Real-time MRI may improve delivery of gene therapy to brain

Phase 1 trial testing MRI-guided gene therapy in 31 AADC deficiency patients

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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An illustration of a scientist holding a flashlight to a giant image of a brain while another examines it with a magnifying glass.

The use of real-time magnetic resonance imaging (MRI) during direct-to-brain delivery of gene therapy may help optimize the safety and effectiveness of such therapeutics for neurological diseases such as aromatic l-amino acid decarboxylase (AADC) deficiency.

In a recent review study published in JAMA Surgery, researchers at the Ohio State University — who have spearheaded the development of this approach — described the possible benefits of the so-called “infuse-as-you-go” optimization strategy that real-time MRI offers.

Proof-of-principle data come from an ongoing Phase 1 clinical trial (NCT02852213), where MRI-guided gene therapy was well tolerated and associated with dramatic clinical improvements for children with AADC deficiency. The trial, expected to include up to 31 patients, 4 years and older, may still be recruiting at sites in Ohio and California.

“Ultimately, this should improve the biologic and clinical understanding of therapeutics, which will lead to optimal clinical care for patients undergoing [direct-to-brain] gene therapy,” Asad S. Akhter, MD, a neurosurgery resident at Ohio State and the study’s first author, said in a university press release.

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“Imaging findings will inform critical insights that can lead to future refinements in delivery parameters,” Akhter added.

The review study was titled “Real-Time Magnetic Resonance Imaging During Convective Gene Therapy Perfusion of the Brain.”

In AADC deficiency, mutations in the DDC gene lead to reduced activity of the AADC enzyme that’s critical for the production of key brain signaling chemicals called neurotransmitters, namely dopamine and serotonin.

A deficiency of these molecules is associated with symptoms that include intellectual disability, movement disorders, dysfunction of involuntary body functions, mood changes, and seizures.

Gene therapy for the extremely rare disease is designed to provide patients with a healthy copy of the DDC gene, restoring AADC activity and neurotransmitter production.

Such therapies can be administered in a variety of different ways. For neurological diseases, a popular approach is convection-enhanced delivery (CED), which enables the precise injection of the treatment into functional brain tissue, called an intraparenchymal infusion.

Ultimately, this should improve the biologic and clinical understanding of therapeutics, which will lead to optimal clinical care for patients undergoing [direct-to-brain] gene therapy.

Upstaza uses convection-enhanced delivery guided by previous MRI scans

Upstaza (eladocagene exuparvovec), a gene therapy approved for AADC deficiency in the European Union and the U.K., uses CED to deliver a healthy copy of DDC directly into the brain’s putamen — the area of the brain with the highest AADC activity. The infusion is guided by previous brain MRI scans.

Now, the researchers discussed the benefits of adding real-time MRI during intraparenchymal gene-therapy delivery to enhance its safety and efficacy for difficult-to-treat neurological disorders.

A real-time MRI technique during the surgery enables doctors to make sure the cannula delivering the gene therapy is in exactly the right place. A tracer molecule is injected when the gene therapy is infused that will show up on the MRI scan anywhere the gene therapy ends up, allowing clinicians to monitor its distribution and manage how much to infuse.

This approach altogether “permits treatment of diseased neuronal circuitry or anatomy through selective perfusion of targeted structures or substructures while avoiding off-target effects,” the researchers wrote.

It also allows doctors to gather more information about the behavior of gene therapies and the viral carriers used to deliver them to patient cells to optimize treatment regimens.

The benefits of the approach have been demonstrated in the ongoing Phase 1 trial involving AADC deficiency patients. The study is being led by Krystof S. Bankiewicz, MD, PhD, the chief scientific officer of Ohio State’s Gene Therapy Institute, a professor of surgery at Ohio State, and one of the study’s authors.

Another distinction to Upstaza’s approach is that the gene therapy in this early trial is delivered not into the putamen, but into the substantia nigra pars compacta and the ventral tegmental area — two brain regions that contain many dopamine-producing cells.

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Early trial results show benefits for resolving oculogyric crises

Early results from seven children in the Phase 1 trial showed a single infusion of the therapy led to complete resolution of oculogyric crises, an eye movement disorder characteristic of AADC deficiency, in six of them. These benefits were sustained for at least two years.

Several children achieved motor milestones such as sitting without support, head control, and hand grasping. Caregivers reported better mood and fewer sleeping and feeding problems.

The researchers noted the surgical and imaging technology needed to employ this approach is “readily available,” although access to MRI systems compatible with use during surgery and a lack of appropriate expertise could be barriers to implementing the strategy.

“Real-time magnetic resonance imaging of gene therapy delivery to the nervous system will be more broadly applied over the next 3 to 5 years as the number of sites with the needed infrastructure and expertise continues to increase,” Bankiewicz said.