Safety Study of Recombinant Adeno-Associated Virus Acid Alpha-Glucosidase to Treat Pompe Disease

• Sponsor: University of Florida (Other)
• Overall Status: Completed
• CT.gov ID: NCT00976352
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 9
• Location: 1
• Arms: 2
• Actual Duration (Months): 63
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Pompe Disease	Drug: rAAV1-CMV-GAA (study agent) Administration; Other: RMST	Phase 1/Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 9 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Masking Description: Open label study
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: Sep 1, 2010
• Actual Primary Completion Date: Dec 1, 2015
• Actual Study Completion Date: Dec 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: rAAV1-CMV-GAA administration-cohort 1 rAAV1-CMV-GAA (study agent) Administration: 1.0 x 10e12 vector genomes. The following study assessments/interventions will be completed: Respiratory Muscle Strength Training (RMST), Safety labs, pulmonary function testing.	Drug: rAAV1-CMV-GAA (study agent) Administration; rAAV1-CMV-GAA via intramuscular injection into the diaphragm. Dose selection for cohort 1: 1.0 x 10e12 vector genomes Cohort 1 will have a total of 3 participants enrolled. Dose selection for cohort 2 and 3: 5.0 x 10e12 vector genomes rAAV1-CMV-GAA. Cohort 2 = 6 subjects.; Other Names: Gene transfer study agent (rAAV1-CMV-GAA) ; Other: RMST; After enrollment and screening visit, the subject will be given a RMST prescription and will complete RMST for a minimum of 4 weeks prior to study agent administration. RMST prescription will be adjusted as needed at Day 14, 90, 180, and 270.; Other Names: Respiratory Muscle Strength Training
Experimental: rAAV1-CMV-GAA administration-cohort 2 rAAV1-CMV-GAA (study agent) Administration: 5.0 x 10e12 vector genomes Cohort 2 = 6 subjects. The following study assessments/interventions will be completed: Respiratory Muscle Strength Training (RMST), Safety labs, pulmonary function testing.	Drug: rAAV1-CMV-GAA (study agent) Administration; rAAV1-CMV-GAA via intramuscular injection into the diaphragm. Dose selection for cohort 1: 1.0 x 10e12 vector genomes Cohort 1 will have a total of 3 participants enrolled. Dose selection for cohort 2 and 3: 5.0 x 10e12 vector genomes rAAV1-CMV-GAA. Cohort 2 = 6 subjects.; Other Names: Gene transfer study agent (rAAV1-CMV-GAA) ; Other: RMST; After enrollment and screening visit, the subject will be given a RMST prescription and will complete RMST for a minimum of 4 weeks prior to study agent administration. RMST prescription will be adjusted as needed at Day 14, 90, 180, and 270.; Other Names: Respiratory Muscle Strength Training

Outcome Measures

Primary Outcome Measures

1. Safety Assessments of the rAAV1-CMV-GAA (Study Agent), Changes Post Study Agent Administration. [Change from baseline to 365 post study agent administration.]

   Change in Adeno-associated virus (AAV) antibody level; Change in Alglucosidase alpha (GAA) Antibody level

Secondary Outcome Measures

1. Maximal Inspiratory Pressure [Baseline and 365 post study agent administration]

   Median (range) Maximal Inspiratory Pressure (MIP), in cm H2O

2. Evaluation of Ventilatory Performance Benefit of rAAV1-CMV-GAA Gene Transfer and Respiratory Muscle Strength Training (RMST) Compared to RMST Alone. [Screening, Baseline, and 365 post study agent administration.]

   Median (range) maximal inspiratory pressure, in cm H2O. Timeframe for RMST training was 90 days prior to rAAV1-CMV-GAA gene transfer. Timeframe for following subjects after rAAV1-CMV-GAA gene transfer was 365 days.

