Revolutionary Approach to Treating Genetic Disease

This month, therapy for human genetic disease entered a new era.

In Dravet syndrome, a defective gene causes insufficient production of a needed protein product, leading to seizures by age one year and high risk of sudden unexpected death in epilepsy (SUDEP). Treatments to control these seizures have limited success; Dravet syndrome became the first disease for which the FDA approved the use of cannabidiol to reduce symptoms ( https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-comprised-active-ingredient-derived-marijuana-treat-rare-severe-forms ).

Earlier this month, a patient with Dravet syndrome received the first dose of a novel treatment which may improve patient well-being by pushing cells to make more of the deficient gene product, but without actually having to replace or repair the mutant gene itself.

The new medicine is called STK-001, designating its number one status in this pioneering approach to treating genetic diseases. STK-001 is also the first clinical treatment by Stoke Therapeutics, a biotechnology company founded to create medications based on this new paradigm.

“We are announcing that the first patient has been dosed with STK-001, which we believe has the potential to be the first-disease modifying medicine for Dravet syndrome, a severe and progressive genetic epilepsy that is characterized by developmental delays and cognitive impairment, in addition to seizure activity,” said Edward M. Kaye, M.D., Chief Executive Officer of Stoke Therapeutics. This “also marks Stoke’s official transition to a clinical-stage biotech company.”

What’s Going On?

To understand how the new treatment approach works, I had to review some molecular biology.

Cell DNA sends its recipe for making proteins to the ribosome assembly lines via a messenger, appropriately named messenger RNA. The mRNA recipe is basically a scroll of ingredients, to be read and transcribed in a particular order. Every so often, the recipe code is interrupted with non-recipe information — in simplified terms, we have the protein-coding portions (called exons) and the interruption portions (introns).

To make a protein, the interruption portions of the code have to be removed, and the remaining recipe portions connected together. Basically, the introns are snipped out and then the exons spliced back in order.

Some additional terminology: the pre-spliced recipe before the introns have been snipped out is called precursor-mRNA or pre-mRNA; the post-spliced, exon-only recipe is called mature mRNA.

What’s the purpose of the intron interruption areas? Some of the introns serve as stop and start signs, which help keep the assembly lines from making too much or too little of a given recipe ingredient. However, with all the snipping and slicing going on to convert a precursor-mRNA into a mature mRNA, sometimes the translation machinery fouls up, producing “nonsense” recipes. In fact, more than one third of alternative splicing events in mammals do not produce functional proteins. These messed-up mRNAs end up getting broken down and recycled; in other words, a lot of mRNA degradation occurs in through nonsense-mediated mRNA decay (NMD).

So, what’s going on in Dravet syndrome? In Dravet (a dominantly inherited disease), one parent’s recipe for a particular protein is completely messed up and can’t produce any functionally useful gene product. The other parent’s recipe is normal, but since the child has only one copy of this properly functioning gene, not enough gene product is produced to meet the child’s cellular needs.

Essentially, the cell is starving for more gene product, which in Dravet syndrome happens to be a particular protein called NaV1.1., a sodium channel found on the surface of nerve cells which facilitates electrical signaling in the brain.

How did Stoke Therapeutics seek to solve this problem? By turning off the “off” signals.

Care to TANGO?

According to Barry Ticho, Stoke Therapeutic’s Chief Medical Officer, “We synthesize small fragments of modified RNA, known as antisense oligonucleotides (ASOs), that are designed to bind to specific stretches of pre-mRNA.”

The ASOs are tools which remove regions present in mRNA that signal the cell to degrade the mRNA. After splicing off that “stop” region, the ASO falls off the scroll and the cell can crank up its gene product making machinery.

The process of using ASOs to rev up the cell’s naturally-occurring protein making machine is abbreviated TANGO — for Targeted Augmentation of Nuclear Gene Output. I guess more accurately, TANGO removes the protein-making brakes rather than flooring the accelerator.

“Preclinical studies have shown that application of our ASO therapy reduces the synthesis of non-productive mRNA and increases the synthesis of productive mRNA,” Ticho notes. “The increased levels of productive mRNA from the functional copy of the gene result in increased protein production, thereby restoring the target protein to near normal levels.”

TANGO does its work without actually changing the patient’s own DNA, as occurs with other gene therapy approaches ( https://dravetsyndromenews.com/2020/05/19/gene-therapy-shows-promise-in-mouse-model-of-dravet-syndrome/#:~:text=Gene%20therapy%20has%20the%20potential,restore%20the%20levels%20of%20NaV1 ).

Stoking future treatments

Dravet syndrome only affects a few thousand patients, and the current study will require prolonged follow-up to establish safety and efficacy. But, for these families TANGO offers some hope of improved quality and perhaps duration of life.

Excitingly, the treatment approach for Dravet may be useful for a variety of similar recessively inherited diseases, including propionic acidemia and autosomal dominant mental retardation. As an ophthalmologist, I was intrigued to read that TANGO-based treatments are being considered for certain forms of ocular inflammation (autoimmune uveitis), Autosomal Dominant Optic Atrophy (ADOA), as well as macular degeneration.

“Stoke was founded on the idea that we could use unique insights in RNA biology to do something that has never been done before,” said Isabel Aznarez, Ph.D., Co-Founder and Vice President, Head of Biology of Stoke Therapeutics. “Rather than address genetic diseases by replacing, repairing or editing faulty genes, we set out to increase – or stoke – protein output from healthy genes. These data show that we can increase full-length, fully functional protein expression from a variety of healthy genes, which supports our hypothesis and may lead to a new way of treating severe genetic diseases.”

You recognized the last name of Stoke Therapeutic’s Chief Medical Officer? Oh, he’s my oldest brother, pushing the boundaries of science to help stamp out suffering and disease. Yeah, I’m kind of proud of him.

Benjamin H. Ticho, MD