Gene silencing: A potential new treatment for rare disease

What if we could control a genetic disorder by turning its effects down or completely off, much like reducing a lighting system’s brightness by pulling down a dimmer switch?

That is essentially how some genetic diseases are being treated: by turning off or silencing the faulty genes responsible, therefore halting or even reversing the damage they cause.

Gene silencing, a recent technology, uses precisely engineered medicines that block the harmful impact of mutated genes and prevent unwanted side effects patients may be unable or unwilling to tolerate. Gene silencing has already advanced from concept to a fast-growing field with a handful of approved drugs and scores more in patient and preclinical testing. The trend has even been dubbed the “RNAissance”.

What is gene silencing?

This technology involves using messenger RNA, a type of ribonucleic acid that copies instructions for making proteins from our DNA, then transfers that recipe from inside each cell’s nucleus to the protein factory in the surrounding cytoplasm. If the DNA is mutated, faulty messenger RNA, or mRNA, can result. That mRNA, in turn, can instruct cells to make too many proteins or ones that do not work correctly, causing disease.

Gene silencing mimics a natural process called RNA interference, RNAi for short, that can defend against viruses, clear up DNA mutations and adjust the level of, or even stop protein production.

To create a gene-silencing drug, synthetic RNA strands are cut into tiny pieces called small interfering RNA, or siRNA. These siRNAs are then linked to a cluster of sugars that functions as a homing device carrying siRNA to the desired cell, known as a GalNAc ligand.

Once injected into the bloodstream, the siRNA therapy pinpoints and binds to the disease-causing mRNA and destroys it. This blocks or reduces production of the faulty protein, so cells can return to a healthy state.

Targeted, effective therapies

For siRNA therapies currently approved or in testing, the target area is cells inside the liver. That’s because of our roughly 30,000 genes, about 14,000 of which are expressed in the liver, meaning that is where the genes are turned on and can direct cells to make RNA and proteins.

Besides the benefits of precise targeting, gene-silencing drugs work for months, so patients may only need one or two treatments annually.  Also, gene silencing’s effects are neither permanent nor passed on to offspring.  Should a problem surface, simply stopping the treatment stops those effects, unlike with gene therapy.

For companies in the gene-silencing space such as Silence Therapeutics, creating precisely engineered, targeted drugs provides confidence they will be safe and do exactly what is intended, even before patient testing begins.

Experience in testing gene-silencing therapies so far shows about half the molecules that successfully conclude Phase I trials also succeed in Phase III. In contrast, the Phase III success rate is just nine percent for small-molecule drugs such as pills, because it is hard to predict which tissues they will enter or what side effects they will cause.

A treatment for rare diseases

Gene silencing, or RNA interference, can potentially treat many disorders caused by defective genes, but a large impact could be in treating patients most in need – those with rare genetic disorders.

Treatments only exist for about five percent of the approximately 7,000 known rare diseases. That leaves millions of people worldwide with a rare, potentially fatal disease with no treatment and little hope.

Several factors are to blame for this. Many genetic disorders have been considered undruggable, meaning they cannot be treated by small-molecule drugs or injected biologic ones. The huge cost and lengthy timeline typical for developing a therapy for a genetic disorder make it difficult to recoup that investment when so few patients need that treatment. Some genetic diseases are poorly understood and there is not enough money going into basic research of their biology.

Using gene silencing to treat rare genetic disorders can overcome those hurdles, particularly in reducing development costs. Creating gene-silencing therapies for rare genetic diseases caused by multiple gene mutations will be more challenging, however.

Future prospects for gene silencing

The first generation of gene silencing therapies has proven the technology’s vast potential, for both common and rare genetic disorders. Now pharmaceutical and biotech companies are working on expanding gene silencing’s use to more conditions, as well as finding ways to improve its precision.

For instance, Silence Therapeutics is using human genetic databases and technology such as artificial intelligence and computer simulation for target “de-risking” – determining whether gene silencing could target one gene to treat a particular disease without affecting other systems or causing side effects, improving chances of its success.

Silence is developing many siRNA therapies, but there are two currently in human clinical trials. SLN360 is in Phase I and is progressing into Phase II, being studied for individuals with elevated levels of high lipoprotein(a), also known as Lp(a). This is a genetically determined cardiovascular risk factor affecting one in five people. It puts them at increased risk of premature heart disease, heart attack or stroke as well as aortic valve narrowing. The therapy is meant to silence the LPA gene, to reduce levels of Lp(a) and the associated cardiovascular risk.

SLN124 is being studied for two rare, genetic blood disorders. It has completed a Phase I study in healthy volunteers and now is in a larger Phase I study of people with non-transfusion-dependent thalassemia. We also plan to start a clinical trial in polycythemia vera – a disease in which too many red cells are produced resulting in increased likelihood of clotting disease.

Any disease caused by a gene primarily expressed in the liver, or roughly 14,000 genes, potentially can be treated by siRNA therapies, yet barely one percent are being targeted by drug developers. That leaves significant opportunity.

The next, and likely greater, challenge will be figuring out how to deliver siRNA therapies to tissue outside the liver, because scientists will need to create a tool as good as the GalNAc ligand that can precisely deliver an attached siRNA molecule to the target tissue – and nowhere else.

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