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

Purpose

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	Intervention	Phase
Pompe Disease	Drug: rAAV1-CMV-GAA Drug: Study agent administration	Phase 1 Phase 2

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Safety Study Intervention Model: Single Group Assignment Masking: Open Label 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

Resource links provided by NLM:

Genetics Home Reference related topics: glycogen storage disease type IX Pompe disease Schindler disease succinic semialdehyde dehydrogenase deficiency

U.S. FDA Resources

Further study details as provided by University of Florida:

Primary Outcome Measures:

Assessment of the safety of intramuscular administration of a recombinant adeno-associated virus, rAAV1-CMV-GAA, vector in children with Pompe disease using ventilatory assistance a minimum of one hour per day. [ Time Frame: Days 1, 2, 3, 14, 30, 60, 90, 180, 270 and 365 of the trial ] [ Designated as safety issue: Yes ]
Ventilatory assistance is defined as any use of ventilation-support (including, but not limited to BiPAP, CPAP, Mechanical Ventilation, Diaphragmatic Pacemaker).

Secondary Outcome Measures:

Impact of gene transfer to the diaphragm will be assessed by detailed pulmonary function studies [ Time Frame: 14, 90, 180, 270, and 365 days post injection ] [ Designated as safety issue: No ]

Estimated Enrollment:	10
Study Start Date:	September 2010
Estimated Study Completion Date:	June 2015
Estimated Primary Completion Date:	December 2013 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Gene Therapy: Cohort 1, rAAV1-CMV-GAA Gene Therapy: Cohort 1, rAAV1-CMV-GAA: Dose selection for cohort 1: 1.0 x 10e12 vector genomes. Cohort 1 will have a total of 3 participants dosed with the study agent.	Drug: rAAV1-CMV-GAA rAAV-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. Other Names: Gene transfer Gene therapy Pompe disease Diaphragm GAA
Experimental: Gene Therapy: Cohort 2,Study agent administration Gene Therapy: Cohort 2,Study agent administration: Dose selection for cohort 2: 5.0 x 10e12 vector genomes Cohort = 3 subjects	Drug: Study agent administration Direct intramuscular injection of study agent to the diaphragm muscle using video assisted thorascopy. Dose selection for cohort 2 and 3: 5.0 x 10e12 vector genomes Other Names: Gene transfer Gene therapy Pompe disease Diaphragm GAA
Experimental: Gene Therapy Cohort 3, Study agent administration Gene Therapy Cohort 3, Study agent administration: Dose selection for cohort 2: 5.0 x 10e12 vector genomes Cohort = 4 subjects	Drug: Study agent administration Direct intramuscular injection of study agent to the diaphragm muscle using video assisted thorascopy. Dose selection for cohort 2 and 3: 5.0 x 10e12 vector genomes Other Names: Gene transfer Gene therapy Pompe disease Diaphragm GAA

Detailed Description:

The goals of the current study are 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 and 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

Ages Eligible for Study:	2 Years to 18 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00976352

Contacts

Contact: Lee Ann Lawson, ARNP	(352) 575-0852	llawson@pedcard.ufl.edu
Contact: Lindsay Falk, BSN	(352) 273-9615	lindsayc@peds.ufl.edu

Locations

United States, Florida
Shands at the University of Florida	Recruiting
Gainesville, Florida, United States, 32610
Principal Investigator: Barry J Byrne, MD, PhD
Sub-Investigator: Thomas Conlon, PhD
Sub-Investigator: Cathryn Mah, PhD
Sub-Investigator: Saleem Islam, MD, MPH
Sub-Investigator: Lee Ann Lawson, ARNP

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

More Information

Additional Information:

Powell Gene Therapy Center This link exits the ClinicalTrials.gov site

Publications:

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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.

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Kishnani PS, Corzo D, Nicolino M, Byrne B, Mandel H, Hwu WL, Leslie N, Levine J, Spencer C, McDonald M, Li J, Dumontier J, Halberthal M, Chien YH, Hopkin R, Vijayaraghavan S, Gruskin D, Bartholomew D, van der Ploeg A, Clancy JP, Parini R, Morin G, Beck M, De la Gastine GS, Jokic M, Thurberg B, Richards S, Bali D, Davison M, Worden MA, Chen YT, Wraith JE. Recombinant human acid [alpha]-glucosidase: major clinical benefits in infantile-onset Pompe disease. Neurology. 2007 Jan 9;68(2):99-109. Epub 2006 Dec 6. Erratum in: Neurology. 2008 Nov 18;71(21):1748.

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, Fraites TJ Jr, Cresawn KO, Zolotukhin I, Lewis MA, Byrne BJ. A new method for recombinant adeno-associated virus vector delivery to murine diaphragm. Mol Ther. 2004 Mar;9(3):458-63.

