Research / Funding

In April 2006, Myozyme (recombinant acid alpha-glucosidase) was approved by the FDA for use in patients with Pompe disease, representing the culmination of efforts by Y.T. Chen, MD, PhD, and colleagues to develop a lifesaving treatment for this deadly condition. With the goal of reproducing the bench-to-bedside approach that generated alglucosidase alfa and now offers hope for patients with Pompe disease, the Chens made a gift to the Department of Pediatrics to establish the Alice and YT Chen Pediatric Genetics and Genomics Research Center. This initiative focuses on translational research for single gene disorders amenable to treatment approaches such as enzyme replacement therapy, small molecule therapy, substrate therapy, gene therapy, and others. Priya Kishnani, MBBS, MD, chief of the Division of Medical Genetics and the lead investigator in the international clinical trials of Myozyme, serves as the medical director of the Center.

The Alice and Y.T. Chen Center for Genetics and Genomics supports a number of studies led by researchers in the Division of Medical Genetics including:

Natural history projects

• Glycogen storage diseases (GSD) I, II, III, IV, and IX

Animal model studies

• Murine model of GSD I, II, III, and IX
• Canine model of GSD I and III
• Feline model of GSD IV

Therapeutic studies

Gene therapy for GSD II, III and IV

• GSD II: using novel AAV vectors to improve the correction of CNS disease in Pompe disease in GSD II mice
• GSD III: developing an innovative gene therapy approach using an AAV vector expressing a bacterial debranching enzyme to overcome the small packaging size of an AAV vector in GSD III mice and dogs
• GSD IV: evaluating AAV-mediated gene therapy in GSD IV mice

Enzyme application for GSD III and IV

• Evaluation of the use of recombinant human GAA (rhGAA,  Alglucosidase alfa) for treatment of cytoplasmic GSD III and GSD IV

Gene therapy for GSD II. GSD II (Pompe disease) is caused by the deficiency of acid alpha glucosidase (GAA), resulting in extensive lysosomal glycogen accumulation in muscle cells. Without treatment, most patients with infantile Pompe disease die from cardiac or respiratory complications within one year of age. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA, alglucosidase alfa) is an FDA approved therapy but has significant limitations including low efficiency in correcting skeletal muscles. Adeno-associated virus (AAV) is an emerging vector for muscle gene therapy because of its effective and stable transduction in striated muscles.

• B. Sun, H. Zhang, L. M. Franco, T. Brown, A. Bird, A. Schneider, and D. D. Koeberl (2005). Correction of glycogen storage disease type II by an adeno-associated virus vector containing a muscle-specific promoter. Mol Ther. 11(6):889-98.
• B. Sun, H. Zhang, D.K. Jr. Benjamin, T. Brown, A. Bird, S.P. Young, A. McVie-Wylie, Y.T. Chen, and D. D. Koeberl.  Enhanced efficacy of an AAV vector encoding chimeric, highly secreted acid alpha-glucosidase in glycogen storage disease type II. Mol Ther. 14(6):822-30, 2006.
• B. Sun, S.P. Young, P. Li, C. Di, T. Brown, M.Z. Salva, S. Li, A. Bird, Z. Yan, R. Auten, S.D. Hauschka, and D. D. Koeberl (2008). Correction of multiple striated muscles in murine Pompe disease through adeno-associated virus-mediated gene therapy. Mol Ther. 16(8): 1366-71.
• B. Sun, S. Li, A. Bird, and D. D. Koeberl (2010). Hydrostatic isolated limb perfusion with adeno-associated virus vectors enhances correction of skeletal muscle in Pompe disease. Gene Ther. 17(12):1500-5.
• S. Li; B. Sun; M. I. Nilsson; A. Bird; M. A. Tarnopolsky; B. L. Thurberg; D. Bali; D. D. Koeberl (2013). Adjunctive β2-agonists reverse neuromuscular involvement in murine Pompe disease. FASEB Journal. 27(1):34-44.

Immune tolerance induction to enhance the efficacy of enzyme replacement therapy (ERT) in Pompe disease. A major obstacle to enzyme replacement therapy (ERT) with recombinant human acid-α-glucosidase (rhGAA, Alglucosidase alfa) for Pompe disease is the development of high titers of anti-rhGAA antibodies in a subset of patients, which often leads to a loss of treatment effectiveness. Therefore a method to induce antigen-specific immune tolerance is highly desired to improve the efficacy of ERT for these patients. We have reported the success of using a variety of immunomodulation approaches including immunomodulatory gene therapy with a low dose AAV vector containing a liver-specific regulatory cassette,  a short-course treatment with a non-depleting anti-CD4 monoclonal antibody, and the use of rapamycin-carrying synthetic vaccine particles (SVP) to induce long-term antigen-specific immune tolerance in Pompe disease mice. Our data suggest that induction of immune tolerance is an effective adjuvant therapy to ERT.

