The seizures began when Samantha Gundel was simply 4 months outdated. By her first birthday, she was taking a cocktail of three totally different anticonvulsant medicines. A vicious cycle of recurrent pneumonia, spurred on by seizure-induced inhalation of regurgitated meals, landed the younger toddler out and in of the hospital close to her Westchester County residence in New York State.
Genetic testing quickly confirmed her medical doctors’ suspicions: Samantha, now age 4, has Dravet syndrome, an incurable type of epilepsy. Her mind was misfiring due to a mutation that’s in contrast to these liable for most genetic illnesses; it’s a sort that has lengthy eluded the potential of correction. Accessible medicine may assist alleviate signs, however there was nothing that might tackle the foundation reason behind her illness.
That’s as a result of the mutation on the coronary heart of Dravet creates a phenomenon often called haploinsufficiency, through which an individual falls in poor health if they’ve solely a single working copy of a gene. That lone gene merely can’t produce sufficient protein to serve its molecular objective. Within the case of Dravet, that implies that electrical signaling between nerve cells will get thrown out of whack, resulting in the sorts of neuronal shock waves that set off seizures.
Most genes aren’t like this. Although the human genome incorporates two copies of just about each gene, one inherited from every guardian, the physique can usually do high-quality with only one.
Not so for genes similar to SCN1A, the principle perpetrator behind Dravet. For SCN1A and hundreds of other known genes like it, there’s a fragile stability of molecular exercise that’s wanted to make sure correct perform. Too little exercise is an issue — and oftentimes, so is too much.
This Goldilocks paradigm partially explains why typical gene remedy methods are ill-suited to the duty of haploinsufficiency correction. With therapies of this sort — several of which are now available to deal with “recessive” genetic illnesses such because the blood dysfunction beta thalassemia and a type of inherited imaginative and prescient loss — the quantity of protein made by an launched gene simply must cross a minimal threshold to undo the illness course of.
In these contexts, it’s not an issue if the added gene is overactive — there’s a ground, however no ceiling, to therapeutic protein ranges. That’s merely not the case with many dosage-sensitive illnesses like Dravet, particularly for mind problems through which an excessive amount of protein can overexcite neuronal exercise, says Gopi Shanker, who served as chief scientific officer of Tevard Biosciences in Cambridge, Massachusetts, till earlier this 12 months. “That’s what makes it tougher,” he says.
Including to the problem: The particular forms of modified viruses which might be used to ferry therapeutic genes into human cells can deal with solely a lot additional DNA — and the genes on the coronary heart of Dravet and plenty of associated haploinsufficiency problems are a lot too massive to suit inside of those supply autos.
Neglected no extra
Confronted with these technical and molecular hurdles, the biotechnology trade lengthy ignored haploinsufficiencies. For greater than 30 years, firms jostled to get a chunk of the drug growth motion in different areas of uncommon genetic illness — for cystic fibrosis, say, or for hemophilia — however situations like Dravet acquired brief shrift. “It’s one of the vital uncared for lessons of dysfunction,” says Navneet Matharu, cofounder and chief scientific officer of Regel Therapeutics, based mostly in Berkeley, California, and Boston.
Not anymore. Because of new therapeutic concepts and a greater understanding of illness processes, Regel, Tevard and a gaggle of different biotech startups are taking purpose at Dravet, with experimental remedies and applied sciences that they are saying ought to function testing grounds for going after haploinsufficiency illnesses extra broadly.
Presently, there’s little to supply sufferers with these maladies apart from medicine to help with symptom management, says Kenneth Myers, a pediatric neurologist at Montreal Kids’s Hospital who cowrote an article about emerging therapies for Dravet and comparable genetic epilepsies within the 2022 challenge of the Annual Evaluate of Pharmacology and Toxicology. However because of new advances, he says, “there’s an enormous purpose for optimism.”
Samantha, for one, now appears to have her illness below management due to a drug known as STK-001; it’s the first ever to be evaluated clinically that addresses the foundation reason behind Dravet.
Between February and April 2022, medical doctors thrice inserted an extended needle into the younger woman’s decrease backbone and injected the investigational remedy, which is designed to bump up ranges of the sodium-shuttling protein whose deficiency is liable for Dravet. It appeared to work. For a time, Samantha lived almost seizure-free — presumably as a result of the elevated protein ranges helped appropriate electrical imbalances in her mind.
She went from epileptic assaults each 7 to 10 days, on common, to nothing for months on finish. Her verbal expertise improved, as did her bodily capabilities. Her gait improved and her tremors disappeared.
Finally, because the remedy wore off, Samantha started to backslide, with seizures returning each couple of weeks or so. However she began receiving extra doses of STK-001 below a brand new trial protocol in October 2022, and since then has skilled solely two epileptic episodes over the span of six months. “It’s actually fairly superb,” says her mom, Jenni Barnao.
