Gene Therapy for AADC Deficiency

(AADC Trial)

Recruiting at 2 trial locations

Overseen By Faizan Qureshi

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: Krystof Bankiewicz

Must not be taking: Anticoagulants, Investigational agents

Disqualifiers: Intracranial neoplasm, Congenital heart disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 90 days between initial doses for Cohort 1

42 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a gene therapy for children with AADC deficiency, a rare condition affecting movement and development due to a lack of a specific enzyme. The main goal is to assess the treatment's safety and effectiveness by delivering a modified virus to certain brain areas. The trial includes different groups receiving varying doses to determine the best approach for future studies. Children who cannot walk independently, have tried other treatments without success, and meet specific medical criteria might be suitable candidates.

As a Phase 1 trial, participants will be among the first to receive this new treatment, aiding researchers in understanding how it works in people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it mentions that participants should have failed to benefit from standard medical therapy. It's best to discuss your current medications with the study team.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that the gene therapy treatment AAV2-hAADC has been safe in previous studies. For example, studies with children who have AADC deficiency reported benefits such as weight gain and fewer episodes of uncontrolled eye movements and muscle movement problems. Another study found that this treatment was well-tolerated and helped improve motor skills in children. Additionally, in adults with Parkinson's disease, a related condition, the treatment was also safe and well-tolerated. Importantly, no deaths occurred in the safety analysis of one study, suggesting a positive safety outcome. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for AADC deficiency, which often involve medications to manage symptoms, AAV2-hAADC is a gene therapy that targets the root cause of the condition. This treatment works by delivering a functional copy of the AADC gene directly into the brain regions affected by the deficiency, using an image-guided method called convection-enhanced delivery. Researchers are excited because this approach has the potential to provide long-lasting benefits by restoring the enzyme production needed for normal neurotransmitter function, potentially reducing or eliminating the need for lifelong medications.

What evidence suggests that this gene therapy might be an effective treatment for AADC deficiency?

Research has shown that a new gene therapy, AAV2-hAADC, could help treat AADC deficiency. In this trial, participants will receive AAV2-hAADC. Studies have found that children who received this therapy gained weight and experienced fewer episodes of uncontrolled eye and body movements. Long-term evidence suggests that this treatment is safe and offers significant benefits. Specifically, children treated with this therapy demonstrated better survival rates and improved quality of life compared to those receiving standard care. These findings offer hope for families seeking effective treatments for AADC deficiency. ^{1 2 5 6 7}

Who Is on the Research Team?

Krystof Bankiewicz, MD, PhD

Principal Investigator

OSU Professor of Neurological Surgery

Are You a Good Fit for This Trial?

This trial is for children aged 4 and older with AADC deficiency, a rare metabolic disorder. They must have a stable medication regimen, confirmed diagnosis through specific tests, be unable to walk independently, and have no recent changes in medications. Children who haven't benefited from standard treatments may qualify. Those with certain medical conditions or previous brain surgery are excluded.

Inclusion Criteria

I am at least 24 months old.

My brain MRI is clear for stereotactic surgery.

Standard treatments haven't improved my eye movement issues or developmental delays.

Exclusion Criteria

I have a blood clotting disorder or need continuous blood thinner treatment.

I have not taken any experimental drugs in the last 60 days.

I do not have major health issues that would make surgery or anesthesia very risky.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Single-stage dose-escalation, open-label safety study of AAV2-hAADC delivered by image-guided convection-enhanced delivery into the substantia nigra pars compacta and the ventral tegmental area

90 days between initial doses for Cohort 1

Follow-up

Participants are monitored for safety and effectiveness after treatment, including adverse events and changes in neurotransmitter metabolite concentrations

2 years

Long-term Follow-up

Evaluation of clinical outcomes such as motor function and quality of life over an extended period

2 years

What Are the Treatments Tested in This Trial?

