Upstaza (eladocagene exuparvovec)
Gene therapy for aromatic L-amino acid decarboxylase (AADC) deficiency
Quick facts about Upstaza
Key takeaways about Upstaza
- First gene therapy for AADC deficiency: Upstaza is the first and only approved gene therapy for this ultra-rare inherited neurological disorder affecting neurotransmitter production
- One-time treatment via brain surgery: Administered as a single intraputaminal infusion under general anesthesia by experienced neurosurgeons, making it a one-time procedure
- Restores neurotransmitter synthesis: Delivers a functional DDC gene that enables the brain to produce AADC enzyme, restoring dopamine and serotonin production
- For patients 18 months and older: Approved for children and adults with confirmed AADC deficiency who are at least 18 months of age
- Approved under exceptional circumstances: Due to the extreme rarity of the condition, long-term efficacy data continues to be collected through patient registries
What Is Upstaza and What Is It Used For?
Upstaza (eladocagene exuparvovec) is a gene therapy medicine used to treat aromatic L-amino acid decarboxylase (AADC) deficiency, an extremely rare inherited disorder that prevents the nervous system from producing essential neurotransmitters. It is approved for patients aged 18 months and older and is administered as a single, one-time infusion directly into the brain.
AADC deficiency is caused by mutations in the DDC gene, which is responsible for producing the enzyme aromatic L-amino acid decarboxylase. This enzyme plays a critical role in the biosynthesis of dopamine and serotonin, two neurotransmitters that are essential for normal brain and nervous system function. Without adequate AADC activity, the body cannot convert L-DOPA to dopamine or 5-hydroxytryptophan to serotonin, resulting in a severe deficiency of these chemical messengers.
The clinical consequences of AADC deficiency are profound. Children with this condition typically present with severe hypotonia (low muscle tone), developmental delay, and movement disorders. Many affected children are unable to hold their heads up, sit independently, or walk. They may also experience oculogyric crises (episodes of sustained involuntary upward eye deviation), feeding difficulties, excessive sweating, temperature instability, and sleep disturbances. The condition significantly impairs quality of life for both patients and their families.
Upstaza works by delivering a functional copy of the human DDC gene directly into brain cells. The active substance, eladocagene exuparvovec, uses a modified adeno-associated virus serotype 2 (AAV2) as a vector to transport the gene into cells in the putamen, a region of the brain where AADC enzyme is normally produced. Once inside the cells, the gene provides instructions for producing functional AADC enzyme, which then enables the synthesis of dopamine and serotonin. The AAV2 vector used in Upstaza does not cause disease in humans and is a well-characterized delivery system in gene therapy.
AADC deficiency is estimated to affect fewer than 1 in 100,000 people worldwide, making it an ultra-rare condition. The disease was first described in 1990, and as of 2024, approximately 350 cases have been identified globally, though the true prevalence may be higher due to underdiagnosis. It follows an autosomal recessive inheritance pattern, meaning both parents must carry a mutation in the DDC gene for a child to be affected.
Upstaza was approved by the European Medicines Agency (EMA) in July 2022 under "exceptional circumstances" due to the rarity of AADC deficiency, which made it impossible to obtain complete clinical data. The EMA reviews any new information annually and updates the product information as needed. Patients may be offered participation in a registry to further evaluate long-term safety and efficacy.
What Should You Know Before Taking Upstaza?
Before treatment with Upstaza, patients and caregivers must be fully informed about the neurosurgical procedure, potential risks including cerebrospinal fluid leakage, dyskinesia, and insomnia, as well as post-operative precautions. Upstaza should not be given to anyone with a known allergy to any of its ingredients.
Contraindications
Upstaza must not be administered to patients who are allergic (hypersensitive) to eladocagene exuparvovec or to any of the other ingredients in the formulation, including potassium chloride, sodium chloride, potassium dihydrogen phosphate, disodium hydrogen phosphate, poloxamer 188, and water for injections. Prior to treatment, the medical team will conduct a thorough assessment to identify any potential allergies or contraindications.
Warnings and Precautions
Several important warnings and precautions apply to treatment with Upstaza. The treating physician will discuss these in detail before the procedure takes place.
