First brain-delivered AAV therapy approved by FDA

Until recently, the rare genetic disease, aromatic L-amino acid decarboxylase (AADC) deficiency, had no cure. The disease, which begins in the first months after birth, affects physical, mental, and behavioral aspects of life, and treatment has mainly targeted symptoms. Things are changing, however, with the introduction of new gene therapies that attack the disease at its source.

FDA approval of kebilidi: A milestone in AAV gene therapy

On November 13, 2024, the Food and Drug Administration (FDA) approved a gene therapy to treat AADC deficiency in children and adults. The drug, from PTC Therapeutics, is the first adeno-associated virus (AAV) gene therapy delivered directly into the brain that the FDA has approved.

How kebilidi works to treat AADC deficiency

The gene therapy called Kebilidi (eladocagene exuparvovec-tneq) is an AAV type 2-based gene therapy that contains the human dopa decarboxylase (DDC) gene, which codes for the production of the AADC enzyme. AADC plays a crucial role in the last step of creating the neurotransmitters dopamine and serotonin. Lower levels of these neurotransmitters lead to impaired communication between neurons.

The safety that they found with this is wonderful. It's a dramatic improvement on motor function and quality of life for these patients.
– Christina Pacak, University of Minnesota

Surgical delivery and overcoming the blood brain barrier

Delivery of Kebilidi requires neurosurgeons to directly administer it to the putamen — a region of the brain involved in regulating movement — with a minimally invasive procedure that uses a 3D positioning system to guide delivery. Getting AAV drugs into the brain is challenging because of the blood-brain barrier, a membrane that helps defend the brain against bacteria, viruses and other harmful substances. This is useful under normal circumstances, but it is a barrier for gene delivery vehicles, said Guangping Gao, a gene therapy researcher at UMass Chan Medical School. To get gene therapies into the brain, surgeons need to inject them directly, or use an AAV serotype like AAV9 that could breach the blood-brain barrier due to the structure of its outer shell and receptor interactions.

Christina Pacak, a molecular biologist from the University of Minnesota, said that surgical delivery can help with the safety aspect of gene therapy. “It keeps the dose relatively low. It doesn’t need to be a systemic thing,” she said. However, this means that doctors can only give this therapy in specific centers with well-established neurosurgical techniques and imaging facilities. “It’s more than just an intravenous infusion, which would be a more simple procedure,” said Pacak. “There are always questions about access to these kinds of therapies for a lot of different reasons.”

Global approvals and clinical trial success

While Kebilidi is the first approval of the drug in the US, eladocagene exuparvovec has already been approved in a number of countries under the brand name Upstaza from PTC Therapeutics. In 2022, the UK and the EU approved Upstaza after three consecutive clinical trials in 26 patients, which found that patients quickly improved within 12 months after gene therapy and longer follow-ups found that three patients gained the ability to walk within three years after therapy (1). The FDA’s approval of Kebilidi was based on the positive safety and efficacy results of a global clinical trial, with long-term follow-up studies ongoing. “The safety that they found with this is wonderful. It's a dramatic improvement on motor function and quality of life for these patients,” said Pacak. “I think it's a real win.”

Gao also pointed out that the central nervous system (CNS) lends itself well to gene therapies like Kebilidi that only require a one-time injection. “The CNS is probably an ideal target for gene therapy drugs because of the nature of the cell types in the brain,” he said. Gao explained that because most neurons are terminally differentiated cells, which means they have reached their final state and can’t divide, they can achieve long-term gene expression from just a single dose.

“Its success or experience we learned from this translation and commercialization will help us to develop other CNS gene therapy products,” said Gao. As the first brain-delivered AAV gene therapy approved in the US, Kebilidi can inform gene therapy efforts to treat other brain diseases.

Frequently asked questions (FAQ)

1. What is AAV gene therapy and how does it work?
AAV gene therapy uses adeno-associated viruses as delivery vehicles to carry corrected genes into cells. In the case of AADC deficiency, the therapy delivers the functional dopa decarboxylase (DDC) gene to restore neurotransmitter production.

2. Why is FDA approval of Kebilidi significant?
The FDA approval marks the first brain-delivered AAV gene therapy in the United States, offering a groundbreaking treatment option for patients with AADC deficiency.

3. How is Kebilidi different from other FDA-approved gene therapies?
Unlike systemic gene therapies, Kebilidi is surgically delivered directly into the brain to bypass the blood-brain barrier, ensuring targeted treatment.

4. Could AAV gene therapy be used to treat other neurological diseases?
Yes, experts believe the success of Kebilidi paves the way for future AAV gene therapies targeting other central nervous system disorders.

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