis.

According to study co-author Professor Kate Quinlan, the discovery is hopeful not only for people with Sickle Cell disease but also for other genetic diseases in which turning certain genes on or off by modifying the methyl groups saves the need to cut DNA strands.

We are excited about the future of epigenetic editing as our study shows that it allows us to boost gene expression without modifying the DNA sequence. Therapies based on this technology are likely to have a reduced risk of unintended negative effects compared to first or second generation CRISPR.

Kate Quinlan, Study Co-Author and Professor, University of New South Wales

In a few years, once animal testing and clinical trials are completed, doctors can employ this new method to treat sickle cell disease. The method will begin by harvesting some of the patient's blood stem cells, producing new red blood cells.

In the lab, scientists would utilize epigenetic editing to remove the methyl chemical tags from the fetal globin gene, reactivating it. The modified cells are then returned to the patient, settling back into the bone marrow and producing better-functioning blood cells.

The Road Ahead

Next, UNSW and St Jude researchers will assess these techniques' efficiency in animal models and explore other CRISPR-related technologies.

“Perhaps the most important thing is that it is now possible to target molecules to individual genes,” added Prof. Crossley.

“Here we removed or added methyl groups but that is just the beginning, there are other changes that one could make that would increase our abilities to alter gene output for therapeutic and agricultural purposes. This is the very beginning of a new age,” concluded Prof. Crossley.