Alpha 1-Antitrypsin Deficiency
Conditions
Keywords
AAT, Emphysema, Gene therapy, DLCO, Augmentation therapy
Brief summary
This is a study of gene therapy to treat alpha 1-antitrypsin (AAT) deficiency. This study aims to treat AAT deficiency with a single administration of AAV8hAAT(AVL), a gene therapy that codes for an oxidation resistant form of the AAT protein, which if safe and if efficacious, will protect the lung on a persistent basis. We hope to learn the safety/toxicity and initial evidence of efficacy of intravenous delivery of this gene therapy to alpha 1-antitrypsin deficient individuals.
Interventions
BIOLOGICALAAV8hAAT(AVL)
AAV8hAAT(AVL) gene transfer vector
Sponsors
Weill Medical College of Cornell University
National Heart, Lung, and Blood Institute (NHLBI)
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* AAT genotype ZZ, or Z null heterozygotes, and if on augmentation therapy, pre-therapy AAT serum levels \<11 μM * Emphysema as assessed by chest high resolution computational tomography (HRCT) * Lung function parameters consistent with mild to moderate loss of lung function and the presence of emphysema. * Troponin T within normal limits * Normal liver ultrasound and serum alpha fetoprotein * Normal kidney function * No contraindications to receiving corticosteroid immunosuppression
Exclusion criteria
* Individuals receiving systemic corticosteroids or other immunosuppressive medications for pre-existing conditions. * Inability to tolerate immunosuppression with corticosteroids (e.g., uncontrolled diabetes) * Individuals with an immunodeficiency disease, or evidence of active infection of any type, including human immunodeficiency virus * Evidence of major central nervous system, major psychiatric, musculoskeletal or immune disorder * Prior history of myocardial infarction or cancer within the past 5 years (other than basal cell carcinoma of the skin) * Decompensated heart failure (NY4A class III-IV at time of baseline clinical assessment) * Abnormal ECG at screening with findings consistent with cardiac disease * Females who are currently pregnant or lactating * Any history of allergies to drugs used for bronchoscopy, including xylocaine, lidocaine, versed, valium, atropine, pilocarpine, isoproterenol, terbutaline, aminophylline, or any local anesthetic * Individuals receiving experimental medications or participating in another experimental protocol for at least 3 months prior to entry to the study * Use of oxygen supplementation * Risk for thromboembolic disease * History of significant cardiovascular disease, hypertension, prior myocardial infarction and/or cerebrovascular event * Individuals who are currently on beta-blockers, or other cardiac therapy related drugs * Prior history of hypersensitivity or anaphylaxis associated with the administration of any AAT product
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety of AAV8hAAT(AVL), as measured by number of subjects with at least 1 serious adverse event. | Approximately 1 year | Serious adverse events will only be included if assessed as related to the gene therapy. |
| Toxicity of AAV8AAT(AVL), as measure by number of subjects with any dose limiting toxicity | Approximately 2 years | If none of the first 4 dosed participants experiences a DLT by the end of Day 28 after treatment (Day 1), the dose of AAV8hAAT(AVL) will be escalated, and the next cohort of participants will start treatment at the next-higher dose level. |
| Establishing a maximum tolerable dose of AAV8hAAT(AVL) | Approximately 2 years | If none of the first 4 participants treated at the highest dose level experiences a DLT by the end of Day 28 after treatment, this dose will be determined to be the maximum administered dose (MAD) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in serum | 4 weeks | Serum levels of AAT will be measured in the blood |
| Efficacy of AAV8hAAT(AVL) as measured by the levels of AAT in lung epithelial lining fluid | 12 months | Levels of AAT in the lung will be measured by bronchoscopy (if performed) |
Countries
United States
Contacts
CONTACTNiamh Savage
CONTACTSandra Hyde
PRINCIPAL_INVESTIGATORRonald G Crystal, MD
Weill Medical College of Cornell University
Outcome results
None listed