Qi Long Lu, MD, PhD
McColl-Lockwood Laboratory for Muscular Dystrophy Research
Department of Neurology
Adjunct Professor, University of North Carolina at Charlotte
Adjunct Professor, School of Pharmacy, University of North Carolina, Chapel Hill
Prior Positions and Experience
||Research Scientist, Clinical Science Centre, MRC (London, UK)
||Research Fellow, Royal Postgraduate Medical School (London, UK)
||Consultant in Pathology, Shanghai Medical University (Shanghai, China)
PhD: 1991, University of London (London, UK)
MS: 1986, Shanghai Medical University (Shanghai, China)
MD: 1976, Shanghai Second Medical University (Shanghai, China)
Development of Therapies for Muscular Dystrophies
Dr. Lu’s main interests are gene therapy, oligonucleotide therapy and read-through strategy for muscular dystrophies with a goal to treat limb-girdle muscular dystrophy (LGMD) type 2I.
Gene therapy uses a normal copy of gene to replace the defected disease gene. Success of the therapy for muscular dystrophies relies on the delivery of a normal copy of the gene into diseased muscles. Gene delivery can be achieved by viruses or non-viral methods. Despite tremendous efforts to translate the potentials of non-viral gene therapy to clinics, effective gene delivery into target cells has been elusive. Dr. Lu and his group have experimented several physical (electroporation, ultrasound) and chemical methods (pluronic polymers and microbubbles) to enhance gene delivery into muscle. Currently, natural and synthetic polymers are being examined and significant progress has been made for enhanced delivery of transgenes in both cell culture and animal models in vivo.
Another ongoing project is the antisense therapy or exon skipping for Duchenne Muscular Dystrophy (DMD), the most common childhood severe muscle wasting disease. DMD is caused by gene defect (mutation) in the dystrophin gene, leading to the failure of muscles to produce essential protein, dystrophin. Exon skipping uses a stretch of synthesized gene sequence (called antisense oligomer) to target specific defected part of the dystrophin gene (these parts are called exons) of the human dystrophin gene. The result of binding of antisense oligomer to the targeted exon leads to the removal of the defective exon from the diseased dystrophin and restores the expression of dystrophin protein. In 2003, Dr. Lu and his team first demonstrated the therapeutic potential of the antisense therapy for DMD. Since then significant progress has been made. His team was the first to show the ability of this therapy to achieve dystrophin expression in muscles throughout the body by systemic delivery of antisense oligomers. His team later again demonstrated the functional improvement of body muscles through systemic treatment of antisense oligomers in models of DMD. More recently, the McColl Lockwood Laboratory further demonstrated that antisense therapy can achieve near normal levels of dystrophin expression in nearly all body muscles including the cardiac muscle with significant improvement in cardiac functions. Long-term maintenance of dystrophin expression and functional improvement of muscles can also be achieved. Dr. Lu's ongoing efforts aim to establish specific and effective oligomers for targeting different human dystrophin exons, to improve the delivery efficiency for antisense oligomers and to optimize treatment regimens for clinic trials of the therapy to the majority of DMD.
To facilitate the development of experimental therapy to muscular dystrophy, Dr. Lu's group has also made great effort to establish and create new models both in vitro and in vivo for identifying potential therapeutic targets, exploring existing drugs and developing new drugs for the treatment of muscular dystrophy. More recently, his group has successfully created several unique models for a special group of muscular dystrophies related to the defects in the gene called Fukutin related protein (FKRP) gene. This allows the McColl Lockwood Laboratory to be able to examine different therapies directly in the models relevant to the background of human muscular dystrophy, thus will significantly enhance the transition of any experimental therapy to clinics.
Wang M, Wu B, Lu P, Cloer C, Tucker JD, Lu QL. Polyethylenimine-modified pluronics (PCMs) improve morpholino oligomer delivery in cell culture and dystrophic mdx mice. Mol Ther. 2013;Jan;21(1):210-6. PMID 23164938
Xu L, Lu PJ, Wang CH, Keramaris E, Qiao C, Xiao B, Blake DJ, Xiao X, Lu QL. Adeno-associated virus 9 mediated FKRP gene therapy restores functional glycosylation of α-dystroglycan and improves muscle functions. Mol Ther. 2013, Oct;21(10):1832-1840. PMID 23817215
Blaeser A, Keramaris E, ChanYM, Sparks S, Cowley D, Xiao X, Lu QL. Mouse models of Fukutin-related protein mutations show a wide range of disease phenotypes. Hum Genet, 2013 Aug;132(8):923-934. PMID 2359163.
Wu B, Lu P, Cloer C, Shaban M, Grewak S, Milazi S, Shah SN, Moulton HM, Lu QL. Long-term rescue of dystrophin expression and improvement in muscle pathology and function in dystrophic mdx mice by peptide-conjugated morpholino. Am J Pathol. 2012, Aug;18(2);392-400. PMID 22683468.
