Kebilidi: What was the first brain injected gene therapy approved by the FDA?

October 10, 2025 •

4 min read

On November 14, 2024, the FDA granted accelerated approval to eladocagene exuparvovec-tneq (brand name Kebilidi), which was the first brain injected gene therapy approved by the FDA. This milestone marks a new era for treating severe, rare neurological disorders by directly targeting the source of the problem in the central nervous system.

Quick Summary

Kebilidi is an adeno-associated virus-based gene therapy that delivers a functional DDC gene directly into the brain to treat AADC deficiency, a rare and life-threatening genetic disorder. It aims to restore neurotransmitter production and improve motor function via a one-time surgical procedure.

Key Points

First Intracranial Gene Therapy: Kebilidi (eladocagene exuparvovec) was the first gene therapy approved by the FDA that is directly injected into the brain.
Treatment for AADC Deficiency: Kebilidi treats Aromatic L-amino acid decarboxylase (AADC) deficiency, a rare and fatal genetic disorder.
Gene Delivery Mechanism: It uses a modified adeno-associated virus (AAV) vector to deliver a functional copy of the DDC gene to brain cells in the putamen.
Restores Neurotransmitter Production: By restoring the AADC enzyme, the therapy enables the brain to produce vital neurotransmitters like dopamine and serotonin.
One-Time Surgical Procedure: The therapy is administered through a single, stereotactic neurosurgical infusion into the brain.
Proven Clinical Benefits: Clinical trials demonstrated significant long-term improvements in motor function, including head control and the ability to sit unassisted.

Kebilidi: The Pioneer of Intracranial Gene Therapy

In a landmark decision, the U.S. Food and Drug Administration (FDA) approved Kebilidi (eladocagene exuparvovec-tneq) on November 14, 2024, for the treatment of aromatic L-amino acid decarboxylase (AADC) deficiency. This marked the first time a gene therapy administered directly into the brain received FDA approval, opening a new frontier in the treatment of genetic disorders affecting the central nervous system. AADC deficiency is a devastating and fatal genetic disorder that severely impacts a patient's physical, mental, and behavioral development. Kebilidi offers a transformative, one-time treatment that addresses the root cause of the condition by restoring the production of critical neurotransmitters.

Understanding Aromatic L-amino Acid Decarboxylase (AADC) Deficiency

AADC deficiency is an inherited, life-threatening disorder caused by mutations in the DDC gene, which is responsible for producing the AADC enzyme. This enzyme is crucial for the final step in the synthesis of important neurotransmitters, including dopamine and serotonin. A deficiency of this enzyme leads to low levels of these neurotransmitters, causing a wide range of debilitating symptoms from infancy, such as:

Severe developmental delays
Hypotonia (weak muscle tone)
Involuntary, abnormal movements (dyskinesia)
Oculogyric crises (painful, seizure-like episodes involving upward eye rotation)
Autonomic nervous system dysfunction, causing issues with temperature regulation, blood pressure, and sweating

Before Kebilidi, treatment was limited to supportive care to manage symptoms, but these approaches did not address the underlying genetic defect.

The Mechanism of Action: Delivering a Healthy Gene to the Brain

Kebilidi, also known as Upstaza in the EU and UK, utilizes a modified adeno-associated virus serotype 2 (AAV2) vector to deliver a functional copy of the DDC gene directly into the brain. The administration is performed via a one-time stereotactic surgical procedure, where the gene therapy is infused into the putamen region of the brain. The putamen is a critical area for motor function and contains the cells that need the AADC enzyme to produce dopamine.

Here’s how the treatment works:

Vector Delivery: The AAV2 vector, which has been rendered harmless and cannot replicate, carries the therapeutic DDC gene.
Targeted Infusion: During the surgical procedure, a neurosurgeon infuses the vector into the putamen.
Gene Expression: Once inside the nerve cells of the putamen, the vector releases the functional DDC gene.
Enzyme Production: The newly introduced gene allows the nerve cells to produce the missing AADC enzyme.
Neurotransmitter Restoration: With restored AADC enzyme activity, the cells can resume normal production of dopamine and serotonin, which in turn leads to a gradual improvement in motor function and other neurological symptoms.

