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

Trial Summary

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.

What data supports the effectiveness of the treatment for AADC deficiency?

Adeno-associated virus (AAV) vectors, like the one used in this treatment, have shown promise in gene therapy for various rare diseases, including AADC deficiency, by delivering therapeutic genes directly to target cells. AAV2 vectors have been successfully used in treating AADC deficiency through direct brain injections, showing good results in clinical settings. ^{1 2 3 4 5}

How is the gene therapy treatment AAV2-hAADC unique for AADC deficiency?

AAV2-hAADC is a gene therapy that uses a virus to deliver a healthy copy of the AADC gene directly into the brain, which is different from traditional treatments that may not address the root genetic cause. This approach aims to provide a long-term solution by enabling the body to produce the necessary enzyme on its own. ^{1 2 4 6 7}

What is the purpose of this trial?

The overall objective of this study is to determine the safety and efficacy of AAV2-hAADC delivered to the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) in children with aromatic L-amino acid decarboxylase (AADC) deficiency.

Research Team

Krystof Bankiewicz, MD, PhD

Principal Investigator

OSU Professor of Neurological Surgery

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

References

1. United States 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. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Phase 2 clinical trial of a recombinant adeno-associated viral vector expressing α1-antitrypsin: interim results. [2022]

3. United States 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. [2013]

4. England pubmed.ncbi.nlm.nih.gov

Recombinant adeno-associated virus vectors in the treatment of rare diseases. [2020]

5. Singapore pubmed.ncbi.nlm.nih.gov

Adeno-associated virus vector-based gene therapies for pediatric diseases. [2023]

6. Germany pubmed.ncbi.nlm.nih.gov

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

7. Germany pubmed.ncbi.nlm.nih.gov

Gene Therapy for Hemophilia-Opportunities and Risks. [2023]