Interventions

• AAV2-hAADC

Trial Overview The study is testing the safety and effectiveness of delivering the gene therapy drug AAV2-hAADC directly into parts of the brain responsible for movement control in kids with AADC deficiency. The goal is to see if this treatment can improve symptoms related to this genetic condition.

How Is the Trial Designed?

Group I: Single treatment arm Experimental Treatment 1 Intervention

Single-stage dose-escalation, open-label safety study of AAV2-hAADC delivered by image-guided convection-enhanced delivery bilaterally into the substantia nigra pars compacta and the ventral tegmental area of pediatric patients with AADC deficiency. Primary aim is to determine the dose for future studies based on safety, biomarkers of pharmacological activity of AADC and clinical outcomes. Cohort 1 (3 subjects) will receive a single low dose of AAV2 hAADC. The total AAV2-hAADC dose will be infused via MR guided infusion into 4 sites in both the left and right SNc and VTA. Dose intervals will be 90 days between the first 3 subjects. Cohort 2 dose (4 subjects) will be determined by Cohort 1 results. Following Cohort 2, Cohort 3/4 will be dose and divided divided by age. Cohorts 3/4 will receive the same dose by MR guided infusion to 1-2 sites bilaterally in-between the SNc and VTA. Cohort 5 (24-47mo old) will have same vector concentration and lower volume of infusion than Cohorts 3/4

AAV2-hAADC is already approved in European Union, United Kingdom, United States for the following indications:

Approved in European Union as Upstaza for:

• Aromatic L-amino acid decarboxylase (AADC) deficiency

Approved in United Kingdom as Upstaza for:

• Aromatic L-amino acid decarboxylase (AADC) deficiency

Approved in United States as Eladocagene exuparvovec for:

• Aromatic L-amino acid decarboxylase (AADC) deficiency

Who Is Running the Clinical Trial?

Krystof Bankiewicz

Lead Sponsor

Trials

1

Recruited

40+

Krzysztof Bankiewicz

Lead Sponsor

Trials

1

Recruited

40+

National Institute of Neurological Disorders and Stroke (NINDS)

Collaborator

Trials

1,403

Recruited

655,000+

University of California, San Francisco

Collaborator

Trials

2,636

Recruited

19,080,000+

Published Research Related to This Trial

Coadministration of low doses of chemotherapeutic agents, such as doxorubicin, significantly enhances the transduction efficiency of rAAV2 vectors in retinal cells without causing toxicity, making it a promising strategy for gene therapy.

In a rat model of inherited retinal degeneration, combining rAAV2-CNTF with doxorubicin resulted in a two-fold increase in photoreceptor layer thickness, indicating improved therapeutic efficacy and protection of retinal cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enhancement of rAAV2-mediated transgene expression in retina cells in vitro and in vivo by coadministration of low-dose chemotherapeutic drugs. Zhang, S., Wu, J., Wu, X., et al.[2013]

Adeno-associated virus (AAV)-mediated gene therapy is a promising treatment option for over 7,000 rare diseases, offering potential advantages over traditional small molecule therapies.

Current clinical trials are primarily focused on safety in phase I/II studies for a limited number of rare diseases, but advancements in AAV vector technology and disease models are expected to enhance preclinical testing and expand future clinical applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recombinant adeno-associated virus vectors in the treatment of rare diseases. Hastie, E., Samulski, RJ.[2020]

Recombinant adeno-associated virus (rAAV) has shown great promise as a gene therapy vector, successfully promoting sustained gene expression in various tissues and demonstrating therapeutic benefits in preclinical models for conditions like hemophilia and vision deficiencies.

Clinical trials using rAAV2 for diseases such as hemophilia B and cystic fibrosis have begun, with early phase I results indicating safety, paving the way for future advancements in gene therapy applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adeno-associated virus as a gene therapy vector: vector development, production and clinical applications. Grieger, JC., Samulski, RJ.[2012]

In a phase I trial involving 12 adults with alpha1-antitrypsin deficiency, the intramuscular injection of a recombinant adeno-associated virus vector showed no serious adverse events, indicating a favorable safety profile for this gene therapy approach.