Dyskinesia and insomnia: Mild to moderate involuntary jerky movements (dyskinesia) or sleep disturbances (insomnia) may develop or worsen approximately one month after treatment and can persist for several months. The healthcare team will determine whether additional treatment is needed to manage these effects.
Surgical complications: As Upstaza is administered through neurosurgery, there are inherent surgical risks to consider. The physician will monitor for complications including cerebrospinal fluid leakage, meningitis (inflammation of the membranes surrounding the brain and spinal cord), and encephalitis (inflammation of brain tissue). In the days immediately following surgery, the medical team will closely monitor for any complications related to the surgery, the underlying disease, and the effects of anesthesia. Some disease symptoms may temporarily worsen during this period.
Residual symptoms: It is important to understand that some symptoms of AADC deficiency may persist even after successful treatment. These residual symptoms can include effects on mood, sweating, and body temperature regulation.
Shedding precautions: After treatment, small amounts of the gene therapy product may be present in the patient's body fluids (such as tears, blood, nasal secretions, and cerebrospinal fluid) for a limited period. This is known as "shedding." Caregivers should wear gloves and place all used dressings and materials that have come into contact with tears and nasal secretions in sealed bags before disposal. These precautions should be followed for 14 days after treatment. This is particularly important for caregivers who are pregnant, breastfeeding, or immunosuppressed.
Blood and organ donation: Patients who have received Upstaza must not donate blood, organs, tissues, or cells for transplantation at any time after treatment, as Upstaza is a gene therapy product.
Upstaza has not been studied in children under 18 months of age, and there is limited experience in children over 12 years. The safety and efficacy in these age groups have not been established. Always discuss the risks and benefits of treatment with the specialist medical team before proceeding.
Pregnancy and Breastfeeding
The effects of Upstaza on pregnancy and the unborn child are not known. Upstaza has not been studied in pregnant or breastfeeding women. There is no information available regarding the effect of Upstaza on male or female fertility. Patients of reproductive age should discuss family planning considerations with their healthcare provider before and after treatment.
Other Medicines and Vaccinations
Patients and caregivers should inform the treating physician about all medicines currently being taken, recently taken, or planned. The physician will confirm whether routine vaccinations can proceed as scheduled or whether adjustments to the vaccination timeline are necessary. This is particularly important as the immune system may be affected by the surgical procedure and anesthesia.
How Does Upstaza Interact with Other Drugs?
As a one-time gene therapy administered directly into the brain, Upstaza has a unique pharmacological profile. Formal drug interaction studies have not been conducted due to its mechanism of action and single-dose administration. However, certain medications used before, during, and after the procedure require careful management.
Because Upstaza is delivered directly to the brain through neurosurgery and acts by providing a gene rather than circulating systemically like conventional drugs, the potential for traditional drug-drug interactions is limited. However, the following considerations are clinically important:
| Medication/Class | Interaction Type | Clinical Consideration |
|---|---|---|
| Dopamine agonists (e.g., pramipexole, ropinirole) | Pharmacological overlap | May need dose adjustment as Upstaza restores endogenous dopamine production; monitor for dyskinesia |
| MAO inhibitors (e.g., selegiline, rasagiline) | Pharmacological overlap | May potentiate dopaminergic effects post-treatment; careful monitoring recommended |
| Immunosuppressants | Potential immune modulation | May affect immune response to AAV2 vector; discuss timing with treatment team |
| Anticoagulants/antiplatelet agents | Surgical risk | Must be discontinued before neurosurgery per surgical protocol; risk of intracranial bleeding |
| Vaccines (live attenuated) | Timing consideration | Vaccination schedule may need adjustment around the time of surgery; consult physician |
| Antiepileptic drugs | Supportive care | May be continued as needed; seizure management should be coordinated with neurology team |
The treating physician and neurosurgical team will conduct a comprehensive medication review before the procedure. Any medications that could interfere with anesthesia, increase bleeding risk, or affect the immune response to the viral vector will be carefully evaluated and managed. Patients should provide a complete list of all prescription and over-the-counter medications, supplements, and herbal products they are taking.
What Is the Correct Dosage of Upstaza?
