Before her first birthday, her parents knew something was seriously wrong. She was weak and inactive. The child, whom we are calling Lisa to protect her privacy, hardly interacted with them, and she was late on every developmental milestone – sitting, walking and speaking her first words.
At the age of 15 months, her pediatrician referred her to a neurologist who noted her blank stares and delayed global development. Lisa was not able to combine two words until she was 3, and she didn’t take part in imaginative play until she was 10.
In 2013, when she was 13, genetic testing revealed that she had a rare mutation in a gene for VAMP2, a protein involved in neurotransmission – the crucial process that allows neurons in the brain to communicate. While the basic biology of VAMP2 was understood, there was no evidence linking this gene to cognitive challenges in patients.
Her neurologist referred Lisa to UC San Francisco’s Elliott Sherr, MD, PhD, a professor of neurology and a specialist in pediatric neurogenetics.
Sherr first saw Lisa when she was a young teenager. “She was nearly catatonic,” he says. “She had trouble moving. She sat in a passive way and didn’t interact – didn’t engage in conversation at all.”
Cognitive tests showed that she couldn’t process information normally and still functioned more at the level of a kindergartener.
If the VAMP2 mutation was the cause, it was wreaking havoc in Lisa’s brain.
VAMP2 is one of a family of “SNARE” proteins which drive membranes to fuse with each other. VAMP2 enables bubble-like vesicles loaded with neurotransmitters to release their cargo across the synapse – the key step in the flow of information between neurons.
Sherr recognized that the single mutation in the gene coding for VAMP2 might severely restrict communication between neurons in Lisa’s brain. But there was no treatment to restore a failing VAMP2 protein.
For some time, Sherr and neuroscientist Susan Voglmaier, MD, PhD, a professor of psychiatry, had been discussing the impacts of neurodevelopmental disorders on psychiatric conditions. Sherr considered a molecular workaround that might compensate for VAMP2’s defect and help recover some of Lisa’s emotional and cognitive capacity.
“We couldn’t fix the defective VAMP2 protein,” he says, “but there are many other features to the signaling pathway – many different protein interactions involved in vesicle fusion and the release of neurotransmitters.
“I hypothesized that over-stimulating one of these other pathways might ramp up release of neurotransmitters and overcome the failure of VAMP2.”
A drug called Ampyra was already in use to treat multiple sclerosis (MS) by boosting poor neuronal signaling to muscles. MS is caused by a different mechanism, but Sherr and Voglmaier hoped the drug could be repurposed to do the same job for neurons hobbled by a VAMP2 mutation.
“It seemed like a promising strategy,” Voglmaier says, “but before we could prescribe it to Lisa or other patients with VAMP2 mutations we needed evidence that it would work.”
In 2015, her lab generated mutations to mimic three different VAMP2 defects in live cultures of mouse neurons. They tested the ability of an Ampyra-like drug to both increase the amount of neurotransmitters released by the neuron and the rate at which they were released. By 2017, results showed that the strategy worked.
They were now ready to find out if Ampyra could help Lisa regain what the VAMP2 mutation had taken away.
In April 2018, Lisa received her first weekly dose of Ampyra. The drug’s effect was surprisingly swift. Sherr and Voglmaier, both seasoned neuroscientists, were startled.
“It was a real awakening for her,” Voglmaier says. “Within two weeks, she started speaking much more – in full sentences. Her cognitive and emotional capacities were still far below that of a typical 18-year old, but her speech was much more coherent, and she interacted with her classmates. She began to make friends.
“It’s incredibly heartwarming. Most of us go through our careers working with such patients and achieving modest improvements. This is what we always hope for – making such an impact in patients’ lives.”
“The tools we have to directly treat kids with cognitive disabilities are nearly zero,” Sherr says. “A transformation like this is rare. The ability to translate new understanding at the molecular level to treat patients – what we really mean by precision medicine – that’s why we do what we do.”
Lisa’s progress has not always been steady, says Roxanne Simmons, MD, a pediatric neurology fellow and lead author on a paper reporting the research and Lisa’s treatment. Simmons has been there for the full ride.
“She is much more interactive. Her memory recall and information processing have improved by more than 50 percent,” she says. “But sometimes she backslides. She has angry outbursts, and her anxiety has worsened.”
Simmons wonders if some of Lisa’s anxiety comes from now being more self-aware – recognizing her own limitations for the first time. “She sometimes says, ‘Dr. Sherr’s medicine isn’t working.’
“Her turnaround from a near-catatonic condition has been dramatic. Who knows how earlier treatment might have impacted her development.”
The research and clinical success was published last month in the journal Human Mutation. Sherr and Voglmaier recognize that much more clinical research is needed to firmly establish the treatment’s effectiveness. But they hope the first success will show the way to overcome debilitating effects caused by mutations in any of 30 other SNARE genes.
Even though the new insight has so far benefited only one patient, its potential to change lives can’t be easily discounted, Voglmaier says. A year after her treatment began, Lisa reached a milestone that she literally could not have imagined. In May 2018, just a month after starting her new medication, she dressed up, joined her classmates and attended her high school prom.