3. Evaluation of Tidal Volume Benefit of rAAV1-CMV-GAA Gene Transfer and Respiratory Muscle Strength Training, Compared to Respiratory Muscle Strength Training Alone. [Screening, Baseline, and Day 365 post study agent administration]

   Best effort tidal volume, referenced to body mass, without use of ventilator assistance. Timeframe for respiratory muscle strength training alone was 90 days prior to dosing, timeframe post adminstration of rAAV1-CMV-GAA was 365 days.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Years to 18 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Shands at the University of Florida	Gainesville	Florida	United States	32610

Sponsors and Collaborators

• University of Florida
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Barry J Byrne, MD, PhD, University of Florida
• Principal Investigator: Shelley Collins, MD, University of Florida

Study Documents (Full-Text)

None provided.

More Information

Publications

• 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.
• Conlon TJ, Erger K, Porvasnik S, Cossette T, Roberts C, Combee L, Islam S, Kelley J, Cloutier D, Clément N, Abernathy CR, Byrne BJ. Preclinical toxicology and biodistribution studies of recombinant adeno-associated virus 1 human acid α-glucosidase. Hum Gene Ther Clin Dev. 2013 Sep;24(3):127-33. doi: 10.1089/humc.2013.147.
• Corti M, Elder M, Falk D, Lawson L, Smith B, Nayak S, Conlon T, Clément 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. pii: 14033.
• 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.
• 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.
• 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. Epub 2007 Jan 23.
• 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.

• Responsible Party: University of Florida
• ClinicalTrials.gov Identifier: NCT00976352
• Other Study ID Numbers: PGTC PD-AAV004-N; P01HL059412-06
• First Posted: Sep 14, 2009
• Last Update Posted: Sep 14, 2018
• Last Verified: Sep 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by University of Florida: Gene Therapy; Pompe Disease; Glycogen Storage Disease
• Additional relevant MeSH terms: Glycogen Storage Disease Type II

Study Results

Participant Flow

Recruitment Details	Subjects were recruited from the Pediatric Neuromuscular Disorders Clinic at the University of Florida. Subjects were also self-referred from the ClinicalTrials.gov listing.
Pre-assignment Detail	All subjects underwent a screening process for eligibility determination as well as for safety evaluations.

Arm/Group Title	rAAV1-CMV-GAA Administration-cohort 1	rAAV1-CMV-GAA Administration-cohort 2
Arm/Group Description	rAAV1-CMV-GAA (study agent) Administration: 1.0 x 10e12 vector genomes. The following study assessments/interventions will be completed: Respiratory Muscle Strength Training (RMST), Safety labs, pulmonary function testing. rAAV1-CMV-GAA (study agent) Administration: rAAV1-CMV-GAA via intramuscular injection into the diaphragm. Dose selection for cohort 1: 1.0 x 10e12 vector genomes Cohort 1 will have a total of 3 participants enrolled. Dose selection for cohort 2 and 3: 5.0 x 10e12 vector genomes rAAV1-CMV-GAA. Cohort 2 = 6 subjects. RMST: After enrollment and screening visit, the subject will be given a RMST prescription and will complete RMST for a minimum of 4 weeks prior to study agent administration. RMST prescription will be adjusted as needed at Day 14, 90, 180, and 270.	rAAV1-CMV-GAA (study agent) Administration: 5.0 x 10e12 vector genomes Cohort 2 = 6 subjects. The following study assessments/interventions will be completed: Respiratory Muscle Strength Training (RMST), Safety labs, pulmonary function testing. rAAV1-CMV-GAA (study agent) Administration: rAAV1-CMV-GAA via intramuscular injection into the diaphragm. Dose selection for cohort 1: 1.0 x 10e12 vector genomes Cohort 1 will have a total of 3 participants enrolled. Dose selection for cohort 2 and 3: 5.0 x 10e12 vector genomes rAAV1-CMV-GAA. Cohort 2 = 6 subjects. RMST: After enrollment and screening visit, the subject will be given a RMST prescription and will complete RMST for a minimum of 4 weeks prior to study agent administration. RMST prescription will be adjusted as needed at Day 14, 90, 180, and 270.
Period Title: Overall Study
STARTED	3	10
COMPLETED	3	6
NOT COMPLETED	0	4