• B. Sun, A. Bird, S.P. Young, P.S. Kishnani, Y-T Chen, and D. D. Koeberl (2007). Enhanced response to enzyme replacement therapy in Pompe disease after the induction of immune tolerance. Am J Hum Genet. 81(5):1042-9.
• B. Sun, S. Li, A. Bird, and D. D. Koeberl (2010). Immunomodulatory gene therapy prevents antibody formation and lethal hypersensitivity reactions in murine Pompe disease. Mol Ther. 18(2):353-60.
• P. Zhang, B. Sun, T. Osada, R. Rodriguiz, X. Yang, X. Luo, A.R. Kemper, T.M. Clay, D.D. Koeberl (2012).  Immunodominant liver-specific expression suppresses transgene-directed immune responses in murine Pompe disease. Hum Gene Ther. 23 (5): 460-72.
• B. Sun, S. G. Banugaria, S. N. Prater, T. T. Patel, K. Fredrickson, D. J. Ringler, A. de Fougerolles, A. S. Rosenberg, H. Waldmann, and P. S. Kishnani (2014). Non-depleting anti-CD4 monoclonal antibody induces immune tolerance to ERT in a murine model of Pompe disease. Mol Genet Metab Reports 1:446-450.
• H. Lim, H. Yi, T.K. Kishimoto, F Gao, B. Sun*, and P.S. Kishnani* (2017). A pilot study on using rapamycin-carrying synthetic vaccine particles (SVP) in conjunction with enzyme replacement therapy to induce immune tolerance in Pompe disease. Mol Genet Metab Reports. 13:18-22.

Therapy development for GSD III. Mutations in the AGL gene cause deficiency of glycogen debranching enzyme, which results in accumulation of structurally abnormal glycogen in liver and muscle. There is no treatment available for this disease. ERT with debranching enzyme is infeasible due to the lack of receptor-mediated enzyme uptake; gene therapy with AAV vector is limited by the small packaging capacity of AAV vector for the delivery of the large human AGL gene. Therefore, alternative treatment approaches should be considered. We reported that rhGAA treatment significantly reduced glycogen levels in primary muscle cells derived from patients with GSD IIIa, suggesting rhGAA is a potential therapy for GSD III. We also demonstrated that daily administration of rapamycin, a specific inhibitor of mTOR, significantly reduced glycogen accumulation in both liver and muscle tissues of GSD IIIa dogs. Moreover, rapamycin treatment effectively prevented liver fibrosis in these dogs. We are currently testing a gene therapy approach to deliver AGL messenger RNA in GSD IIII dogs.

• B. Sun, K Fredrickson, S Austin, AA Tolun, BL Thurberg, WE Kraus, D Bali, Y-T Chen, P.S. Kishnani (2013). Alglucosidase alfa enzyme replacement therapy as a therapeutic approach for glycogen storage disease type III. Mol Genet Metab. 108(2):145-7.
• H. Yi, E.D. Brooks, B.L. Thurberg, J.C. Fyfe, P.S. Kishnani, and B. Sun (2014). Correction of glycogen storage disease type III with rapamycin in a canine model. J Mol Med (Berl), 92(6):641-50.
• E.D. Brooks, P.S. Kishnani, S. Austin, B.L. Thurberg, S.P. Young, H. Yi, J.C. Fyfe, and B. Sun (2016). Natural Progression of Canine Glycogen Storage Disease Type IIIa. Comp Med. 66(1):41-51.

Therapy development for GSD IV. Deficiency of glycogen branching enzyme (GBE) causes GSD IV, resulting in deposition of less branched, poorly soluble polysaccharides (polyglucosan bodies) in muscle, liver, and the central nervous system. There is no effective treatment for this disease. Recently, we demonstrated that systemic injection of an AAV9 vector expressing human GBE in GSD IV mice at young age completely prevented glycogen accumulation in the cardiac and skeletal muscles, and partially corrected liver and the brain. We are also interesting in developing substrate reduction therapy using small molecule drugs.

• H. Yi, Q. Zhang, C. Yang, P.S. Kishnani, and B. Sun (2016). A modified enzymatic method for measurement of glycogen content in glycogen storage disease type IV. JIMD Rep. 30: 89–94.
• H. Yi, F. Gao, S.L. Austin, P. S. Kishnani, and B. Sun (2016). Alglucosidase alfa treatment alleviates liver disease in a mouse model of glycogen storage disease type IV. Mol Genet Metab Reports. 9:31-33.
• H. Yi, Q. Zhang, C. Yang, P.S. Kishnani, and B. Sun (2017). Systemic correction of murine glycogen storage disease type IV by an AAV-mediated gene therapy. Hum Gene Ther.  28 (3): 286-294.

Y.T. Chen and his wife, Alice, have generously supported medical genetics research in the Department of Pediatrics with gifts including a professorship (C.L. and Su Chen Professorship), an associate/assistant professorship, and a fellowship (Alice Chen Fellowship in Pediatric Genetics and Genomics), to launch and operate the Y.T. and Alice Chen Pediatric Genetics and Genomics Research Center at Duke.

Current and past awardees of this support include:

Professorships

Priya Kishnani, MBBS, MD
C.L. and Su Chen Professor of Pediatrics
FY2008 - present

Fellows and Postdoctoral Fellows

Kim Wen Ng, MD
House Staff
FY17/18

Su Jin Choi, PhD
Postdoctoral Associate
FY17/18

Aditi Korlimarla, MBBS
Postdoctoral Associate
FY17/18

Carine Halaby, MD
Postdoctoral Associate
FY16/17 - FY17/18

Mrudu Herbert, MBBS
Postdoctoral Associate
FY16/17 - FY17/18

Mugdha Rairikar, MBBS
Postdoctoral Associate
FY16/17

Mari Mori, MD
House Staff
FY15/16