Nearly all muscular dystrophies are caused by mutations in specific genes, leading to the loss or reduction of function. Gene therapy to provide a normal copy of the defected gene to the diseased muscles could effectively rescue the muscles or even cure some of the diseases. The laboratory has been experimenting with both viral and non-viral delivery techniques with a focus on FKRP gene-related muscular dystrophies. Therapeutic effect of gene replacement has been achieved both in cell culture systems and in diseased models in vivo. This program is supported by North Carolina Biotechnology Center, MDA, NIH as well as the Carolinas Muscular Dystrophy Research Endowment.

AAV gene therapy has been the most effective strategy to deliver normal copies of the FKRP gene to the body-wide muscles, including the heart. The AAV-delivered FKRP gene will produce functional FKRP protein inside diseased muscle fibers and restore the glycosylation of a-DG. Consequently, the link between fibers and surrounding connective tissues will be restored and further muscle damage prevented. AAV gene therapy can be highly effective, achieving almost the same levels of glycosylation of a-DG as detected in the normal skeletal and cardiac muscles. Also important, AAV gene therapy can restore muscle functions with the elimination of diseased muscle pathology when treated at early stage. While there are still some barriers and unknown factors which might affect the efficacy of AAV gene therapy in clinical settings, such as variation in the immune response to AAV serotypes, diseases stages and dose-requirement for safety and efficacy in individual patients, this treatment is now under active development by 2 companies and expected to move to clinical trial in 2022.

As an enzyme, FKRP uses ribitol as part of its substrate to add the sugar to the a-DG protein, enabling the muscles to assemble the completed sugar chain with capacity to link the fiber to surrounding connective tissue. Almost all mutated FKRP retains partial function, able to add the sugar to a-DG with reduced capacity. When extra ribitol is present in diseased muscles, mutant FKRP can work more efficiently, adding more sugars to a-DG and restoring the link between fiber and surrounding connective tissues.

The efficacy of ribitol treatment has been established in mouse model with FKRP mutations. This includes improvement in muscle pathology and function with long-term treatment. This approach has several advantages and disadvantages. Ribitol is a metabolite normally present in all body muscles, and animal studies show it is safe and tolerable with daily effective dose. Although the increase in glycosylation in disease muscles is relatively lower, the distribution of enhancement is highly homogeneous to all muscle fibers, thus providing better protection from muscle damage. ML Bio Solutions/Bridgebio Pharma has announced the dosing of LGDM2i patients with ribitol. McColl Lockwood Lab continues its effort to improve the efficacy by experimenting a combined treatment strategy with other drugs and gene therapy.

The aim of this program is to identify existing drugs or compounds and to synthesize new drugs to improve the functions of dystrophic muscles and to prevent progression of muscle wasting. Drug screening platform to identify candidates for enhancing the addition of sugars on a DG (glycosylation) has been established and applied to screen large drug libraries. The program has also identified several drugs with potential to treat muscular dystrophy. One class of the drugs shown to be promising is the selective estrogen receptor modulators (SERM) such as tamoxifen and raloxifene. Long term treatment (1 year) in mouse models significantly ameliorate the disease progression with reduction in muscle pathology and improvement in muscle functions. The treatment also significantly mitigates bone loss, one of the common side effects of muscle disuse. This program is partly supported by both National Institutes of Health (NIH) and private funding. New drug candidates to improve muscle functions are also being tested.

DMD is caused by mutations in the dystrophin gene. Such mutations abolish the ability of the gene to produce the dystrophin protein. Antisense therapy uses synthetic pieces of a gene sequence (antisense oligo) to target specific parts (called exons) of the human dystrophin gene, where the mutation occurs. The binding of antisense oligo to its targeted exon removes the defective part of the gene and restores the production of dystrophin protein which is missing in the DMD patients.

In 2003, Dr. Lu first demonstrated the therapeutic potential of antisense therapy in models of DMD in vivo. Since then, significant progress has been made in the McColl-Lockwood Laboratory and other laboratories around the world. The McColl-Lockwood Laboratory has demonstrated restoration of dystrophin expression in body-wide muscles of murine models of DMD by means of systemic delivery of antisense oligomers. Long-term maintenance of dystrophin expression and functional improvement of muscles can also be achieved. The laboratory has also established techniques for identifying effective antisense oligomers as the drugs in cell culture and in vivo, essential for antisense drug development into clinical trials. Full restoration of dystrophin in heart muscle has been accomplished with improved functions.

