CAMBRIDGE, Massachusetts—Daniel Fischer’s daughter, Natasha, has Dravet syndrome. So does Warren Lammert’s daughter, Sylvie. Together, the two entrepreneurs are determined to treat, if not outright cure, a disease that has upended the lives of both men and their families.
Their startup, Tevard Biosciences, employs 20 people at a shared office about half a mile from the Massachusetts Institute of Technology (MIT) in downtown Cambridge.
Tevard happens to be Dravet spelled backward—a reflection of the company’s mission to “reverse Dravet.” It aims to do this by using transfer RNA (tRNA) to modulate RNA function to treat Dravet and other rare diseases usually not amenable to traditional gene therapy. Simply put, tRNA links the messenger RNA (mRNA) molecule and the chain of amino acids that make up a protein.
Similar Stories of Sudden Symptom Onset
For Lammert, the news that changed the trajectory of his career as a financial analyst came suddenly.
“My daughter was born in 1997 and had been developing normally until 9 months of age,” he told Rare Disease Advisor during a recent interview at Tevard headquarters. “I was on a business trip in California and got a call that she had 2 seizures. I immediately headed for the airport and flew home to Denver to find Sylvie in the hospital. She ended up in the [intensive care unit (ICU)] for 2 weeks.”
After that initial emergency, Sylvie had a 3-month respite. Then the seizures started again.
“We tried a drug but it didn’t work, then a second drug, then a third, a fourth, and a fifth,” he said. “Nothing worked.”
Fischer, a businessman who immigrated to the United States in 2000 from Caracas, Venezuela, has a similar story.
“Natasha had her first seizure when she was 6 months of age. At that time, we had no idea what was going on. It was in the middle of the night. My wife called her dad, who’s a pediatrician. He asked us to take a video. Right away, he said she’s having a seizure. At that time, we thought it was just a febrile seizure,” he said, using the term for a generally harmless, temporary condition resulting from high fever often caused by an infection.
“The next day, we took her to the neurologist,” Fischer continued. “To make a long story short, about 2 or 3 months later, she got diagnosed with Dravet syndrome. Every time she had a seizure, she ended up intubated in the ICU.”
After being put on a series of therapies, Natasha is considerably better. She suffers “only” 4-5 seizures a night (all her seizures are now nocturnal), down from 30-40 perhaps 5 years ago.
“For some reason, when she’s asleep, there are different stages of sleep that trigger seizures. Also, if she goes outside and it’s very hot, that can be a trigger. Fever is also a very well-known trigger among children with Dravet,” Fischer said. “In Natasha’s case, there was a time when visual patterns were a trigger; not only flashing lights but also if I had on a shirt with squares. She’d look at it, and that would trigger a seizure.”
Targeting the Root Cause of Disease
By coincidence, the two men met at an investors’ conference organized by Lammert. After a series of other biotech ventures, they joined with molecular biologist Harvey Lodish, PhD, and launched Tevard.
They selected the Boston area, Fischer said, “because it has a very vibrant biotech community, and also because we had a zebrafish lab at MIT and we already knew a lot of the technology.”
Today, Sylvie is 26, and Natasha is 13. They are among 5000 to 10,000 Americans with this rare disease, according to the Cherry Hill, New Jersey-based Dravet Syndrome Foundation. Also known as severe myoclonic epilepsy of infancy, it affects 1 in 15,700 live births, and symptoms generally begin at 2 to 15 months of age. Most patients with Dravet have a mutation in the sodium channel gene SCN1A.
“Dravet . . . is much more than only seizures. Kids with Dravet have very severe cognitive impairment, balance issues, and high rates of mortality,” Fischer said. “We wanted to really try to develop a cure for Dravet that would target not only one of its symptoms—which are the seizures—but also the root cause of the disease.”
In June 2018, the US Food and Drug Administration (FDA) approved an oral cannabidiol solution known as Epidiolex® to treat Dravet as well as another rare epilepsy, Lennox-Gastaut syndrome. Both girls soon began taking the medication—the first derived from marijuana ever to win FDA approval for any disease. Five years later, Sylvie is still on it. Natasha is not.
Other antiseizure drugs used to treat kids with Dravet include clobazam (Onfi®), stiripentol (Diacomit®), topiramate (Topamax®), and valproate (Depakote®). Yet another treatment Fischer said has been “extremely effective” is fenfluramine (Fintepla®), originally developed as an appetite suppressant.
“Several companies are working on either gene therapy or tRNA therapy, like we are, to treat the root cause of the disease,” he said. “Even if we can’t cure it, at least we’re looking at treating the disease holistically, and not only trying to reduce seizures.”
According to Fischer, the company’s scientific cofounders, Lodish and Jeff Coller, PhD, came up with the idea of using tRNAs to modulate RNA function. Two platforms based on tRNAs are currently being studied. In the first, which Tevard calls Suppressor tRNAs, a viral vector is used to express a patented tRNA in targeted cells. A normal amino acid is inserted at the site of the premature stop codon, generating a normal functional protein.
The second platform, known as Enhancer tRNAs, is designed for diseases caused by haploinsufficiency, which occurs when one copy of a gene is deleted or contains a loss-of-function mutation. By using a viral vector to overexpress a unique combination of endogenous tRNAs in targeted cells, scientists hope to increase the amount of protein produced by the wild-type, or functional, copy of the specific gene to its normal level.
“We’d target what are called nonoptimal codons in the message. We get them to become more optimal and then produce more protein from that healthy good‑working copy of the gene,” he explained. “In theory, with that therapy, we could treat 100% of the patients in the population.”
Vertex and Tevard Take Aim at DMD
With that in mind, Tevard recently signed a 4-year collaboration with Vertex Pharmaceuticals to develop a treatment for Duchenne muscular dystrophy (DMD), using similar tRNA technology.
Neither Tevard nor Vertex—which reported $8.93 billion in 2022 revenues from its 4 therapies for cystic fibrosis—would disclose the terms of the deal, announced February 28, 2023.
Mike Cooke, senior vice president of Vertex Cell and Genetic Therapies, said in a joint press release that his Boston-based company is “excited to partner with Tevard and add their suppressor tRNA technology to our portfolio as another tool we can use to develop treatments for DMD patients with nonsense mutations.”
The idea, Fischer said, “is to try and treat the 13-15% of Duchenne patients with nonsense mutations by producing full-length dystrophin from a nonfunctional gene. We’re working on Duchenne, but with the option of expanding into the broader space of muscular dystrophy in general, as well as an option for a second indication which is undisclosed.”
Added Lammert: “It takes a lot of money, tens of millions of dollars, especially as we go into manufacturing right now. We have raised substantial investor money, and this would allow us to double the size of our company.”
Fischer said he still remembers when his daughter was diagnosed with Dravet 9 years ago and he asked the medical staff about potential gene therapies to treat the disease. The doctor told him the possibility was so remote, he shouldn’t get his hopes up thinking about it.
But times have changed, and Fischer is more hopeful than ever.
“My job is finding cures for my kids and other kids with severe diseases,” he said, recalling how once, he was giving a speech and someone in the audience asked how he separated his professional and personal lives.
“I thought for a moment, and I said, ‘Actually I don’t,’” he said. “When I get home from work, my wife and other kids always ask me, ‘Daddy, have you found a cure for Natasha?’ In the end, what I’m doing is part of all our lives. And that gives us hope.”