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Scientists are thinking the unthinkable: CRISPR might one day reverse devastating brain diseases

April 10, 2018

Monica Coenraads’ daughter has never spoken since she blurted out “duck!” while taking a bath soon before her first birthday, and has never walked. Chelsea lost the ability to hold her sippy cup and stopped responding when Coenraads played “can you touch your nose?” She cannot use her hands, and must be fed through a tube, all of which is tragically standard for girls with severe Rett syndrome, a brain disorder that usually strikes during toddlerhood and is caused by a genetic mutation.

It may seem unlikely, then, that such a devastating condition is near the front of the line of brain disorders that scientists believe might one day be treated with genome editing technologies such as CRISPR. By “treated,” they don’t mean just keeping a disease from getting worse. They mean reversing the damage and giving the brain a second chance: CRISPR would penetrate the brain of a patient who has lived with a disorder for years and repair the mutation that caused it, unleashing the brain’s capacity of neuroplasticity to weave new circuitry, grow new neurons, or otherwise do right what it did wrong when the mutant gene called the shots.

This possibility, said Coenraads, executive director of the Rett Syndrome Research Trust, “gives every parent of a child with a neurodevelopmental disorder hope.”

That’s not the view only of someone who needs to believe. The hottest question at the intersection of brains and genes is whether genome editing like CRISPR might reverse complicated brain disorders such as autism, Fragile X syndrome, frontotemporal dementia, Huntington’s disease, schizophrenia, and others.

“The answer is yes,” said MIT neuroscientist Guoping Feng. “It is not only possible, it will be successful. There will be technical problems, but we will solve them.”

Formidable challenges stand in the way of CRISPR'ing damaged brains, and scientists are all too aware that success in mice is often followed by failure in patients. Making this work requires an enormous leap beyond the simpler diseases that scientists are currently thinking of CRISPR’ing. To cure sickle cell disease via CRISPR, for instance, it should be enough to switch on production of normal blood cells, which in mice can be done with a simple DNA edit. Result: healthy blood cells and no more sickle cell disease. To cure some forms of blindness, it should be enough to delete a gene that cripples the eye’s photoreceptors. Result: healthy photoreceptors, vision restored.

The brain is, needless to say, enormously more complex than blood cells or photoreceptors. And once it gets miswired, went traditional thinking, that was that.

“We had this idea that if you don't put the brain together right during development, you can't reverse it,” said neurobiologist Alcino Silva of UCLA’s Brain Research Institute. “Some changes in brain architecture during development are so dramatic, that might be true. But in more than 30 studies, we’ve seen that when you intervene in adult mice you can often completely reverse” a neurological disease.

He and others base their optimism on the brain’s ability to change its structure, wiring, and, therefore, function in response to circumstance. After a stroke, for instance, adult brains can (with therapy) draft healthy regions to assume the jobs of damaged ones. Now, more and more studies are showing that genetic tweaks can undo half a lifetime of brain abnormalities.

Two years ago, MIT’s Feng and his colleagues “rescued” adult mice that had a mutation causing an autism-like disorder (the mutation causes about 1 percent of all autism spectrum cases in people), by giving them a healthy version of the gene, called Shank3, with a technique that predates CRISPR. For the first time in their lives, the mice preferred checking out and socializing with strangers (of the rodent variety) to hanging out with inanimate objects. And they stopped the repetitive, violent licking and biting that had made their fur look like a victim of a squadron of moths.

After normal Shank3 began functioning, the mice’s brains also changed for the better. Shank3 makes a protein which, when healthy, stabilizes synapses and ensures the smooth transmission of signals from neuron to neuron. “Without it, your synapses are abnormal,” Feng said, “and every sensory input coming in is abnormal” — which is perhaps why people with autism often find intense sounds or other environmental stimuli intolerable. After the Shank3 repair, neurons worked more normally and made more numerous and more stable synapses.