Comparison: Kebilidi vs. Zolgensma

While both Kebilidi and Zolgensma are groundbreaking AAV-based gene therapies, they differ significantly in their administration, target, and disease focus. Zolgensma, approved in 2019 for spinal muscular atrophy (SMA), is administered intravenously, whereas Kebilidi is surgically delivered directly into the brain.


Feature	Kebilidi (eladocagene exuparvovec)	Zolgensma (onasemnogene abeparvovec)
FDA Approval	November 2024	May 2019
Disease Treated	Aromatic L-amino acid decarboxylase (AADC) deficiency	Spinal Muscular Atrophy (SMA)
Targeted Gene	DDC gene	SMN1 gene
Administration Route	Direct injection into the brain (putamen) via surgery	Single intravenous (IV) infusion
Targeted Area	Central nervous system (brain)	Systemic (body-wide, affecting motor neurons)
Mechanism	Delivers a functional DDC gene to restore dopamine production	Delivers a functional SMN1 gene to produce SMN protein
Patient Age	18 months and older	Pediatric patients less than two years of age with SMA

Clinical Evidence and Outcomes

The FDA's accelerated approval of Kebilidi was based on data from several clinical trials, which showed significant and sustained improvements in patients with AADC deficiency. Key findings included:

Long-Term Efficacy: Follow-up studies demonstrated that patients experienced long-term reductions in symptom severity.
Motor Function Improvements: Many patients showed transformational neurological improvements, such as gaining head control and the ability to sit unassisted.
Safety Profile: The treatment was generally well-tolerated, with common side effects including initial insomnia, irritability, and dyskinesia. Transient elevations in liver enzymes and decreases in platelet count were also observed but managed with monitoring.

The Significance of the Approval

The FDA's approval of the first brain-injected gene therapy is a major milestone for several reasons:

It validates the potential of directly delivering genetic material to the central nervous system to treat neurological disorders.
It provides hope for patients with other neurogenetic diseases that are difficult to treat with systemic therapies.
It demonstrates the increasing maturity of gene therapy technology and regulatory pathways for these advanced therapies.
It opens the door for further research and development into targeted, in-vivo gene therapies for a host of conditions affecting the brain.

Conclusion

Kebilidi's approval represents a significant step forward in the field of gene therapy and neuroscience. By providing a one-time treatment that addresses the underlying genetic cause of AADC deficiency, it offers a transformative solution for patients and their families who previously had limited options. This landmark achievement not only provides a new therapeutic option but also paves the way for future innovations in treating genetic neurological disorders by directly targeting the brain. The success of Kebilidi highlights the ongoing progress in developing safe and effective treatments for debilitating genetic conditions.

For more detailed information on AADC deficiency and gene therapy, you can visit the American Society of Gene & Cell Therapy website.

Note: The content mentions the brand name Upstaza, which is used in Europe, but the article focuses on the FDA-approved brand name Kebilidi for the US market.

Frequently Asked Questions

Kebilidi is the brand name for eladocagene exuparvovec-tneq, the first FDA-approved gene therapy to be injected directly into the brain. It is used to treat Aromatic L-amino acid decarboxylase (AADC) deficiency.

The FDA granted accelerated approval for Kebilidi on November 14, 2024, for the treatment of AADC deficiency.

Kebilidi is administered through a single, one-time stereotactic surgical procedure where the therapy is infused directly into the putamen region of the brain.

Kebilidi is indicated for adult and pediatric patients with a confirmed diagnosis of aromatic L-amino acid decarboxylase (AADC) deficiency.

Yes, eladocagene exuparvovec is sold under the brand name Kebilidi in the US and under the brand name Upstaza in the European Union and the UK.

The therapy uses an AAV vector to deliver a working copy of the DDC gene to nerve cells in the brain. This allows the cells to produce the missing AADC enzyme, which is necessary for creating dopamine and serotonin.

Common side effects include initial insomnia, irritability, and dyskinesia. Other side effects may include elevations in liver enzymes and changes in platelet count.

While both are AAV-based gene therapies, Kebilidi is injected directly into the brain for AADC deficiency, whereas Zolgensma is given via an IV for spinal muscular atrophy. Kebilidi is the first to use the intracranial delivery route.