Without fail, David Liu of the Broad Institute gets at least 20 messages every week from desperate parents. Their child, they’ll explain, has an ultrarare and devastating disorder caused by a mutant gene. Can he help them develop a gene therapy?
Dr. Liu, a gene-editing researcher, answers honestly: Although the science is there — researchers can edit and silence the genes that cause disease relatively easily — the system for developing treatments for rare diseases is just not economically feasible. It typically takes years and hundreds of millions of dollars.
The catchphrase, said Dr. Wendy Chung of Boston Children’s Hospital, is “too rare to care.”
Now, Dr. Liu, Dr. Chung and their colleagues at the Broad Institute, Boston Children’s and the Jackson Laboratory are hoping to change that mentality. On Tuesday, they announced the start of a new nonprofit, the Center for Therapeutic Genetics, to develop gene therapy treatments that can be used and reused in disease after disease.
Treatments developed by the center would be viewed more like routine procedures than drugs. In each case, all that would be changed are the instructions to a gene editor. There would be no need to start anew for every patient.
In principle, with more centers like this one, the new approach could improve the lives of millions of people, Dr. Liu said. About 400 million people worldwide and 25 to 30 million in the United States have a rare disease. Half are children, and a third die before they turn 5.
The project is starting with a $34.5 million contract from the Advanced Research Projects Agency for Health, a federal agency that supports high-risk, high-reward medical research. It will begin by focusing on neurological disorders that can result in seizures. That work, the researchers hope, will demonstrate how an editing system that fixes mutations in brain cells can be used for more than one genetic brain disease, including ones that strike adults, like Huntington’s.
The first, called alternating hemiplegia of childhood, or AHC, affects just 400 children in the United States. Among them is 10-year-old Annabel Frost. Her parents, Simon Frost and Nina English Frost, who live in Washington, have made getting gene therapy for children with AHC the center of their lives.
When Annabel was 2 months old she started having seizure-like episodes and recurrent bouts of paralysis — her limbs, even her whole body, would be immobile for days or as long as a week. Her parents crossed the country, consulting with neurologists, but no one knew what was wrong.
After they finally received a diagnosis of AHC and learned there was no cure, the Frosts formed a nonprofit and began raising money; they have raised more than $4 million in the past eight years. But expecting families to follow that path — doing fund-raising, organizing golf tournaments, sponsoring 5K races — “is very unfair,” said Dr. Chung, especially when parents are caring for a sick child. And it is still almost never enough to get a company interested in developing a treatment.
Ms. Frost said she and Mr. Frost knew that. So their foundation deliberately supported research that laid the groundwork for a gene therapy for AHC. Then they approached Dr. Liu. “We did not simply bring David a disease and ask him to solve it,” Ms. Frost said. “We brought him a developed scientific opportunity.”
Dr. Liu’s group had extended the life of mice with Niemann-Pick, a genetic brain disease, which gave them hope. For AHC, Ms. Frost said, “we wanted him to target the same cells.”
But it is much easier to get a gene editor to the brain of a mouse than to the brain of a person. With mice, scientists can just inject the editor into their tiny brains. With humans, that won’t work. The challenge is to get a disabled virus carrying gene-editing instructions through the blood-brain barrier, a membrane that protects the brain from infections and toxins.
But researchers at the Broad Institute led by Ben Deverman have found a way. They can hijack a carrier protein that delivers iron into the brain.
That discovery, said Dr. Timothy Yu, a team member from Boston Children’s, “was a real lightbulb moment.”
Treatment will involve an intravenous injection of the engineered virus, which will shuttle through the blood-brain barrier and enter the brain’s intracellular space. From there the editor will enter brain cells where it will slide along the DNA to the mutation. Then the editor will turn the mutated gene into the healthy one.
The plan is to initially treat children most severely affected by AHC. Annabel is not among them, so she will not be first in line.
The method will also be used to treat another neurological disorder, a genetic form of severe childhood epilepsy, Dravet syndrome, which occurs in about one in 15,700 births. Twenty percent of patients die before age 18, said Mary Anne Meskis, the chief executive and co-founder of the Dravet Syndrome Foundation. Many die in their sleep.
“Our parents live in fear every day that when we put our child to sleep at night the child might not wake up,” said Ms. Meskis, who lives near Asheville, N.C.
Ms. Meskis’s 26-year-old son Elliot had his first seizure when he was 6 months old. It lasted an hour before emergency room doctors could stop it. The next month he had another. The next month, another. When Elliot was 18 months old he also began to have thousands of brief seizures every day in which he would blink or suddenly jerk his head. He had episodes of paralysis, which could last for days or even a week.
His parents finally got a diagnosis of Dravet when Elliot was 4. He began taking multiple daily medications that reduced the length of his seizures, but he functions at the level of a 3-to-5-year-old and doesn’t have expressive language.
Dr. Liu and his colleagues have corrected Dravet in mice by injecting a gene editor into the animals’ brains, a proof of principle. Now they will try it in humans.
Elliot’s brain may be too damaged at his age for gene therapy to cure him. The hope, though, is that it might help or cure young children.
The center is not going to solve the problem of getting genetic therapies to patients overnight, its founders emphasized. But the researchers hope the work will lead to methodologies that other doctors can pick up and apply to their own patients.
To achieve that, the center will make its work public whenever possible. That’s something that for-profit companies typically don’t do but that is needed to make real progress, said Dr. Mark Kay, who is the head of the Division of Human Gene Therapy at Stanford University and not involved with the new center. “I really like and support this idea,” Dr. Kay said.
It will be hard at first, Dr. Chung predicted. But she feels a sense of urgency.
“My patients don’t have time to wait,” she said. “We will lose a generation.”
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