“Is it a treatment? No.… However that is completely our greatest shot,” Barnao says. “There’s positively one thing with this drug that’s excellent. Her mind is simply working higher.”
Give a lift
The STK-001 therapy depends on the truth that the conventional exercise of genes is considerably inefficient and wasteful. When genes get decoded into mRNA, the ensuing sequences require additional chopping and splicing earlier than they’re mature and able to function guides for making protein. However usually, this course of is sloppy and doesn’t lead to usable product.
Which is the place STK-001 is available in.
A type of “antisense” remedy, STK-001 consists of brief, artificial items of RNA which might be tailored to stay to a part of the SCN1A gene transcript and, because of this, make productive chopping and splicing extra environment friendly. The artificial items glom on to mRNA from the one working model of the gene that individuals with Dravet have and assist to make sure that undesirable bits of the mRNA sequence are spliced out, simply as a film editor may lower scenes that detract from a movie’s story. Consequently, extra useful ion channel protein will get made than would in any other case occur.
Protein ranges don’t get fully again to regular. According to mouse studies, there’s a 50 p.c to 60 p.c increase, not a full doubling of the related protein within the mind. However that bump appears to be sufficient to make an actual influence on sufferers’ lives.
Stoke Therapeutics, the corporate in Bedford, Massachusetts, that’s behind STK-001, reported on the American Epilepsy Society’s 2022 Annual Assembly that 20 of the primary 27 Dravet sufferers to obtain a number of doses of the remedy in early trials skilled reductions in seizure frequency. The best advantages have been noticed amongst younger youngsters like Samantha whose brains have collected much less injury from years of debilitating seizures and irregular cell perform. Bigger confirmatory trials that might result in advertising approval are scheduled to start subsequent 12 months.
Stoke is hardly alone in its quest to repair Dravet and haploinsufficiency problems extra usually. A number of different biotech startups are nearing scientific trials with their very own technological approaches to enhancing what working gene exercise stays. Encoded Therapeutics, for instance, will quickly start enrolling members for a trial of its experimental Dravet remedy, ETX-001; it makes use of an engineered virus to deliver a protein that ramps up SCN1A gene activity in order that many extra mRNA copies are product of the one, useful gene.
And if any of those firms reach reversing the course of Dravet, their applied sciences may then be tailored to tackle any comparable illness, says Orrin Devinsky, a neurologist at NYU Langone Well being who works with a number of of the companies and is concerned in Samantha’s care. “An efficient remedy would supply a possible platform to handle different haploinsufficiencies,” he says.
(Credit score:Knowable Journal)
Corporations are engaged on quite a lot of approaches for treating Dravet syndrome. The identical strategies could possibly be utilized to different haploinsufficiency illnesses.
New targets, new ways
Stoke will quickly put that concept to the take a look at.
Buoyed by the early promise of its Dravet therapeutic, the corporate developed a second drug candidate, STK-002, that equally targets splicing to show nonproductive gene transcripts into constructive ones. However on this case, it’s designed to deal with an inherited imaginative and prescient dysfunction often called autosomal dominant optic atrophy, brought on by haploinsufficiency of a gene known as OPA1. On this illness, a single working copy of OPA1 isn’t sufficient to maintain correct nerve signaling from the eyes to the mind.
Medical analysis of STK-002 is anticipated to start out subsequent 12 months. In the meantime, in partnership with Acadia Prescribed drugs of San Diego, Stoke can also be exploring treatments for Rett syndrome and SYNGAP1-related mental incapacity, each extreme mind problems brought on by inadequate protein ranges.
Stoke’s splice-modulating method flows naturally from the success of one other antisense drug, Spinraza. Developed by Ionis Prescribed drugs in collaboration with Biogen, Spinraza additionally works on splicing of mRNA transcripts to advertise manufacturing of a lacking protein. In 2016, it grew to become the primary remedy authorized for treating a uncommon neuromuscular dysfunction known as spinal muscular atrophy (SMA).
SMA is considerably totally different, although. It isn’t a haploinsufficiency — it happens when each gene copies are faulty, not only one — however it’s an uncommon illness from a genetics standpoint. Due to a quirk within the human genome, it seems that individuals have a type of backup gene that doesn’t usually perform as a result of its mRNA undergoes defective splicing. With Spinraza appearing as a information to assist the mRNA splice accurately, that backup gene can be made operational and do the job that the broken gene copies can’t do.
Few illnesses are like this. However Stoke’s scientific cofounders, molecular geneticist Adrian Krainer of Chilly Spring Harbor Laboratory in New York (who helped to develop Spinraza) and his former postdoctoral researcher Isabel Aznarez, realized that there was a complete world of different illnesses — haploinsufficiencies — for which any such splice modulation could possibly be helpful.
