Gene therapy trials show a wider window for changing the course of rare diseases

TWhen he realized that the parents of a one-year-old girl were having a hard time holding his head, he suspected something was wrong. This was just the first to miss many development milestones.

By the time she was eight, the girl was still unable to sit alone, hold toys, or greet her. She couldn’t sleep for more than an hour or two at a time. Several times a week, her body suddenly stiffened, her eyes froze on one side of her face, sometimes taking hours. Known as intraocular translocation, this symptomatology is a tragic standard symptomatology of AADC deficiency, a very rare hereditary disorder that starves the brain with dopamine and serotonin, the essential molecules that allow brain cells to communicate with each other. is.

Given the nature of her age and her condition, this girl may have seemed like a candidate unlikely to receive gene therapy.that is The issue of lively scientific debate Whether it is possible to actually undo some of the wiring defects in the brain long after birth by correcting the genetic errors that cause developmental disabilities like her. However, at the age of eight, she was second in the patient in a groundbreaking clinical trial. This suggests it’s not too late. Gene therapy To help such children. Doctors at the University of California, San Francisco used it to slide her into an MRI machine and guide the needle deep into her brain to inject a harmless virus that carries a healthy copy of the AADC gene.

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A few weeks after surgery, dopamine began to flow between her neurons. A few months later she started getting up. The translocation on the eyeball stopped and I slept mercilessly. Today, patient 2, who is 10 years old, can walk without help. She is also starting to talk using a speech generator.Her remarkable progress Reported on Monday at Nature Communications, With similarly compelling data from the other 6 pediatric patients on trial.

This was a small Phase 1 study designed solely for testing safety. But striking results are not only about viable strategies for treating neglected and catastrophic illnesses, but also about the ability of neuroscientists to make new connections after being released from the genetic death penalty. It suggests the possibility of a drastic change in what we think is.

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Toni Pearson, a pediatric neurologist at the University of Washington School of Medicine, said: Lead author of new research in St. Louis. “We still believe that the sooner this is offered, the more likely it is to be profitable, but I think we are still discovering what the window of plasticity is for progress. I will. “

The idea for this trial was born in 2012, shortly after Pearson met patient number 2. At that time, Pearson was at Columbia University and had just begun collaborative research with the Krystof Bankiewicz, a neurosurgeon at the University of California, San Francisco. Bankiewicz is currently a professor of neurosurgery at The Ohio State University Wexner Medical Center and also treated patients in this trial. He recently figured out a way to package the AADC gene in a harmless virus. Treating patients with Parkinson’s disease.. It also suffers from problems caused by dopamine deficiency, as neurons that normally produce neurotransmitters die gradually.

Dopamine lasts only a minute or two in the bloodstream. Therefore, patients with Parkinson’s disease are instead treated with its metabolic precursor, L-DOPA. This is also easy to manufacture and can be administered orally. When it moves to the brain, L-dopa is broken down into dopamine by the AADC enzyme. Bankiewicz’s idea of ​​gene therapy for Parkinson’s disease was to help the remaining neurons more efficiently transform the treatment into usable forms of neurotransmitters.

Patients with AADC deficiency have another problem. Their neurons are not dead. They are structurally intact and stir L-DOPA well. But then they ran into obstacles. Their AADC gene is broken and does not make an enzyme that performs the important last step to convert to dopamine. And without it, neurons are individually healthy, but unable to communicate with each other.

Pearson and Bankiewicz thought that if they could deliver a healthy copy of the AADC gene to the part of the midbrain where dopaminergic neurons gather, they could take advantage of all that intact circuit. Once inside the neuron, this particular virus had the knack of traveling along the length of each axon and often extending to different brain regions until it reached the synapse where dopamine production occurs.

AADC is also involved in the final stages of serotonin production, but these neurons are located in more inaccessible parts of the brainstem. Therefore, researchers decided to target only dopamine-producing cells.

They applied for funding from the National Institute of Neurological Disorders and Stroke (NINDS) and were awarded approximately $ 3 million to produce the necessary viral vectors and conduct toxicological studies before starting clinical trials. They started administration to the first patient in 2017. Only patients over the age of 4 were accepted because images need to be used to guide gene therapy to the depths of the brain. procedure.

Nature reported that seven patients between the ages of 4 and 9 were treated and had no side effects. Using the fluorescent version of L-DOPA that appears on PET scans, researchers were able to observe that within a few weeks all patients had regained their ability to convert it to dopamine. As expected, gene therapy did not alter the patient’s serotonin levels.

Three months after surgery, 6 out of 7 patients no longer experienced intraocular translocation. Eighteen months later, four began to sit independently and two were able to walk with the help of adults.

“This is very exciting data,” said Jill Morris, director of the NINDS program, who oversees the exam. “It was a truly original study in showing the benefits of gene therapy and how it can change the lives of children with hereditary diseases.”

Seven months after receiving treatment, one study participant died suddenly. This is not uncommon in patients with AADC deficiency. Death was determined to be unrelated to gene therapy. Larger trials are currently planned that focus on the effectiveness of gene therapy.

“The sample size was small, which had great benefits for some patients, but did not fully recover,” said Guoping, a neuroscientist at the Massachusetts Institute of Technology. Probably all cells affected by the disease. Because it didn’t reach the mold. ” Feng Shui who was not involved in the study. Still, he said he felt the results were incredibly promising. Feng firmly believes that genome editing tools like CRISPR may one day reverse more complex brain disorders such as autism, Huntington’s disease, and schizophrenia. He and others have shown that it is possible to do so with mice and other animal models, but so far not with humans.

“Because humans are different, this kind of translational experiment is needed in this area, and it is difficult to predict how the results will be maintained,” Feng said. “What we have now is some of the earliest human evidence that there is actually a fairly large postnatal window in which it may be beneficial to correct a genetic mutation.”