Baseline Characteristics

Arm/Group Title	rAAV1-CMV-GAA Administration-cohort 1	rAAV1-CMV-GAA Administration-cohort 2	Total
Arm/Group Description	rAAV1-CMV-GAA (study agent) Administration: 1.0 x 10e12 vector genomes. The following study assessments/interventions will be completed: Respiratory Muscle Strength Training (RMST), Safety labs, pulmonary function testing. rAAV1-CMV-GAA (study agent) Administration: rAAV1-CMV-GAA via intramuscular injection into the diaphragm. Dose selection for cohort 1: 1.0 x 10e12 vector genomes Cohort 1 will have a total of 3 participants enrolled. Dose selection for cohort 2 and 3: 5.0 x 10e12 vector genomes rAAV1-CMV-GAA. Cohort 2 = 6 subjects. RMST: After enrollment and screening visit, the subject will be given a RMST prescription and will complete RMST for a minimum of 4 weeks prior to study agent administration. RMST prescription will be adjusted as needed at Day 14, 90, 180, and 270.	rAAV1-CMV-GAA (study agent) Administration: 5.0 x 10e12 vector genomes Cohort 2 = 6 subjects. The following study assessments/interventions will be completed: Respiratory Muscle Strength Training (RMST), Safety labs, pulmonary function testing. rAAV1-CMV-GAA (study agent) Administration: rAAV1-CMV-GAA via intramuscular injection into the diaphragm. Dose selection for cohort 1: 1.0 x 10e12 vector genomes Cohort 1 will have a total of 3 participants enrolled. Dose selection for cohort 2 and 3: 5.0 x 10e12 vector genomes rAAV1-CMV-GAA. Cohort 2 = 6 subjects. RMST: After enrollment and screening visit, the subject will be given a RMST prescription and will complete RMST for a minimum of 4 weeks prior to study agent administration. RMST prescription will be adjusted as needed at Day 14, 90, 180, and 270.	Total of all reporting groups
Overall Participants	3	6	9
Age (Count of Participants)
<=18 years	3 100%	6 100%	9 100%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%
Age (months) [Mean (Full Range) ]
Mean (Full Range) [months]	90	67.3	74.8
Sex: Female, Male (Count of Participants)
Female	0 0%	3 50%	3 33.3%
Male	3 100%	3 50%	6 66.7%
Region of Enrollment (Count of Participants)
United States	3 100%	6 100%	9 100%

Outcome Measures

1. Primary Outcome

Title	Safety Assessments of the rAAV1-CMV-GAA (Study Agent), Changes Post Study Agent Administration.
Description	Change in Adeno-associated virus (AAV) antibody level; Change in Alglucosidase alpha (GAA) Antibody level
Time Frame	Change from baseline to 365 post study agent administration.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	rAAV1-CMV-GAA Administration-cohort 1	rAAV1-CMV-GAA Administration-cohort 2
Arm/Group Description	rAAV1-CMV-GAA (study agent) Administration: 1.0 x 10e12 vector genomes. The following study assessments/interventions will be completed: Respiratory Muscle Strength Training (RMST), Safety labs, pulmonary function testing. rAAV1-CMV-GAA (study agent) Administration: rAAV1-CMV-GAA via intramuscular injection into the diaphragm. Dose selection for cohort 1: 1.0 x 10e12 vector genomes Cohort 1 will have a total of 3 participants enrolled. Dose selection for cohort 2 and 3: 5.0 x 10e12 vector genomes rAAV1-CMV-GAA. Cohort 2 = 6 subjects. RMST: After enrollment and screening visit, the subject will be given a RMST prescription and will complete RMST for a minimum of 4 weeks prior to study agent administration. RMST prescription will be adjusted as needed at Day 14, 90, 180, and 270.	rAAV1-CMV-GAA (study agent) Administration: 5.0 x 10e12 vector genomes Cohort 2 = 6 subjects. The following study assessments/interventions will be completed: Respiratory Muscle Strength Training (RMST), Safety labs, pulmonary function testing. rAAV1-CMV-GAA (study agent) Administration: rAAV1-CMV-GAA via intramuscular injection into the diaphragm. Dose selection for cohort 1: 1.0 x 10e12 vector genomes Cohort 1 will have a total of 3 participants enrolled. Dose selection for cohort 2 and 3: 5.0 x 10e12 vector genomes rAAV1-CMV-GAA. Cohort 2 = 6 subjects. RMST: After enrollment and screening visit, the subject will be given a RMST prescription and will complete RMST for a minimum of 4 weeks prior to study agent administration. RMST prescription will be adjusted as needed at Day 14, 90, 180, and 270.
Measure Participants	3	6
AAV1antibody Level -Screening	40,031 (65324.18978)	29,638 (12395.02473)
AAV1antibody Level - Day 365	5,509,882 (3051265.999)	1,907,161 (3,189,557)
GAA Antibody level - Screening	415.6666667 (61.71169527)	330.4 (271.1112318)
GAA Antibody level - Day 365	504.3333333 (63.88531391)	494.3333333 (371.6481311)