Exon skipping is able to restore the expression of patient’s own dystrophin with better function when compared with AAV-delivered mini-dystrophin. However, low delivery capacity with naked antisense oligo to body-wide muscles limits the degree of efficacy in clinic trials. The McColl Lockwood Lab is making further effort to improve delivery efficiency with the aim to achieve systemic and long-term higher efficacy.

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Vannoy CH, Leroy V, Broniowska K, Lu QL. Metabolomics Analysis of Skeletal Muscles from FKRP-Deficient Mice Indicates Improvement After Gene Replacement Therapy. Sci Rep. 2019 Jul 11;9(1):10070.

Wang M, Wu B, Shah SN, Lu P, Lu Q. Aminoglycoside Enhances the Delivery of Antisense Morpholino Oligonucleotides In Vitro and in mdx Mice. Mol Ther Nucleic Acids. 2019 Jun 7;16:663-674

Vila MC, Novak JS, Benny Klimek M, Li N4, Morales M, Fritz AG, Edwards K, Boehler JF, Hogarth MW, Kinder TB, Zhang A, Mazala D, Fiorillo AA, Douglas B, Chen YW, van den Anker J, Lu QL, Hathout Y, Hoffman EP, Partridge TA, Nagaraju K. Morpholino-induced exon skipping stimulates cell-mediated and humoral responses to dystrophin in mdx mice. J Pathol. 2019 Mar 18. doi: 10.1002/path.5263.

Cataldi MP, Lu P, Blaeser A, Lu QL. Ribitol restores functionally glycosylated α-dystroglycan and improves muscle function in dystrophic FKRP-mutant mice. Nat Commun. 2018 Aug 27;9(1):3448.

Wang M, Wu B, Shah SN, Lu P, Lu Q. Saponins enhance exon skipping of 2'-O-methyl phosphorothioate oligonucleotide in vitro and in vivo. Drug Des Devel Ther. 2018 Oct 31;12:3705-3715

Vannoy CH, Leroy V, Lu QL. Dose-Dependent Effects of FKRP Gene-Replacement Therapy on Functional Rescue and Longevity in Dystrophic Mice. Mol Ther Methods Clin Dev. 2018 Oct 13;11:106-120

Tucker JD, Lu PJ, Xiao X, Lu QL. Overexpression of Mutant FKRP Restores Functional Glycosylation and Improves Dystrophic Phenotype in FKRP Mutant Mice. Mol Ther Nucleic Acids. 2018 Jun 1;11:216-227.

Yu Q, Morales M, Li N, Fritz AG, Ruobing R, Blaeser A, Francois E, Lu QL, Nagaraju K, Spurney CF. Skeletal, cardiac, and respiratory muscle function and histopathology in the P448Lneo- mouse model of FKRP-deficient muscular dystrophy. Skelet Muscle. 2018 Apr 6;8(1):13.

Wu B, Shah SN, Lu P, Bollinger LE, Blaeser A, Sparks S, Harper AD, LuQL. Long-Term Treatment of Tamoxifen and Raloxifene Alleviates Dystrophic Phenotype and Enhances Muscle Functions of FKRPDystroglycanopathy. Am J Pathol. 2018 Apr;188(4):1069-1080

Blaeser A, Awano H, Lu P, Lu QL. Distinct expression of functionally glycosylated alpha-dystroglycan in muscle and non-muscle tissues of FKRP mutant mice. PLoS One. 2018 Jan 10;13(1):e0191016.

Wang M, Wu B, Shah SN, Lu P, Lu Q. Saponins as Natural Adjuvant for Antisense Morpholino Oligonucleotides Delivery In Vitro and in mdx Mice. Oligonucleotides Delivery In Vitro and in mdx Mice. Mol Ther Nucleic Acids. 2018 Jun 1;11:192-202.

Wu B, Wang M, Shah S, Lu QL. In Vivo Evaluation of Dystrophin Exon Skipping in mdx Mice. Methods Mol Biol. 2018;1828:231-247. doi: 10.1007/978-1-4939-8651-4_14. PMID: 30171545

Frattini P, Villa C, De Santis F, Meregalli M, Belicchi M, Erratico S, Bella P, Raimondi MT, Lu Q, Torrente Y. Autologous intramuscular transplantation of engineered satellite cells induces exosome-mediated systemic expression of Fukutin-related protein and rescues disease phenotype in a murine model of limb-girdle muscular dystrophy type 2I. Hum Mol Genet. 2017 Oct 1;26(19):3682-3698.