Lu QL, Wu B. Systemic delivery of antisense oligomer in animal models and its implications for treating DMD. Methods Mol Biol. 2012;867:393-405. PMID 22454075.
Lu QL, Yokota T, Takeda S, Garcia L, Muntoni F, Partridge T. The status of exon skipping as a therapeutic approach to duchenne muscular dystrophy. Mol Ther 2011;10:9-15. PMID 20978473.
Wang M, Tucker JD, Lu P, Wu B, Cloer C, Lu QL. Tris[2-(acryloyloxy)ethyl]isocyanurate cross-linked low-molecular-weight polyethykenimine as gene delivery carriers in cell culture and dystrophic mdx mice. Bioconjub Chem. 2012 Apr 18;23(4):837-45. PMID 22443086
Wu B, Benrashid E, Lu P, Lu QL. Targeted skipping of human dystrophin exons in transgenic mouse model systemically for antisense drug development. PLoS One 2011;6:e19906. PMID 21611204.
Wu B, Xiao B, Cloer C, Shaban M, Lu QL. One year treatment of morpholino antisense oligomer improves skeletal and cardiac muscle functions in dystrophic mdx mice. Mol Ther 2011;19:576-83. PMID 21179007.
Hu Y, Wu B, Zillmer A, Lu P, Benrashid E, Wang M, Doran T, Shaban M, Wu X, Lu QL. Guanine analogues enhance antisense oligonucleotide-induced exon skipping in dystrophin gene in vitro and in vivo. Mol Ther 2010;18:812-8 [PMID: 20087314]
Chan YM, Keramaris-Vrantsis E, Lidov H, Norton JH, Zinchenko N, Gruber HE, Thresher R, Blake DJ, Ashar J, & Lu QL. Fukutin-related protein is essential for mouse muscle, brain and eye development and mutation recapitulates the wide clinical spectrums of dystroglycanopathies. Hum Mol Genet 2010 Aug 11 (in press). [PMID: 20675713]
Moulton HM, Wu B, Jearawiriyapaisarn N, Sazani P, Lu QL, Kole R. Peptide-morpholino conjugate: a promising therapeutic for Duchenne muscular dystrophy. Ann N Y Acad Sci 2009;1175:55-60. [PMID: 19796077]
Wu B, Lu P, Benrashid E, Malik S, Ashar J, Doran TJ, Lu QL. Dose-dependent restoration of dystrophin expression in cardiac muscle of dystrophic mice by systemically delivered morpholino. Gene Ther 2010;17:132-40. [PMID: 19759562]
Lu PJ, Zillmer A, Wu X, Lochmuller H, Vachris J, Blake D, Chan YM, Lu QL. Mutations alter secretion of fukutin-related protein. Biochim Biophys Acta 2010;1802:253-8. [PMID: 19900540]
Yokota T, Lu QL, Partridge T, Kobayashi M, Nakamura A, Takeda S, Hoffman E. Efficacy of systemic morpholino exon-skipping in duchenne dystrophy dogs. Ann Neurol 2009;65:667-76. [PMID: 19288467]
Wu B, Li Y, Morcos PA, Doran TJ, Lu P, Octa-guanidine Morpholino Restores Dystrophin Expression in Cardiac and Skeletal Muscles and Ameliorates Pathology in Dystrophic mdx Mice. Mol Ther 2009;17:864-71. [PMID: 19277018]
Wu B, Moulton HM, Iversen PL, Jiang J, Li J, Li JB, Spurney CF, Sali A, Guerron AD, Nagaraju K, Doran T, Lu PJ, Xiao X & Lu QL. Effective rescue of dystrophin improves cardiac function in dystrophin-deficient mice by a modified morpholino oligomer. Proc Natl Acad Sci USA 2008;105:14814-9. [PMID: 18806224]
Current, Recent and Pending Grant Support
Grant Title: Antisense therapy for DMD-Optimization and toxicology of AON for exon 45 skipping
Funding Agency: NIH, NINDS
Role: Principal Investigator
Grant Title: Pediatric toxicity and efficacy in long-terms systemic treatment with antisense
Funding Agency: Children’ Research Institute/NIH/NICHD
Grant Title: Center for Research Translation of Systemic Exon-Skipping in Muscular Dystrophy-Project II
Funding Agency: Children’s Research Institute/NIH/NICHD
Grant Title: Morpholino antisense oligonucleotide and systemic delivery
Funding Agency: Department of Defense (USAMRMC)
Role: Principal Investigator
Grant Title: Exon 50 skipping for treatment of Duchenne muscular dystrophy
Funding Agency: FED
Role: Principal Investigator