2. Secondary Outcome

Title	Maximal Inspiratory Pressure
Description	Median (range) Maximal Inspiratory Pressure (MIP), in cm H2O
Time Frame	Baseline and 365 post study agent administration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	rAAV1-CMV-GAA Administration-cohort 1	rAAV1-CMV-GAA Administration-cohort 2
Arm/Group Description	rAAV1-CMV-GAA (study agent) Administration: 1.0 x 10e12 vector genomes. The following study assessments/interventions will be completed: Respiratory Muscle Strength Training (RMST), Safety labs, pulmonary function testing. rAAV1-CMV-GAA (study agent) Administration: rAAV1-CMV-GAA via intramuscular injection into the diaphragm. Dose selection for cohort 1: 1.0 x 10e12 vector genomes Cohort 1 will have a total of 3 participants enrolled. Dose selection for cohort 2 and 3: 5.0 x 10e12 vector genomes rAAV1-CMV-GAA. Cohort 2 = 6 subjects. RMST: After enrollment and screening visit, the subject will be given a RMST prescription and will complete RMST for a minimum of 4 weeks prior to study agent administration. RMST prescription will be adjusted as needed at Day 14, 90, 180, and 270.	rAAV1-CMV-GAA (study agent) Administration: 5.0 x 10e12 vector genomes Cohort 2 = 6 subjects. The following study assessments/interventions will be completed: Respiratory Muscle Strength Training (RMST), Safety labs, pulmonary function testing. rAAV1-CMV-GAA (study agent) Administration: rAAV1-CMV-GAA via intramuscular injection into the diaphragm. Dose selection for cohort 1: 1.0 x 10e12 vector genomes Cohort 1 will have a total of 3 participants enrolled. Dose selection for cohort 2 and 3: 5.0 x 10e12 vector genomes rAAV1-CMV-GAA. Cohort 2 = 6 subjects. RMST: After enrollment and screening visit, the subject will be given a RMST prescription and will complete RMST for a minimum of 4 weeks prior to study agent administration. RMST prescription will be adjusted as needed at Day 14, 90, 180, and 270.
Measure Participants	3	6
Baseline	6	61
Day 365	6	56