Vannoy CH, Xiao W, Lu P, Xiao X, Lu QL. Efficacy of Gene Therapy Is Dependent on Disease Progression in Dystrophic Mice with Mutations in the FKRP Gene. Mol Ther Methods Clin Dev. 2017 Mar 8;5:31-42.

Mingxing Wang, Bo Wu, Peijuan Lu, Sapana N. Shah, Jason D. Tucker, Lauren E. Bollinger and Qilong Lu. Evaluation of Amphiphilic Peptide Modified Antisense Morpholino Oligonucleotides in vitro and in Dystrophic mdx Mice. Polymers. 2017, 9, 177.

Vannoy CH, Zhou H, Qiao C, Xiao X, Bang AG, Lu QL. Adeno-Associated Virus-Mediated Mini-Agrin Delivery Is Unable to Rescue Disease Phenotype in a Mouse Model of Limb Girdle Muscular Dystrophy Type 2I. Am J Pathol. 2017 Feb;187(2):431-440.

Blaeser A, Awano H, Wu B, Lu QL. Progressive Dystrophic Pathology in Diaphragm and Impairment of Cardiac Function in FKRP P448L Mutant Mice. PLoS One. 2016 Oct 6;11(10):e0164187.

Keramaris E, Lu PJ, Tucker J, Lu QL. Expression of glycosylated α-dystroglycan in newborn skeletal and cardiac muscles of fukutin related protein (FKRP) mutant mice. Muscle Nerve. 2017 Apr;55(4):582-590.

Wang M, Wu B, Tucker JD, Shah SN, Lu P, Bollinger LE, Lu Q. Tween 85-Modified Low Molecular Weight PEI Enhances Exon-Skipping of Antisense Morpholino Oligomer In Vitro and in mdx Mice. Mol Ther Nucleic Acids. 2017 Dec 15;9:120-131

Wang M, Wu B, Shah SN, Lu P, Lu Q. Polyquaternium-mediated delivery of morpholino oligonucleotides for exon-skipping in vitro and in mdx mice. Drug Deliv. 2017 Nov;24(1):952-961.

Wang M, Wu B, Tucker JD, Bollinger LE, Lu P, Lu Q. Poly(ester amine) Composed of Polyethylenimine and Pluronic Enhance Delivery of Antisense Oligonucleotides In Vitro and in Dystrophic mdx Mice. Mol Ther Nucleic Acids. 2016 Aug 2;5(8):e341.

Maricelli JW, Lu QL, Lin DC, Rodgers BD. Trendelenburg-Like Gait, Instability and Altered Step Patterns in a Mouse Model for Limb Girdle Muscular Dystrophy 2i. PLoS One. 2016 Sep 14;11(9):e0161984.

Wang M, Wu B, Tucker JD, Lu P, Lu Q. Cationic polyelectrolyte-mediated delivery of antisense morpholino oligonucleotides for exon-skipping in vitro and in mdx mice. Int J Nanomedicine. 2015 Sep 3;10:5635-4.

Bo Wu, Sapana N. Shah, Peijuan Lu, Stephanie Milazi, Lauren E. Bollinger, Anthony Blaeser, Kyle L. Madden, Taylor M. Luckie, Michael D. Cox, Susan Sparks, Amy D. Harper, Qi Long Lu.. Glucocorticoid steroid and Alendronate treatment alleviate dystrophic phenotype with enhanced functional glycosylation of α-dystroglycan in mouse model of Limb Girdle Muscular Dystrophy with FKRP mutation. Am J Pathol. 2016 Jun;186(6):1635-48.