Upstaza is administered as a single, one-time dose of 1.8 x 1011 vector genomes, delivered through four intraputaminal infusions (two per putamen) during a neurosurgical procedure. The dose is the same for all eligible patients regardless of age or weight.
Unlike conventional medicines that require ongoing dosing, Upstaza is designed to be given only once. The gene therapy delivers a permanent copy of the functional DDC gene to brain cells, where it continues to direct production of the AADC enzyme over time. There is no need for repeat dosing, and re-administration has not been studied.
How Upstaza Is Administered
Upstaza is administered in an operating room by neurosurgeons experienced in stereotactic brain surgery, under carefully controlled aseptic conditions. The procedure takes place under general anesthesia and involves the following steps:
- Stereotactic planning: The neurosurgeon defines four target sites in the putamen (two anterior and two posterior points, bilaterally) using standard stereotactic neurosurgical planning techniques.
- Surgical access: Two small openings (burr holes) are made in the skull, one on each side. The surgical openings are made through both the skull bone and the dura mater.
- Cannula placement and infusion: An infusion cannula is guided to each target point using stereotactic instruments. At each of the four target sites, 0.08 mL of Upstaza is infused at a rate of 0.003 mL/min, giving a total infusion volume of 0.320 mL (1.8 x 1011 vector genomes).
- Closure and imaging: After the infusions are complete, the skull openings are closed and the patient undergoes post-operative brain imaging (MRI or CT scan) to confirm that no complications such as bleeding have occurred.
Dosage Summary
Total dose: 1.8 x 1011 vector genomes (vg)
Volume per infusion site: 0.08 mL (0.45 x 1011 vg)
Number of infusion sites: 4 (2 per putamen: anterior and posterior)
Total infusion volume: 0.320 mL
Infusion rate: 0.003 mL/min per site
Population: Same dose for all patients aged 18 months and older
Post-operative Care
After the procedure, the patient must remain at or near the hospital for at least 48 hours. During this time, the medical team will monitor for any complications from the surgery, anesthesia, or the gene therapy itself. Two scheduled follow-up visits are planned:
- First follow-up (approximately 1 week post-surgery): Assessment for surgical complications, early recovery evaluation, and monitoring for initial side effects.
- Second follow-up (approximately 3 weeks post-surgery): Continued monitoring of recovery, assessment for dyskinesia and insomnia, and evaluation of any treatment-related effects.
Long-term follow-up care is managed jointly by the neurosurgeon and the referring neurologist. Patients will be offered participation in a patient registry to help evaluate the long-term safety and efficacy of Upstaza treatment under real-world clinical conditions.
Overdose
Because Upstaza is administered by a specialized medical team in a controlled hospital setting, overdose is highly unlikely. The precise volume at each infusion site is carefully controlled using calibrated infusion pumps. In the unlikely event that more than the intended dose is administered, the medical team will monitor the patient for any adverse effects and provide supportive treatment as needed.
What Are the Side Effects of Upstaza?
The most common side effects directly attributable to Upstaza are insomnia (difficulty sleeping) and dyskinesia (involuntary movements), which typically appear about one month after treatment. Additional side effects are associated with the neurosurgical procedure itself, including anemia, cerebrospinal fluid leakage, and pneumonia.
Like all medicines, Upstaza can cause side effects, although not everybody gets them. It is important to distinguish between side effects caused by the gene therapy itself and those related to the surgical procedure and anesthesia. The following side effects have been reported in clinical studies:
Side Effects from Upstaza (Gene Therapy)
Very Common
May affect more than 1 in 10 patients
- Insomnia (difficulty sleeping)
- Dyskinesia (involuntary jerky movements)
Common
May affect up to 1 in 10 patients
- Feeding difficulties
- Irritability
- Increased salivation (hypersalivation)
Dyskinesia and insomnia are the most characteristic side effects of Upstaza and are thought to reflect the onset of neurotransmitter production as the gene therapy begins to work. These effects typically appear approximately one month after the procedure and may persist for several months. The treating physician will assess whether medication is needed to manage these symptoms. In most cases, they are mild to moderate in severity and tend to improve over time as the nervous system adjusts to the restored neurotransmitter production.