3. Secondary Outcome

Title	Evaluation of Ventilatory Performance Benefit of rAAV1-CMV-GAA Gene Transfer and Respiratory Muscle Strength Training (RMST) Compared to RMST Alone.
Description	Median (range) maximal inspiratory pressure, in cm H2O. Timeframe for RMST training was 90 days prior to rAAV1-CMV-GAA gene transfer. Timeframe for following subjects after rAAV1-CMV-GAA gene transfer was 365 days.
Time Frame	Screening, Baseline, and 365 post study agent administration.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	rAAV1-CMV-GAA Administration-cohort 1	rAAV1-CMV-GAA Administration-cohort 2
Arm/Group Description	rAAV1-CMV-GAA (study agent) Administration: 1.0 x 10e12 vector genomes. The following study assessments/interventions will be completed: Respiratory Muscle Strength Training (RMST), Safety labs, pulmonary function testing. rAAV1-CMV-GAA (study agent) Administration: rAAV1-CMV-GAA via intramuscular injection into the diaphragm. Dose selection for cohort 1: 1.0 x 10e12 vector genomes Cohort 1 will have a total of 3 participants enrolled. Dose selection for cohort 2 and 3: 5.0 x 10e12 vector genomes rAAV1-CMV-GAA. Cohort 2 = 6 subjects. RMST: After enrollment and screening visit, the subject will be given a RMST prescription and will complete RMST for a minimum of 4 weeks prior to study agent administration. RMST prescription will be adjusted as needed at Day 14, 90, 180, and 270 after dosing.	rAAV1-CMV-GAA (study agent) Administration: 5.0 x 10e12 vector genomes Cohort 2 = 6 subjects. The following study assessments/interventions will be completed: Respiratory Muscle Strength Training (RMST), Safety labs, pulmonary function testing. rAAV1-CMV-GAA (study agent) Administration: rAAV1-CMV-GAA via intramuscular injection into the diaphragm. Dose selection for cohort 1: 1.0 x 10e12 vector genomes Cohort 1 will have a total of 3 participants enrolled. Dose selection for cohort 2 and 3: 5.0 x 10e12 vector genomes rAAV1-CMV-GAA. Cohort 2 = 6 subjects. RMST: After enrollment and screening visit, the subject will be given a RMST prescription and will complete RMST for a minimum of 4 weeks prior to study agent administration. RMST prescription will be adjusted as needed at Day 14, 90, 180, and 270 after dosing.
Measure Participants	3	6
Screening	6.85	60.8
Baseline	5.85	60.8
Day 365	5.7	55.6

4. Secondary Outcome

Title	Evaluation of Tidal Volume Benefit of rAAV1-CMV-GAA Gene Transfer and Respiratory Muscle Strength Training, Compared to Respiratory Muscle Strength Training Alone.
Description	Best effort tidal volume, referenced to body mass, without use of ventilator assistance. Timeframe for respiratory muscle strength training alone was 90 days prior to dosing, timeframe post adminstration of rAAV1-CMV-GAA was 365 days.
Time Frame	Screening, Baseline, and Day 365 post study agent administration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	rAAV1-CMV-GAA Administration-cohort 1	rAAV1-CMV-GAA Administration-cohort 2
Arm/Group Description	RMST: After enrollment and screening visit, the subject will be given a RMST prescription and will complete RMST for a minimum of 4 weeks prior to study agent administration. RMST prescription will be adjusted as needed at Day 14, 90, 180, and 270 after dosing.	RMST: After enrollment and screening visit, the subject will be given a RMST prescription and will complete RMST for a minimum of 4 weeks prior to study agent administration. RMST prescription will be adjusted as needed at Day 14, 90, 180, and 270 after dosing.
Measure Participants	3	6
Screening	2.8	7.9
Baseline	2.0	7.3
Day 365	3.4	9.1

