MRI-guided gene therapy targets serotonin in AADC deficiency
Study: Method delivers treatment to multiple parts of the brain
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Researchers have developed a real-time, MRI-guided method to deliver Kebilidi (eladocagene exuparvovec-tneq), an approved gene therapy for people with AADC deficiency, to multiple brain regions, according to a study in nonhuman primates (NHPs).
AADC deficiency is characterized by low levels of dopamine and serotonin, two neurotransmitters. While current delivery of Kebilidi into the putamen or midbrain restores dopamine production, it fails to improve serotonin production because it does not reach the relevant brainstem region.
“This broader targeting approach aims to enhance serotonin modulation and restore [neurological] balance, with potential benefits for cognitive and behavioral function in children with AADC deficiency undergoing gene therapy,” researchers wrote.
Details of the new method were described in the study, “Advancing AADC Deficiency Therapy Through MR-Guided Multisite Delivery of AAV2-hAADC to Dopaminergic and Serotonergic Pathways in the Brainstem,” published in Molecular Therapy Advances.
Gene therapy has little effect on serotonin levels
In AADC deficiency, mutations in the DDC gene disrupt the activity of an enzyme involved in the manufacturing of dopamine and serotonin, neurotransmitters that facilitate nerve cell communication in the brain and throughout the body. A lack of neurotransmitters leads to symptoms such as developmental delays, cognitive and behavioral problems, and movement disorders.
Kebilidi, sold as Upstaza in the European Union and the U.K., is an approved gene therapy for children and adults with AADC deficiency. It uses a modified adeno-associated virus serotype 2 (AAV2) to deliver a functional copy of the DDC gene to the putamen in the midbrain, restoring enzyme function and dopamine production.
While gene therapy can rescue dopamine synthesis, it has little effect on serotonin levels, likely because it does not adequately cover serotonin-producing neurons in the brainstem.
To address this gap and restore serotonin levels, a team led by researchers at The Ohio State University examined the feasibility of infusing the gene therapy into both the midbrain and the brainstem using real-time MR-guided delivery in adult NHPs.
“Restoring [serotonin] signaling may be critical for improving cognitive and behavioral outcomes, which are still not fully addressed by current dopamine-focused therapies,” the team wrote.
MRI scans showed treatment reached the intended brain areas
Half of the animals received gene therapy, while the other half received a saline solution for comparison. Before treatment, MRI scans were used to precisely locate the target brain areas. Small openings were made in the skull, and a special device was implanted to ensure accurate placement.
Using real-time MRI, doctors guided a thin tube to the midbrain region and slowly delivered the treatment. After a short pause, the same tube was moved deeper into the brainstem, where another dose was given. After the infusions, the tube and guidance device were carefully removed, and the surgical area was closed.
Post-treatment MRI scans showed the treatment reached the intended brain areas, but coverage varied from one animal to another. Still, when the results from all animals were combined, maps showed that the treatment consistently reached key target areas in the midbrain and brainstem.
NHPs that received the gene therapy showed much higher levels of the AADC enzyme in the targeted brain areas than those that received saline. Increases in dopamine- and serotonin-related brain regions confirmed that the therapy reached the correct locations and was active.
Higher AADC levels were also detected in connected brain regions, especially in animals where the treatment covered more of the target areas. Animals given saline did not show these changes. Measurements of cerebrospinal fluid, which surrounds the brain and spinal cord, showed no significant effect on dopamine or serotonin levels, indicating no widespread changes in brain chemistry.
This study demonstrated the safety and tolerability of a multi-target approach, supporting the potential inclusion of serotonergic nuclei in the clinical development of [gene therapy] for treating [AADC deficiency].
All animals tolerated the surgical dosing procedure, with no adverse events reported. Body weight, general activity, and behavior remained stable, with no behavioral abnormalities observed.
Elevated levels of neurofilament light chain, a marker of nerve damage, were detected in the blood one month after the procedure and returned to normal levels shortly thereafter. The team suggested this was likely due to the short-term trauma caused by tissue disruption during tube insertion.
Other blood tests and tissue examinations showed no abnormalities, except for a small accumulation of inflammatory cells near the tube tracts, but not in the surrounding tissue.
Increases in AADC activity did not cause behavioral problems or brain damage. Tissue testing showed that AADC overexpression led to mild, localized inflammation at the injection sites, limited to the treated areas and not seen elsewhere in the brain. Similar, but milder, changes were also observed in saline-treated animals.
Blood tests showed no signs of a body-wide immune response over five months. Some treated animals developed low levels of antibodies against AAV2, but this didn’t reduce treatment efficacy.
“This study demonstrated the safety and tolerability of a multi-target approach, supporting the potential inclusion of serotonergic nuclei in the clinical development of [gene therapy] for treating [AADC deficiency],” the researchers wrote.
