$14.6M NINDS Award Will Advance Gene Therapy From Ohio State Team

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by Steve Bryson, PhD |

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The ongoing clinical evaluation of a new gene therapy to treat aromatic L-amino acid decarboxylase (AADC) deficiency has been boosted by a $14.6 million award from the National Institute of Neurological Disorders and Stroke (NINDS).

Researchers at The Ohio State University Wexner Medical Center and College of Medicine have found that the investigational gene therapy dramatically improves motor function and quality of life in AADC children in a Phase 1 clinical trial (NCT02852213).

The grant will now enable researchers to initiate a multi-center study with patients treated at Ohio State and at the University of California San Francisco. NINDS, part of the National Institutes of Health, seeks to advance knowledge of the brain and nervous system.

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“This major federal award truly defines science with impact,” Carol Bradford, MD, dean of the Ohio State College of Medicine, said in a university press release. “The exploratory clinical trial will pave the way to provide this disease-modifying gene therapy for AADC deficiency and future gene therapies for other neurological disorders.”

The AADC enzyme carries out the last step in the production of dopamine and serotonin, two molecules — neurotransmitters — that act as messengers between nerve cells in the brain and the rest of the body. Mutations in the encoding DDC gene lead to reduced activity of the AADC enzyme and less dopamine and serotonin.

Changes in the levels of these chemical messengers disrupt the communication between the brain and the body, causing symptoms that include developmental delays, intellectual disability, emotional problems, muscle weakness, abnormal movements, and oculogyric crises — the involuntary upward movement of the eyes.

“Without this enzyme, children lack muscle control, and are usually unable to speak, feed themselves or even hold up their head,” said Krystof Bankiewicz, MD, PhD, principal investigator of the trial and professor of neurological surgery at Ohio State College of Medicine.

“They also suffer from seizure-like episodes called oculogyric crises that can last for hours,” he said.

The investigational gene therapy is designed to correct the genetic mutation and to restore AADC production by providing a healthy copy of the DDC gene directly into patients’ brains.

Using a harmless virus, the gene is particularly delivered to two regions of the midbrain — the substantia nigra pars compacta and the ventral tegmental area — which contain dopamine-producing neurons with intact nerve projections in AADC patients.

Of note, this strategy differs from the investigational gene therapy PTC-AADC by PTC Therapeutics, which targets a different area of the brain called the putamen.

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“Delivery of a functional copy of the [DDC] gene would significantly reduce suffering in afflicted patients and pave the way for registration of other gene therapies for neurological disease,” Bankiewicz said.

The new clinical trial builds on a Phase 1 study (NCT02852213), conducted by Ohio State and the University of California San Francisco, and funded by the NIH. The trial enrolled seven children with AADC deficiency, ages 4 to 9.

The gene therapy was generally safe and well-tolerated, and improved motor function and quality of life for these children. Three months after treatment, six out of the seven children no longer experienced oculogyric crises, and this was sustained for at least two years.

At one year after the therapy’s administration, six patients had gained head control, four sat without support, three were able to reach and grasp, and one could speak about 50 words. Treatment also led to fewer feeding and sleeping difficulties, as well as sustained improvements in mood, as reported by caregivers.

“In our earlier study, oculogyric crises stopped a few weeks after the surgery and patients’ sleep, mood and irritability improved,” said Bankiewicz. “Most study participants gained head control and muscular tone, developed purposeful movements and some were able to sit up and start to walk without support, regardless of their age.”

To date, eight children with AADC deficiency have been treated in the U.S. trial, along with an additional 15 in Poland given the therapy under a compassionate use program, Bankiewicz said.