Wang M, Wu B, Tucker JD, Lu P, Lu Q. Poly(ester amine) constructed from polyethylenimine and pluronic for gene delivery in vitro and in vivo. Drug Deliv. 2016 Mar 29:1-10. [Epub ahead of print] PMID:26960992

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Awano H, Blaeser A, Keramaris E, Xu L, Tucker J, Wu B, Lu P, Lu QL. Restoration of functional glycosylation of α-Dystroglycan in FKRP mutant mice is associated with muscle regeneration. Am J Pathol. 2015 Jul;185(7):2025-2037. doi: 10.1016/j.ajpath.2015.03.017

Awano H, Blaeser A, Wu B, Lu P, Keramaris-Vrantsis E, Lu Q. Dystroglycanopathy muscles lacking functional glycosylation of alpha-dystroglycan retain regeneration capacity. Neuromuscular Disord 2015 Jun:25(6):474-84

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Mingxing Wang*, Bo Wu, Jason D Tucker, Peijuan Lu and Qilong Lu. Tris[2 (Acryloyloxy) Ethyl]Isocyanurate Cross-Linked Polyethylenimine Enhanced Exon-Skipping of Antisense 2′-Omethyl Phosphorothioate Oligonucleotide in vitro and in vivo. J Nanomed Nanotechnol 2015, 6:1

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Mingxing Wang, Bo Wu,1 Jay D. Tucker, Peijuan Lu, Caryn Cloer, and Qi Long Lu. Evaluation of Tris[2-(Acryloyloxy)Ethyl] Isocyanurate Cross-Linked Polyethylenimine as Antisense Morpholino Oligomer Delivery Vehicle. Hum Gene Ther. 2014 May;25(5):419-27

Lu QL, Cirak S, Partridge T. What Can We Learn from Clinical Trials of Exon Skipping for DMD? Mol Ther Nucleic Acids. 2014; 3(3): e152.

Qi-long Lu, Sebahattin Cirak and Terence Partridge. What Can We Learn From Clinical Trials of Exon Skipping. Molecular Therapy – Nucleic Acids. 3, e152; doi:10.1038/mtna.2014.6 March 11 2014

Vannoy C, Xu L, Keramaris E, Lu P, Xiao X, Lu Q. AAV-Mediated Overexpression of LARGE Rescues α-Dystroglycan Function in Dystrophic Mice with Mutations in the Fukutin-related Protein. Hum Gene Ther Methods. 2014 Jun;25(3):187-96

Bo Wu, Caryn Cloer, Stephanie Milazi, Mona Shaban, Sapana N Shah, Lauren Marston-Poe, Peijuan Lu, Hong M. Moulton, Qi Long Lu. Exon Skipping Restores Dystrophin Expression, but Fails to Prevent Disease Progression in Later Stage Dystrophic Dko Mice. Gene Ther. 2014 Sep;21(9):785-93

Wang M, Wu B, Lu P, Tucker JD, Milazi S, Shah SN, Lu QL Pluronic-PEI copolymers enhance exon-skipping of 2'-O-methyl phosphorothioate oligonucleotide in cell culture and dystrophic mdx mice. Gene Ther. 2014 Jan;21(1):52-9. doi: 10.1038/gt.2013.57. Epub 2013 Oct 17

Anthony Blaeser; Susan Sparks; Susan C. Brown; Kevin Campbell, Qi Lu. Third International Workshop for Glycosylation Defects in Muscular Dystrophies, 18–19 April 2013, Charlotte, USA Brain Pathology, Brain Pathology. Volume 24, Issue 3, pages 280–284, April 2014

Lei Xu, Lu PJ., Wang CH., Keramaris E., Qiao CP., 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. Molecular Therapy 2013

Wang M., Wu B., Lu P., Milazi S., Shah SN., Lu QL. l. Pluronic-PEI copolymers enhance exon skipping of 2’-O-methyle phosphorothioate oligonucleotide in cell culture and dystrophic mdx mice. Gene Ther. 2013 Oct 17. doi: 10.1038/gt.2013.57

Blaeser A, Keramaris E, Chan YM, Sparks S, Cowley D, Xiao X, Lu QL. Mouse models of fukutin-related protein mutations show a wide range of disease phenotypes. Human Genetics, 2013 Aug;132(8):923-34

Wang GQ and Lu QL. A Nitrate Ester of Sedative Alkyl Alcohol Improves Muscle Function and Structure in a Murine Model of Duchenne Muscular Dystrophy. Molecular Pharmaceutics Mol Pharm. 2013 Oct 7;10(10):3862-70.