Spinraza was the prototype. Stoke’s portfolio is filled with the next-generation editions. “We introduced it to the subsequent stage,” says Aznarez, who now serves as head of discovery analysis at Stoke.
Putting a stability
There was a time when Dravet researchers have been extra targeted on conventional gene alternative therapies. They aimed to insert a working model of the SCN1A gene into the genome of a virus after which introduce the engineered virus into mind cells. The issues proved manifold, although.
For starters, the virus autos usually utilized in gene remedy methods — adeno-associated viruses (AAVs) — are too small to carry all 6,030 of the DNA letters that represent the SCN1A gene sequence.
Researchers tried a number of potential workarounds. At College Faculty London, for instance, gene therapist Rajvinder Karda and her colleagues break up the SCN1A gene in half and delivered each elements into mice in several virus carriers. And on the College of Toronto, neuroscientist David Hampson and his group tried introducing a smaller gene that would slot in a single AAV vector and compensate for the SCN1A deficiency in an oblique method.
However none of these efforts superior previous mouse experiments. And whereas it’s technically feasible to deliver the entire SCN1A gene into cells if you happen to use different kinds of viral vectors, as researchers on the College of Navarra in Spain confirmed in mice, these viruses are usually thought-about unsafe to be used in individuals.
What’s extra, even when gene alternative could possibly be made to work, there are a lot of causes to assume it could not be excellent for illnesses like Dravet through which the underlying defect is mediated by an imbalance of protein ranges. The quantity of protein produced by these sorts of gene therapies might be unpredictable, and so are the forms of cells that find yourself manufacturing the proteins.
To get protein ranges good, scientists say, it’s best to comply with the cell’s personal lead, tapping into the ways in which it naturally produces the protein of curiosity solely in sure tissues of the physique, after which offering a therapeutic nudge to help the method alongside.
CAMP4 Therapeutics, for instance, is utilizing antisense therapies, like Stoke. However as a substitute of focusing on the splicing of gene transcripts, CAMP4’s medicine are directed at regulatory molecules that act like rheostats to manage how a lot of these transcripts are made within the first place. By blocking or stabilizing totally different regulatory molecules, the corporate claims it could possibly ramp up the exercise of goal genes in a exact and tunable method.
“It’s mainly educating the physique to do it somewhat bit higher,” says Josh Mandel-Brehm, president and CEO of CAMP4, which relies in Cambridge, Massachusetts.
In concept, the gene-editing expertise often called CRISPR may obviate the necessity for all of those therapeutic approaches. Gene enhancing lets you completely appropriate a mistake in a gene — so one may edit a defective DNA sequence to appropriate it and render children with Dravet or another haploinsufficiency illness pretty much as good as new.
However the expertise is nowhere close to prepared for prime time. (A number of the first CRISPR therapies to be examined in youngsters have failed to demonstrate much benefit.) Plus, any gene-correction remedy must be tailor-made to the distinctive nature of a given affected person’s mutations — and there are greater than 1,200 Dravet-causing mutations within the SCN1A gene alone.
That’s why Jeff Coller, an RNA biologist at Johns Hopkins College and a scientific cofounder of Tevard, prefers therapeutic methods that may tackle all method of disease-causing alterations in a gene of curiosity, as most firms are doing now. “Having a mutation-agnostic expertise is a method of going after your entire cohort of sufferers,” he says.
Tevard, whose mission is to “reverse” Dravet syndrome (the corporate’s identify is Dravet spelled backward), is approaching this problem in varied methods. Some contain engineered variations of different RNAs which might be key for protein manufacturing; often called “switch” RNAs, they assist to ferry amino acid building blocks to the growing protein strands. Others are supposed to help bring beneficial regulatory molecules to websites of SCN1A gene exercise.
However all of Tevard’s therapeutic candidates stay a minimum of a 12 months away from scientific testing, whereas STK-001 is in human trials right this moment. So the corporate’s chief government, Daniel Fischer — who, together with board chair and cofounder Warren Lammert, has a daughter affected by Dravet — is contemplating enrolling his little one, now 13, within the Stoke trial somewhat than ready for his personal firm’s efforts to bear fruit.
“We’re open to any method that may assist our daughters,” Fischer mentioned over lunch final November on the firm’s headquarters.“And assist individuals with Dravet usually,” added Lammert. “We’d like to see a lot of this stuff succeed.”
Editor’s observe: This text was amended on April 14, 2023, to appropriate Gopi Shanker’s relationship with Tevard Biosciences. Shanker is Tevard’s former chief scientific officer; he’s now chief scientific officer with Beam Therapeutics.
10.1146/knowable-041323-1
Elie Dolgin is a science journalist in Somerville, Massachusetts. This text initially appeared in Knowable Magazine, an impartial journalistic endeavor from Annual Opinions. You possibly can learn the unique here.
