Clinical trial NCT00976352: Safety Study of Recombinant Adeno-Associated Virus Acid Alpha-Glucosidase to Treat Pompe Disease
Official title: Phase I/II Trial of Diaphragm Delivery of Recombinant Adeno-Associated Virus Acid Alpha-Glucosidase (rAAV1-CMV-GAA) Gene Vector in Patients With Pompe Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Pompe Disease
Keywords: Gene Therapy
Pompe Disease
Glycogen Storage Disease
Lead sponsor: University of Florida
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2009-09-14
Enrollment: 9
Sex: ALL
Minimum age (years): 2
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: Pompe disease is an inherited condition of acid alpha-glucosidase (GAA) deficiency resulting in lysosomal accumulation of glycogen in all tissues. Glycogen accumulation leads to muscle dysfunction and profound muscle weakness. A wide spectrum of disease is characteristic and the most severe patients have cardiorespiratory failure, often fatal in the first two years of life. Researchers have developed a way to introduce the normal GAA gene into muscle cells with the expectation that the GAA protein will be produced at levels sufficient to reduce glycogen accumulation. This study will evaluate the safety of the experimental gene transfer procedure in individuals with GAA deficiency. The study will also determine what dose may be required to achieve improvement in measures of respiratory function.

Detailed description: The goal of the current study is to evaluate an experimental gene transfer procedure in which normal copies of the GAA gene are inserted into cells. In this study, a modified virus, adeno-associated virus (AAV), has been engineered to carry a normal copy of the GAA gene, known as rAAV1-CMV-hGAA, which is used to place normal copies of the GAA gene into diaphragm muscle cells. The purpose of this study is to evaluate the safety of rAAV1-CMV-hGAA delivery into individuals with GAA deficiency (Pompe Disease).

Participants currently using enzyme replacement therapy will continue to receive their regular medical regimen during the 12 month duration of the study. Participants will first attend a screening study visit to confirm study eligibility. Participants will then attend a 3-5 day inpatient visit, during which they will receive a series of intradiaphragmatic injections consisting of the study agent (rAAV1-CMV-hGAA). Follow-up study visits will occur on Days 14, 90, 180, 270 and 365. Participants will have yearly follow-up evaluations by either telephone or mail for a total of 15 years, or as required by the FDA and other regulatory agencies.

Eligibility criteria: Inclusion Criteria:

* Male or female subjects 2-18 years of age.
* Have a diagnosis of Pompe, as defined by protein assay, DNA sequence of the acid alpha-glucosidase gene and clinical symptoms of the disease.
* Using assisted ventilation at baseline. Mechanical Ventilation is defined as any use of ventilation support, (including but not limited to BiPAP, CPAP), a minimum of 1 hours per day.
* Willing to discontinue aspirin, aspirin-containing products and other drugs that may alter platelet function, 7 days prior to dosing, resuming 24 hours after the dose has been administered.

Exclusion Criteria:

The subject must not:

* Have required acute, as distinguished from long-term, maintenance or chronic suppressive, oral or intravenous antibiotic therapy for a respiratory infection within 15 days prior to baseline screening.
* Have required oral or systemic corticosteroids within the last 15 days prior to baseline screening.
* Have a platelet count less than 75,000/ cu mm.
* Have an INR greater than 1.3.
* Serological evidence of hepatitis B, hepatitis C, or HIV positive.
* Be currently or within the past 30 days participating in any other research protocol involving investigational agents or therapies.
* Have received gene transfer agents within the past 6 months.
* Have history of platelet dysfunction, evidence of abnormal platelet function at screening or history of recent use of drugs that may alter platelet function which the subject is unable/unwilling to discontinue for study agent administration.
* Have any other concurrent condition which, in the opinion of the investigator, would make the subject unsuitable for the study.

