FDA Approves First Gene Therapy Directly Administered to the Brain for AADC Deficiency
Key Insights
The FDA granted accelerated approval to KEBILIDI™, a gene therapy for AADC deficiency (search), marking the first such therapy directly administered to the brain.
KEBILIDI™ delivers a healthy copy of the DDC gene via a modified virus, restoring dopamine production in patients with AADC deficiency (search).
Clinical trials demonstrated significant improvements in motor function and development in treated children, including the youngest patient who experienced remarkable progress.
The U.S. Food and Drug Administration (FDA) has granted accelerated approval to KEBILIDI™ (eladocagene exuparvovec), a gene therapy developed by PTC Therapeutics Inc., for the treatment of aromatic L-amino acid decarboxylase (AADC) deficiency. This marks a significant milestone as the first gene therapy approved in the United States that is directly administered to the brain.
AADC Deficiency and the Promise of Gene Therapy
AADC deficiency (search) is a rare, inherited genetic disorder caused by mutations in the DDC gene, leading to a deficiency in the AADC enzyme. This enzyme is crucial for the production of dopamine and serotonin, neurotransmitters essential for proper brain function, motor control, and overall development. The condition manifests in infancy with symptoms including muscle weakness, movement disorders, and developmental delays. Before this approval, treatment options were limited to managing symptoms, with little impact on the underlying cause.
KEBILIDI™ addresses the root cause of AADC deficiency (search) by delivering a functional copy of the DDC gene directly into the putamen, a region of the brain critical for motor control. The therapy utilizes a modified adeno-associated virus (AAV9) to deliver the gene, which then enables brain cells to produce the missing AADC enzyme and restore dopamine production.
Clinical Trial Results and Patient Outcomes
The approval was based on data from clinical trials demonstrating the safety and efficacy of KEBILIDI™. One notable case is that of Sriansh Ojha, who at 16 months old, became the youngest patient to receive the gene therapy as part of a clinical trial. Prior to treatment, Sriansh experienced severe motor and developmental impairments. Following the gene therapy, Sriansh showed remarkable improvements, including the ability to sit up independently and make developmental progress.
Donald Gilbert, MD, MS, a movement disorder expert at Cincinnati Children’s Hospital, emphasized the transformative impact of the therapy. "The way that a missing gene can be put in the brain in the place where it’s needed, in a single-day treatment, and then produce what is needed for the rest of a child’s life is amazing," said Gilbert.
The gene therapy, initially developed in Taiwan, has been tested since 2010 and approved for use in the European Union, the United Kingdom, and Israel in 2023. To date, approximately 30 children worldwide have received the treatment.
Surgical Procedure and Adaptations
The administration of KEBILIDI™ involves a stereotactic neurosurgical procedure to precisely deliver the AAV9 vector containing the DDC gene into the putamen. For younger patients like Sriansh, the surgical team at Cincinnati Children’s, led by Sudhakar Vadivelu, DO, adapted the procedure to accommodate the smaller anatomy and unique physiological considerations of infants. These modifications included changes to the surgical apparatus, burr hole placement, and anesthesia protocols.
"Adapting the procedure for the youngest children was important because the youngest patient has had one of the best outcomes. It’s a clear early difference right off the bat," Vadivelu noted.
The Future of AADC Deficiency Treatment
With the approval of KEBILIDI™, early diagnosis and treatment are now critical for maximizing patient outcomes. Gilbert suggests that AADC deficiency (search) could be included in newborn screening programs, similar to phenylketonuria (PKU) and other treatable genetic conditions. This would allow for early intervention and potentially prevent the severe neurological impairments associated with the disease.
"This is the first time there has been a therapy where you put a missing gene directly into the brain," Gilbert stated, highlighting the potential for gene therapy to address other genetic brain disorders in the future.