Side Effects from the Surgical Procedure
Very Common (Surgery-related)
May affect more than 1 in 10 patients
- Anemia (low red blood cell count)
- Cerebrospinal fluid leakage (symptoms may include headache, nausea, vomiting, neck pain or stiffness, altered hearing, imbalance, dizziness, or vertigo)
Side Effects in the First Two Weeks After Surgery
The following side effects may occur within the first two weeks after the procedure, primarily due to the effects of general anesthesia and the neurosurgical operation itself:
Very Common (Post-operative)
May affect more than 1 in 10 patients
- Pneumonia (lung infection)
- Hypokalemia (low potassium levels in the blood)
- Irritability
- Hypotension (low blood pressure)
- Gastrointestinal bleeding, diarrhea
- Pressure sores (decubitus ulcers)
- Fever (pyrexia)
- Abnormal breathing sounds
Common (Post-operative)
May affect up to 1 in 10 patients
- Gastroenteritis (stomach and intestinal infection)
- Dyskinesia (involuntary jerky movements)
- Cyanosis (bluish skin discoloration due to low oxygen)
- Hypovolemic shock (severe loss of blood or body fluids)
- Respiratory failure
- Mouth ulcers
- Diaper rash, skin rash
- Hypothermia (low body temperature)
- Tooth extraction
Many of the surgical and post-operative side effects are expected consequences of any neurosurgical procedure performed under general anesthesia, particularly in young children with severe neurological conditions. The medical team is prepared to manage these complications and will closely monitor patients throughout the recovery period. It is essential that caregivers promptly report any concerning symptoms to the healthcare team.
It is important to report any suspected side effects after treatment with Upstaza. Reporting allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients can report suspected adverse reactions to their national medicines regulatory authority.
How Should You Store Upstaza?
Upstaza must be stored and transported frozen at -65°C or below. It is thawed before use and must be used within 6 hours of thawing. Once thawed, it must not be refrozen. Storage and handling are exclusively managed by hospital pharmacy staff.
Patients and caregivers do not need to handle or store Upstaza themselves, as the medicine is exclusively managed by hospital pharmacy and surgical teams. However, understanding the storage requirements helps appreciate the complexity and precision involved in gene therapy treatment.
Upstaza is delivered to the hospital frozen and must be maintained in its outer carton at a temperature of -65°C or below until preparation for use. The thawing process is carefully controlled: the frozen vial is allowed to thaw upright at room temperature until the contents are completely liquid. After thawing, the vial is gently inverted approximately three times (never shaken) and visually inspected. If particles, cloudiness, or discoloration are observed, the product must not be used.
Once thawed, the clock begins on a strict 6-hour window during which the product must be drawn into a syringe, transported to the operating room, and infused into the patient. This tight timeline requires precise coordination between the pharmacy team, the neurosurgical team, and the anesthesia team. The product must not be refrozen after thawing. Each vial is for single use only, and any unused product must be disposed of according to local guidelines for pharmaceutical waste.
The expiry date is printed on the outer carton. Do not use Upstaza after the stated expiry date.
What Does Upstaza Contain?
Each 0.5 mL vial of Upstaza contains 2.8 x 1011 vector genomes of eladocagene exuparvovec as the active substance, along with excipients including potassium chloride, sodium chloride, and poloxamer 188. The solution is clear to slightly opalescent and colorless to slightly white.
Active Substance
The active substance is eladocagene exuparvovec, a recombinant adeno-associated viral vector serotype 2 (AAV2) containing a functional copy of the human DDC gene. Each 0.5 mL vial contains 2.8 x 1011 (280 billion) vector genomes. The AAV2 vector is a non-pathogenic virus that has been genetically modified to carry the therapeutic gene and cannot replicate or cause disease in humans.
Excipients (Inactive Ingredients)
- Potassium chloride - buffer component
- Sodium chloride - maintains osmolality
- Potassium dihydrogen phosphate - buffer component
- Disodium hydrogen phosphate - buffer component
- Poloxamer 188 - surfactant to prevent viral aggregation
- Water for injections - solvent
Upstaza contains less than 1 mmol (23 mg) of sodium per dose, meaning it is essentially "sodium-free." It also contains less than 1 mmol (39 mg) of potassium per dose, making it essentially "potassium-free." These low levels are not clinically significant.