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.

Nakai H, Yant SR, Storm TA, Fuess S, Meuse L, Kay MA. Extrachromosomal recombinant adeno-associated virus vector genomes are primarily responsible for stable liver transduction in vivo. J Virol. 2001 Aug;75(15):6969-76.

Nicolino MP, Puech JP, Kremer EJ, Reuser AJ, Mbebi C, Verdière-Sahuqué M, Kahn A, Poenaru L. Adenovirus-mediated transfer of the acid alpha-glucosidase gene into fibroblasts, myoblasts and myotubes from patients with glycogen storage disease type II leads to high level expression of enzyme and corrects glycogen accumulation. Hum Mol Genet. 1998 Oct;7(11):1695-702.

Pacak CA, Mah CS, Thattaliyath BD, Conlon TJ, Lewis MA, Cloutier DE, Zolotukhin I, Tarantal AF, Byrne BJ. Recombinant adeno-associated virus serotype 9 leads to preferential cardiac transduction in vivo. Circ Res. 2006 Aug 18;99(4):e3-9. Epub 2006 Jul 27.

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.

Pauly DF, Johns DC, Matelis LA, Lawrence JH, Byrne BJ, Kessler PD. Complete correction of acid alpha-glucosidase deficiency in Pompe disease fibroblasts in vitro, and lysosomally targeted expression in neonatal rat cardiac and skeletal muscle. Gene Ther. 1998 Apr;5(4):473-80.

Raben N, Nagaraju K, Lee E, Kessler P, Byrne B, Lee L, LaMarca M, King C, Ward J, Sauer B, Plotz P. Targeted disruption of the acid alpha-glucosidase gene in mice causes an illness with critical features of both infantile and adult human glycogen storage disease type II. J Biol Chem. 1998 Jul 24;273(30):19086-92.

van der Ploeg AT, Bolhuis PA, Wolterman RA, Visser JW, Loonen MC, Busch HF, Reuser AJ. Prospect for enzyme therapy in glycogenosis II variants: a study on cultured muscle cells. J Neurol. 1988 Sep;235(7):392-6.

Van der Ploeg AT, Loonen MC, Bolhuis PA, Busch HM, Reuser AJ, Galjaard H. Receptor-mediated uptake of acid alpha-glucosidase corrects lysosomal glycogen storage in cultured skeletal muscle. Pediatr Res. 1988 Jul;24(1):90-4.

Xiao W, Chirmule N, Berta SC, McCullough B, Gao G, Wilson JM. Gene therapy vectors based on adeno-associated virus type 1. J Virol. 1999 May;73(5):3994-4003.

Xiao X, Li J, McCown TJ, Samulski RJ. Gene transfer by adeno-associated virus vectors into the central nervous system. Exp Neurol. 1997 Mar;144(1):113-24. Review.

Xiao X, Li J, Samulski RJ. Efficient long-term gene transfer into muscle tissue of immunocompetent mice by adeno-associated virus vector. J Virol. 1996 Nov;70(11):8098-108.

Zolotukhin S, Byrne BJ, Mason E, Zolotukhin I, Potter M, Chesnut K, Summerford C, Samulski RJ, Muzyczka N. Recombinant adeno-associated virus purification using novel methods improves infectious titer and yield. Gene Ther. 1999 Jun;6(6):973-85.

Zolotukhin S, Potter M, Zolotukhin I, Sakai Y, Loiler S, Fraites TJ Jr, Chiodo VA, Phillipsberg T, Muzyczka N, Hauswirth WW, Flotte TR, Byrne BJ, Snyder RO. Production and purification of serotype 1, 2, and 5 recombinant adeno-associated viral vectors. Methods. 2002 Oct;28(2):158-67.

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Byrne BJ, Falk DJ, Clément 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.

Responsible Party:	University of Florida
ClinicalTrials.gov Identifier:	NCT00976352 History of Changes
Other Study ID Numbers:	PGTC PD-AAV004
Study First Received:	July 13, 2009
Last Updated:	November 26, 2012
Health Authority:	United States: Food and Drug Administration

Keywords provided by University of Florida:

Gene Therapy
Pompe Disease
Glycogen Storage Disease

Additional relevant MeSH terms:

Glycogen Storage Disease Type II
Lysosomal Storage Diseases, Nervous System
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases

Metabolism, Inborn Errors
Genetic Diseases, Inborn
Glycogen Storage Disease
Carbohydrate Metabolism, Inborn Errors
Lysosomal Storage Diseases
Metabolic Diseases

ClinicalTrials.gov processed this record on May 21, 2013