AAV2 gene therapy vector movement tracked over time in rat brain study
AADC protein expression remained sustained as capsid signals declined
Written by |
Through a series of long-term experiments using rats, a team of U.S. scientists has tracked how an AAV2-based gene therapy vector similar to the one used in Kebilidi (eladocagene exuparvovec-tneq), an approved gene therapy for AADC deficiency, travels through the brain.
Results showed that capsid signals from the vector declined over time, especially at the injection site, while AADC protein expression remained sustained for more than a year.
The study, “AAV2 capsid clearance and neuronal trafficking dynamics in the central nervous system,” was published in Gene Therapy.
AADC deficiency is a genetic disorder caused by mutations in the DDC gene, which provides instructions to make the enzyme AADC. This enzyme is needed to make certain brain signaling molecules. In people with AADC deficiency, the enzyme is faulty or missing, so these signaling molecules cannot be made properly, disrupting brain signaling.
Kebilidi uses AAV2 vector to deliver DDC
Kebilidi, branded as Upstaza in Europe, is an approved gene therapy that delivers a healthy copy of the DDC gene to brain cells, allowing them to produce a functional AADC enzyme. It is sold by PTC Therapeutics. The study was conducted by researchers at The Ohio State University and did not report PTC involvement.
To deliver its genetic payload to brain cells, Kebilidi uses a viral vector — that is, a virus engineered to deliver a therapeutic gene rather than cause infection. Kebilidi uses an AAV2-based vector.
After delivering the therapeutic gene, the capsid, or outer shell of the viral vector, is expected to be processed, broken down, or cleared by cells. But there has not been much detailed information on exactly how the AAV2 vector moves through the brain, or how that movement relates to AADC protein expression over time.
In this study, scientists treated rats with an AAV2-based gene therapy designed to deliver the DDC gene, similar in concept to Kebilidi. The researchers then conducted detailed analyses of the rats’ brains at various time points, ranging from just a few days after treatment to more than a year later, to track how the vector moved through the brain and how AADC protein expression changed over time.
Results showed that, in the days immediately following gene therapy, AAV2 capsids were widely detectable in targeted brain regions. Over time, capsid signals declined, while AADC protein expression increased and remained sustained through the longest follow-up, more than a year after treatment.
“Overall, this work advances the understanding of AAV2 biology in the adult brain,” the researchers concluded. “These insights may support the rational design, optimization, and interpretation of AAV2-based gene therapy programs.”