Kendall, G.C., Ekaterina I. Mokhonova, Miriana Moran, Natalia E. Sejbuk, Derek W. Wang, Oscar Silva, Richard T. Wang, Leonel Martinez, Qi L. Lu, Robert Damoiseaux, Melissa J. Spencer, Stanley F. Nelson, M. Carrie Miceli. Dantrolene enhances antisense-mediated exon skipping in human and mouse models of Duchenne muscular dystrophy. Science Translational Medicine 2012 Dec 12;4(164):164ra160. doi: 10.1126/scitranslmed.3005054.

Mingxing Wang, Jay D. Tucker, Peijuan Lu, Bo Wu, Qilong Lu. Tris[2-(acryloyloxy)ethyl]isocyanurate Cross-Linked Low-Molecular-Weight Polyethylenimine as Gene Delivery Carriers in Cell Culture and Dystrophic mdx Mice. Bioconjugate Chemistry. Bioconjug Chem. 2012 Mar 25

Bo Wu, Peijuan Lu, Caryn Cloer, Mona Shaban, Snimar Grewal, Stephanie Milazi, Sapana N Shah, Hong M. Moulton, Qi Long Lu. 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, 181(2):392-400.

Atsushi Kuga, Motoi Kanagawa, Atsushi Sudo, Yiumo Michael Chan, Michiko Tajiri, Hiroshi Manya, Yamato Kikkawa, Motoyoshi Nomizu, Kazuhiro Kobayashi, Tamao Endo, Qi L. Lu, Yoshinao Wada, and Tatsushi Toda. Absence of post-phosphoryl　modification　in　dystroglycanopathy　mouse　models　and　wild-type tissues expressing a non-laminin binding form of alpha-dystroglycan. Journal of Biological chemistry. The Journal of Biological Chemistry, 287, 9560-9567.

Mingxing Wang, Peijuan Lu, Bo Wu, Jay D. Tucker, Caryn Cloer, Qilong Lu. High Efficiency and Low Toxicity of Polyethyleneimine Modified Pluronics (PEI-Pluronic) as Gene Delivery Carriers in Cell Culture and Dystrophic mdx Mice . Journal of Materials Chemistry J. Mater. Chem., 2012,22, 6038-6046

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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 Jan;19(1):9-15.

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Yiumo Michael Chan, Elizabeth Keramaris-Vrantsis, Hart Lidov, James H. Norton, Natalia Zinchenko, Helen E. Gruber, Randy Thresher, Derek J. Blake, Jignya Ashar, Jeffrey Rosenfeld and Qi L. Lu. 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) 19(20): 3995-4006

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Wang GQ, Burczynski FJ, Hasinoff BB, Zhang KD, Lu QL, and Anderson JE. Development of a nitric oxide-releasing analog of the muscle relaxant guaifenesin for skeletal muscle satellite myogenesis. Molecular Pharmaceutics. 2009; 6(3):895-904.

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 Mar 13. PMID: 19288467

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Yokota T, Lu Q, Morgon JE, Davies KE, Fisher S, Tekada S, Partridge T, Expansion of revertant fibers in dystrophic mdx muscles reflects activity of muscle precursor cells and serves as an index of muscle regeneration. J Cell Sci. 2006,119:2679-87.

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Yun-Chao Chen, Hai-Dong Liang, Qing-Ping Zhang, Martin JK Blomley, Lu Q. L. Pluronic block copolymers: novel functions in ultrasound-mediated gene transfer and against cell damage. Ultrasound in Medicine and Biology. Ultrasound Med Biol. 2006 Jan;32(1):131-7.

Lu Q. L., Rabinowitz A., Chen Y. C., Toshifumi Y., Yin H. F., Alter J., Jadoon A., Bou-Gharios G. and Partridge T. Systemic delivery of antisense oligoribonucleotide restores dystrophin expression in body-wide skeletal muscles. Proc. Natl. Acad. Sci. USA, 2005 4;102:198-203.

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Lu Qi and Terence A. Partridge Antisense therapy corrects nonsense mutation by exon skipping. Discovery Medicine, 2003, 3(19):39-44

*This is the first publication proved that oligonucleotide mediated exon skipping can achieve therapeutic effect in vivo locally with improved functions

Lu Q. L, Christopher J. Mann, Fang Lou, Georges Bou-Gharios, Glenn E. Morris, Shao-an Xue, Sue Fletcher, Terence A. Partridge & Stephen D. Wilton. Functional amounts of dystrophin produced by skipping the mutated exon in the mdx dystrophic mouse. Nature Medicine 2003, 9:1009-1015