Adverse Events

Time Frame	Data on adverse events were collected on all subjects for 1 year after dosing.
Arm/Group Title	rAAV1-CMV-GAA Administration-cohort 1		rAAV1-CMV-GAA Administration-cohort 2
Arm/Group Description	rAAV1-CMV-GAA (study agent) Administration: 1.0 x 10e12 vector genomes. The following study assessments/interventions will be completed: Respiratory Muscle Strength Training (RMST), Safety labs, pulmonary function testing. rAAV1-CMV-GAA (study agent) Administration: rAAV1-CMV-GAA via intramuscular injection into the diaphragm. Dose selection for cohort 1: 1.0 x 10e12 vector genomes Cohort 1 will have a total of 3 participants enrolled. Dose selection for cohort 2 and 3: 5.0 x 10e12 vector genomes rAAV1-CMV-GAA. Cohort 2 = 6 subjects. RMST: After enrollment and screening visit, the subject will be given a RMST prescription and will complete RMST for a minimum of 4 weeks prior to study agent administration. RMST prescription will be adjusted as needed at Day 14, 90, 180, and 270.		rAAV1-CMV-GAA (study agent) Administration: 5.0 x 10e12 vector genomes Cohort 2 = 6 subjects. The following study assessments/interventions will be completed: Respiratory Muscle Strength Training (RMST), Safety labs, pulmonary function testing. rAAV1-CMV-GAA (study agent) Administration: rAAV1-CMV-GAA via intramuscular injection into the diaphragm. Dose selection for cohort 1: 1.0 x 10e12 vector genomes Cohort 1 will have a total of 3 participants enrolled. Dose selection for cohort 2 and 3: 5.0 x 10e12 vector genomes rAAV1-CMV-GAA. Cohort 2 = 6 subjects. RMST: After enrollment and screening visit, the subject will be given a RMST prescription and will complete RMST for a minimum of 4 weeks prior to study agent administration. RMST prescription will be adjusted as needed at Day 14, 90, 180, and 270.
All Cause Mortality
	rAAV1-CMV-GAA Administration-cohort 1		rAAV1-CMV-GAA Administration-cohort 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/3 (33.3%)		0/9 (0%)
Serious Adverse Events
	rAAV1-CMV-GAA Administration-cohort 1		rAAV1-CMV-GAA Administration-cohort 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/3 (33.3%)		3/9 (33.3%)
Blood and lymphatic system disorders
Bacteremia accompanied by fever	0/3 (0%)	0	1/9 (11.1%)	1
Cardiac disorders
Bilateral pericardial effusion	0/3 (0%)	0	1/9 (11.1%)	1
Supraventricular tachycardia	1/3 (33.3%)	1	0/9 (0%)	0
General disorders
Hospitalization	0/3 (0%)	0	3/9 (33.3%)	3
Respiratory, thoracic and mediastinal disorders
Right-sided spontaneous pneumothorax	1/3 (33.3%)	1	0/9 (0%)	0
Bilateral pleural effusion	0/3 (0%)	0	1/9 (11.1%)	1
Right upper lobe collapse with respiratory distress and Clostridium difficile gastritis	0/3 (0%)	0	1/9 (11.1%)	2
Desaturation Episode	0/3 (0%)	0	1/9 (11.1%)	1
Hospitalization: dehydration, increased work of breathing	0/3 (0%)	0	1/9 (11.1%)	1
hospitalization, worsening CHF, pulmonary edema	0/3 (0%)	0	1/9 (11.1%)	1
Other (Not Including Serious) Adverse Events
	rAAV1-CMV-GAA Administration-cohort 1		rAAV1-CMV-GAA Administration-cohort 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		9/9 (100%)
Blood and lymphatic system disorders
Nosebleed	0/3 (0%)	0	1/9 (11.1%)	1
Cardiac disorders
Tachycardia	1/3 (33.3%)	2	0/9 (0%)	0
Ear and labyrinth disorders
ear infection and fluids	1/3 (33.3%)	2	2/9 (22.2%)	2
Eye disorders
eye infection	0/3 (0%)	0	1/9 (11.1%)	2
Gastrointestinal disorders
Reflux and Diarrhea, G-tube problems	3/3 (100%)	3	4/9 (44.4%)	8
General disorders
fever, bacteremia, Dehydration	3/3 (100%)	4	5/9 (55.6%)	7
Pain	2/3 (66.7%)	3	4/9 (44.4%)	9
Hypokalemia and Hypoglycemia	1/3 (33.3%)	1	1/9 (11.1%)	2
Musculoskeletal and connective tissue disorders
Contracturs and scoliosis	1/3 (33.3%)	2	1/9 (11.1%)	3
Renal and urinary disorders
urinary issues	1/3 (33.3%)	1	2/9 (22.2%)	2
Respiratory, thoracic and mediastinal disorders
Respiratory Tract Infection	2/3 (66.7%)	2	2/9 (22.2%)	3
Pneumothorax/Capnothorax	3/3 (100%)	5	3/9 (33.3%)	3
respiratory symthomps	3/3 (100%)	10	7/9 (77.8%)	18
Pneumonia	0/3 (0%)	0	1/9 (11.1%)	1
Pulmonary and chest problems	1/3 (33.3%)	2	2/9 (22.2%)	2
Trachestomy	0/3 (0%)	0	1/9 (11.1%)	1
Skin and subcutaneous tissue disorders
Skin issue	2/3 (66.7%)	5	3/9 (33.3%)	6

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.