The trial demonstrated that vector DNA was detected in the blood of nearly all participants receiving higher doses, and one subject exhibited low-level expression of the therapeutic protein, suggesting potential efficacy in delivering the alpha1-antitrypsin gene, although results were complicated by prior protein replacement therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of intramuscular injection of a recombinant adeno-associated virus serotype 2 alphal-antitrypsin (AAT) vector in AAT-deficient adults. Brantly, ML., Spencer, LT., Humphries, M., et al.[2021]

In a phase 2 clinical trial involving nine individuals with α(1)-antitrypsin deficiency, the rAAV vector expressing human AAT was well tolerated, showing only mild side effects and no serious adverse events, indicating a favorable safety profile for this gene therapy approach.

The treatment resulted in a dose-dependent increase in serum levels of normal human AAT, peaking at day 30 and persisting for at least 90 days, although achieving therapeutic levels will require further enhancements in vector design or delivery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 clinical trial of a recombinant adeno-associated viral vector expressing α1-antitrypsin: interim results. Flotte, TR., Trapnell, BC., Humphries, M., et al.[2022]

Adeno-associated virus (AAV) gene therapy has shown promising results in treating conditions like aromatic l-amino acid decarboxylase deficiency and spinal muscular atrophy, with over 2000 patients treated using the AAV9 vector, which can cross the blood-brain barrier.

While AAV vectors are generally considered safe due to their low integration into chromosomes, there have been reports of serious adverse events, prompting ongoing research to create more efficient vectors that require lower dosages.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adeno-associated virus vector-based gene therapies for pediatric diseases. Muramatsu, K., Muramatsu, SI.[2023]

AAV-based gene therapy for hemophilia A has shown promising results, with patients experiencing a significant reduction in bleeding episodes (53% to 96%) after treatment, and maintaining elevated clotting factor levels for up to six years.

The most common side effect of this therapy is an inflammatory response, which occurs in 17% to 89% of patients and may require temporary immunosuppression, highlighting the need for careful monitoring and management during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene Therapy for Hemophilia-Opportunities and Risks. Miesbach, W., Klamroth, R., Oldenburg, J., et al.[2023]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37803205/

Long-Term Outcomes of Eladocagene Exuparvovec ... Patients treated with eladocagene exuparvovec were found to have improved survival and quality of life benefits compared to patients treated with BSC.

2. jamanetwork.com jamanetwork.com/journals/jama/fullarticle/2831389

Eladocagene Exuparvovec for Aromatic L-Amino Acid ... All children in Study AADC-002 had the severe phenotype at baseline. The primary efficacy outcome that served as the basis for the approval ...

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1465324921001523

88 safety and improved efficacy outcomes in children with ... In children with AADC deficiency who received eladocagene exuparvovec gene therapy, body weight increased and oculogyric crises and dyskinesia improved.

4. cell.com cell.com/molecular-therapy-family/molecular-therapy/fulltext/S1525-0016(21)00576-1

Long-term efficacy and safety of eladocagene exuparvovec ... Eladocagene exuparvovec treatment for aromatic L-amino acid decarboxylase deficiency provides durable and meaningful benefits with a favorable safety profile.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10611606/

Long-Term Outcomes of Eladocagene Exuparvovec ... To estimate the long-term benefits of eladocagene exuparvovec in patients with AADC deficiency compared with BSC, a model has been developed ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8822132/

Long-term efficacy and safety of eladocagene exuparvovec ... The first gene therapy trials showed that intraputaminal infusion of eladocagene exuparvovec is well tolerated and improves motor development in children with ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT01395641

Study Details | NCT01395641 | A Phase I/II Clinical Trial for ... This study is to prove the safety and efficacy of AAV2-hAADC treatment for patients with Aromatic L-amino acid decarboxylase (AADC) deficiency. Official Title.