Feng's approach hasn’t led to attempts to do that in people; the pre-CRISPR way he inserted a repair gene is almost certainly too kludgy for human therapy. But it was the first demonstration that even after autism symptoms appear in a mouse, and even after neurons or circuits have taken a disastrously wrong turn, the pathology is reversible.

“I have very high hopes that you can go in with CRISPR and fix a gene even in adults," which is why scientists try it in adult mice, Feng said. Such repairs could be "highly beneficial and even a cure because the brain can rewire.”

Scientists and patient advocates have the same hopes for Rett syndrome. In this disorder, a mutation in a gene on the X chromosome cripples a protein called MeCP2 that regulates a slew of genes, including some that affect neurons. As a result, neurons don’t mature properly and don’t sprout as many spines connecting them into an information-carrying circuit, leaving patients like Chelsea unable to move or speak.

More than a decade ago, scientists genetically engineered mice so the gene for MeCP2 could be turned off and on like a light switch. When the gene was disabled, the mice developed Rett-like brain and behavior abnormalities. But turning it on, even well into adulthood, reversed the neurological symptoms. “You couldn’t tell them from normal mice,” Coenraads said. “If you restore MECP2 at any age in mice, every symptom that was tested reverts to normal or near normal": a cure.

That study, like the Shank3 experiment, dangled the possibility of curing a devastating brain disease. But the required genetic tools didn’t exist. With CRISPR, they do.

With $600,000 from Coenraads’ group, biologist Rudolf Jaenisch and colleagues at MIT’s Whitehead Institute are using CRISPR to rescue mouse brains crippled by mutant MeCP2. Although CRISPR’s fame rests on its talent for repairing disease-causing genes, it can also make molecular tweaks to turn genes on or off, Jaenisch discovered in 2016. For Rett, he plans to use CRISPR to turn on the silent but healthy copy of the MeCP2 gene that most patients have.

He is trying something similar for Fragile X syndrome, the most common cause of intellectual disability in boys. When CRISPR removed gene-silencing molecules on the FMR1 gene in neurons growing in lab dishes, Jaenisch reported this year, the neurons' electrical activity — previously as chaotic as a July lightning storm — returned to normal. The next step is to see if that works in mouse brains.

Despite the brain’s ability to bounce back from years of abnormal development, there are daunting hurdles in the way of CRISPR’ing it back to health.

One challenge is identifying what DNA needs repair. Although the Shank3 form of autism, Rett syndrome, Fragile X, and a few other brain disorders are caused by a single gene — making the target obvious — others are not. Fully 108 genes have been implicated in schizophrenia, for instance; it won’t be trivial to figure out which to target.

Also, CRISPR can insert a repair gene only into the genome of dividing cells. Neurons don't divide, though scientists have some ideas to make neurons accept repair DNA anyway. And it's not clear whether viruses, the usual workhorses for delivering CRISPR into cells, can deliver their genome-editing package to only the right cells. There are hundreds of kinds of neurons and other kinds of brain cells, but only some are involved in a given brain disorder.

“The main challenge will be delivering into the brain and figuring out how to get it into specific cell types,” said Patrick Hsu of the Salk Institute, who last month reported using a new CRISPR system to repair human neurons, in lab dishes, which contained a mutation that causes frontotemporal dementia. “That’s what will really move the cheese.”

Scientists at the forefront of using CRISPR to repair brains regard these as solvable problems. For instance, attaching certain molecules to CRISPR causes it to function only in glia or only in neurons, Hsu said, though the technology is still imperfect.

Neuroscientists have been insisting for a decade that success in reversing certain neurodevelopmental disorders in adult mice means that damaged human brains are not a lost cause. Only now, with CRISPR, might the genetic tools be up to the challenge.

"Twenty years ago we would have said, no, genome editing can't help in brain diseases where genes act early and cause al sorts of wiring problems," said Dr. Daniel Geschwind, a neurogeneticist at UCLA. “But study after study shows us that the is modifiable even in adulthood. We have to be optimistic."

Published with the permission of Stat News