Primary outcomes:
measure: Safety Assessments of the rAAV1-CMV-GAA (Study Agent), Changes Post Study Agent Administration.
timeFrame: Change from baseline to 365 post study agent administration.
Secondary outcomes:
measure: Maximal Inspiratory Pressure
timeFrame: Baseline and 365 post study agent administration
measure: Evaluation of Ventilatory Performance Benefit of rAAV1-CMV-GAA Gene Transfer and Respiratory Muscle Strength Training (RMST) Compared to RMST Alone.
timeFrame: Screening, Baseline, and 365 post study agent administration.
measure: Evaluation of Tidal Volume Benefit of rAAV1-CMV-GAA Gene Transfer and Respiratory Muscle Strength Training, Compared to Respiratory Muscle Strength Training Alone.
timeFrame: Screening, Baseline, and Day 365 post study agent administration
Other outcomes:
Locations:
city: Gainesville
country: United States
facility: Shands at the University of Florida
state: Florida
Study officials:
affiliation: University of Florida
name: Barry J Byrne, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Florida
name: Shelley Collins, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Fraites TJ Jr, Schleissing MR, Shanely RA, Walter GA, Cloutier DA, Zolotukhin I, Pauly DF, Raben N, Plotz PH, Powers SK, Kessler PD, Byrne BJ. Correction of the enzymatic and functional deficits in a model of Pompe disease using adeno-associated virus vectors. Mol Ther. 2002 May;5(5 Pt 1):571-8. doi: 10.1006/mthe.2002.0580.
citation: Mah C, Cresawn KO, Fraites TJ Jr, Pacak CA, Lewis MA, Zolotukhin I, Byrne BJ. Sustained correction of glycogen storage disease type II using adeno-associated virus serotype 1 vectors. Gene Ther. 2005 Sep;12(18):1405-9. doi: 10.1038/sj.gt.3302550.
citation: Mah C, Pacak CA, Cresawn KO, Deruisseau LR, Germain S, Lewis MA, Cloutier DA, Fuller DD, Byrne BJ. Physiological correction of Pompe disease by systemic delivery of adeno-associated virus serotype 1 vectors. Mol Ther. 2007 Mar;15(3):501-7. doi: 10.1038/sj.mt.6300100. Epub 2007 Jan 23.
citation: Pauly DF, Fraites TJ, Toma C, Bayes HS, Huie ML, Hirschhorn R, Plotz PH, Raben N, Kessler PD, Byrne BJ. Intercellular transfer of the virally derived precursor form of acid alpha-glucosidase corrects the enzyme deficiency in inherited cardioskeletal myopathy Pompe disease. Hum Gene Ther. 2001 Mar 20;12(5):527-38. doi: 10.1089/104303401300042447.
citation: Conlon TJ, Erger K, Porvasnik S, Cossette T, Roberts C, Combee L, Islam S, Kelley J, Cloutier D, Clement N, Abernathy CR, Byrne BJ. Preclinical toxicology and biodistribution studies of recombinant adeno-associated virus 1 human acid alpha-glucosidase. Hum Gene Ther Clin Dev. 2013 Sep;24(3):127-33. doi: 10.1089/humc.2013.147.
citation: Byrne BJ. Pathway for approval of a gene therapy orphan product: treading new ground. Mol Ther. 2013 Aug;21(8):1465-6. doi: 10.1038/mt.2013.157. No abstract available.
citation: Corti M, Elder M, Falk D, Lawson L, Smith B, Nayak S, Conlon T, Clement N, Erger K, Lavassani E, Green M, Doerfler P, Herzog R, Byrne B. B-Cell Depletion is Protective Against Anti-AAV Capsid Immune Response: A Human Subject Case Study. Mol Ther Methods Clin Dev. 2014;1:14033-. doi: 10.1038/mtm.2014.33.
citation: Smith BK, Collins SW, Conlon TJ, Mah CS, Lawson LA, Martin AD, Fuller DD, Cleaver BD, Clement N, Phillips D, Islam S, Dobjia N, Byrne BJ. Phase I/II trial of adeno-associated virus-mediated alpha-glucosidase gene therapy to the diaphragm for chronic respiratory failure in Pompe disease: initial safety and ventilatory outcomes. Hum Gene Ther. 2013 Jun;24(6):630-40. doi: 10.1089/hum.2012.250.
citation: Byrne BJ, Falk DJ, Clement N, Mah CS. Gene therapy approaches for lysosomal storage disease: next-generation treatment. Hum Gene Ther. 2012 Aug;23(8):808-15. doi: 10.1089/hum.2012.140.