Packaging
Upstaza is supplied as a clear to slightly opalescent, colorless to slightly white solution for infusion in a clear glass vial. Each carton contains one single-use vial. The product is manufactured by Almac Pharma Services (Ireland) Limited and marketed by PTC Therapeutics International Limited, Dublin, Ireland.
Frequently Asked Questions About Upstaza
Upstaza is used to treat patients aged 18 months and older with aromatic L-amino acid decarboxylase (AADC) deficiency, an ultra-rare inherited neurological disorder. AADC deficiency prevents the brain from producing essential neurotransmitters (dopamine and serotonin), causing severe developmental delays, movement difficulties, feeding problems, and other neurological symptoms. Upstaza is the first gene therapy approved for this condition.
Upstaza is administered through a neurosurgical procedure under general anesthesia. The neurosurgeon makes two small holes in the skull and uses stereotactic guidance to infuse the gene therapy into four precise locations in the putamen (a brain structure involved in movement). The total infusion delivers 0.320 mL of solution. After the procedure, the patient undergoes brain imaging and stays near the hospital for at least 48 hours, with follow-up visits at 1 and 3 weeks.
The most common side effects directly related to Upstaza are insomnia and dyskinesia (involuntary movements), which typically appear about one month after treatment. Side effects related to the surgery include anemia, cerebrospinal fluid leakage, pneumonia, low potassium levels, and fever. Most side effects are manageable and the medical team will closely monitor the patient throughout recovery.
No, Upstaza is designed as a single, one-time treatment. The gene therapy delivers a permanent functional copy of the DDC gene to brain cells, enabling ongoing production of the AADC enzyme. There are no data on repeat administration. The one-time nature of the treatment is a key advantage of gene therapy over conventional long-term medications.
AADC deficiency is an extremely rare inherited genetic disorder caused by mutations in the DDC gene. This gene controls production of the enzyme aromatic L-amino acid decarboxylase, which is essential for making the neurotransmitters dopamine and serotonin. Without this enzyme, children experience severe developmental delays, hypotonia (low muscle tone), movement disorders, oculogyric crises, feeding difficulties, and impaired cognitive development. It is estimated to affect fewer than 1 in 100,000 people worldwide.
Upstaza provides a functional copy of the DDC gene that enables the brain to produce the AADC enzyme and restore neurotransmitter synthesis. Clinical studies have shown significant improvements in motor function, developmental milestones, and quality of life. However, some symptoms of AADC deficiency may persist after treatment, particularly those related to mood, sweating, and temperature regulation. Because the condition is so rare, Upstaza was approved under exceptional circumstances, and long-term data continues to be collected through patient registries.
References
All information in this article is based on the following international medical sources and regulatory documents:
- European Medicines Agency (EMA). Upstaza (eladocagene exuparvovec) - Summary of Product Characteristics. First authorized July 2022, last updated April 2025. Available at: EMA - Upstaza EPAR.
- Wassenberg T, Molero-Luis M, Jeltsch K, et al. Consensus guideline for the diagnosis and treatment of aromatic l-amino acid decarboxylase (AADC) deficiency. Orphanet Journal of Rare Diseases. 2017;12(1):12. doi:10.1186/s13023-016-0522-z.
- Chien YH, Lee NC, Tseng SH, et al. Efficacy and safety of AAV2 gene therapy in children with aromatic L-amino acid decarboxylase deficiency: an open-label, phase 1/2 trial. Lancet Child Adolesc Health. 2017;1(4):265-273. doi:10.1016/S2352-4642(17)30125-6.
- Kojima K, Nakajima T, Taga N, et al. Gene therapy improves motor and mental function of aromatic l-amino acid decarboxylase deficiency. Brain. 2019;142(2):322-333. doi:10.1093/brain/awy331.
- PTC Therapeutics International Limited. Upstaza Package Leaflet: Information for the Patient. Last revised April 2025.
- European Medicines Agency. Assessment report: Upstaza. Procedure No. EMEA/H/C/005352/0000. Committee for Medicinal Products for Human Use (CHMP), 2022.
- World Health Organization (WHO). International Classification of Diseases, 11th Revision (ICD-11). Geneva: World Health Organization; 2019.
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