Plasmapheresis Eliminates the Negative Impact of AAV Antibodies on Microdystrophin Gene Expression Following Vascular Delivery

Overview

Journal Mol Ther

Publisher Cell Press

Specialties Molecular Biology
Pharmacology

Date 2013 Nov 8

PMID 24196577

Citations 98

Authors

L G Chicoine

C L Montgomery

W G Bremer

K M Shontz

D A Griffin

K N Heller

S Lewis

V Malik

W E Grose

C J Shilling

K J Campbell

T J Preston

B D Coley

P T Martin

C M Walker

K R Clark

Z Sahenk

J R Mendell

L R Rodino-Klapac

Affiliations

Soon will be listed here.

Abstract

Duchenne muscular dystrophy is a monogenic disease potentially treatable by gene replacement. Use of recombinant adeno-associated virus (AAV) will ultimately require a vascular approach to broadly transduce muscle cells. We tested the impact of preexisting AAV antibodies on microdystrophin expression following vascular delivery to nonhuman primates. Rhesus macaques were treated by isolated limb perfusion using a fluoroscopically guided catheter. In addition to serostatus stratification, the animals were placed into one of the three immune suppression groups: no immune suppression, prednisone, and triple immune suppression (prednisone, tacrolimus, and mycophenolate mofetil). The animals were analyzed for transgene expression at 3 or 6 months. Microdystrophin expression was visualized in AAV, rhesus serotype 74 sero-negative animals (mean: 48.0 ± 20.8%) that was attenuated in sero-positive animals (19.6 ± 18.7%). Immunosuppression did not affect transgene expression. Importantly, removal of AAV binding antibodies by plasmapheresis in AAV sero-positive animals resulted in high-level transduction (60.8 ± 18.0%), which is comparable with that of AAV sero-negative animals (53.7 ± 7.6%), whereas non-pheresed sero-positive animals demonstrated significantly lower transduction levels (10.1 ± 6.0%). These data support the hypothesis that removal of AAV binding antibodies by plasmapheresis permits successful and sustained gene transfer in the presence of preexisting immunity (natural infection) to AAV.

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References

McMaster P, Mirza D, Ismail T, Vennarecci G, Patapis P, Mayer A . Therapeutic drug monitoring of tacrolimus in clinical transplantation. Ther Drug Monit. 1995; 17(6):602-5. DOI: 10.1097/00007691-199512000-00010. View

Cortese I, Chaudhry V, So Y, Cantor F, Cornblath D, Rae-Grant A . Evidence-based guideline update: Plasmapheresis in neurologic disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2011; 76(3):294-300. PMC: 3034395. DOI: 10.1212/WNL.0b013e318207b1f6. View

Boutin S, Monteilhet V, Veron P, Leborgne C, Benveniste O, Montus M . Prevalence of serum IgG and neutralizing factors against adeno-associated virus (AAV) types 1, 2, 5, 6, 8, and 9 in the healthy population: implications for gene therapy using AAV vectors. Hum Gene Ther. 2010; 21(6):704-12. DOI: 10.1089/hum.2009.182. View

Mendell J, Rodino-Klapac L, Rosales-Quintero X, Kota J, Coley B, Galloway G . Limb-girdle muscular dystrophy type 2D gene therapy restores alpha-sarcoglycan and associated proteins. Ann Neurol. 2009; 66(3):290-7. PMC: 6014624. DOI: 10.1002/ana.21732. View

Shield M, Haugen H, Clegg C, Hauschka S . E-box sites and a proximal regulatory region of the muscle creatine kinase gene differentially regulate expression in diverse skeletal muscles and cardiac muscle of transgenic mice. Mol Cell Biol. 1996; 16(9):5058-68. PMC: 231507. DOI: 10.1128/MCB.16.9.5058. View

Rodino-Klapac L, Montgomery C, Bremer W, Shontz K, Malik V, Davis N . Persistent expression of FLAG-tagged micro dystrophin in nonhuman primates following intramuscular and vascular delivery. Mol Ther. 2009; 18(1):109-17. PMC: 2839222. DOI: 10.1038/mt.2009.254. View

Hurlbut G, Ziegler R, Nietupski J, Foley J, Woodworth L, Meyers E . Preexisting immunity and low expression in primates highlight translational challenges for liver-directed AAV8-mediated gene therapy. Mol Ther. 2010; 18(11):1983-94. PMC: 2990518. DOI: 10.1038/mt.2010.175. View

Mendell J, Shilling C, Leslie N, Flanigan K, Al-Dahhak R, Gastier-Foster J . Evidence-based path to newborn screening for Duchenne muscular dystrophy. Ann Neurol. 2012; 71(3):304-13. DOI: 10.1002/ana.23528. View

Yuasa K, Sakamoto M, Miyagoe-Suzuki Y, Tanouchi A, Yamamoto H, Li J . Adeno-associated virus vector-mediated gene transfer into dystrophin-deficient skeletal muscles evokes enhanced immune response against the transgene product. Gene Ther. 2002; 9(23):1576-88. DOI: 10.1038/sj.gt.3301829. View

10.

Mendell J, Rodino-Klapac L, Sahenk Z, Roush K, Bird L, Lowes L . Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann Neurol. 2013; 74(5):637-47. DOI: 10.1002/ana.23982. View

11.

Nathwani A, Tuddenham E, Rangarajan S, Rosales C, McIntosh J, Linch D . Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med. 2011; 365(25):2357-65. PMC: 3265081. DOI: 10.1056/NEJMoa1108046. View

12.

Rabinowitz J, Rolling F, Li C, Conrath H, Xiao W, Xiao X . Cross-packaging of a single adeno-associated virus (AAV) type 2 vector genome into multiple AAV serotypes enables transduction with broad specificity. J Virol. 2001; 76(2):791-801. PMC: 136844. DOI: 10.1128/jvi.76.2.791-801.2002. View

13.

Simari R, Yang Z, Ling X, Stephan D, Perkins N, Nabel G . Requirements for enhanced transgene expression by untranslated sequences from the human cytomegalovirus immediate-early gene. Mol Med. 1999; 4(11):700-6. PMC: 2230344. View

14.

Mendell J, Moxley R, Griggs R, Brooke M, Fenichel G, Miller J . Randomized, double-blind six-month trial of prednisone in Duchenne's muscular dystrophy. N Engl J Med. 1989; 320(24):1592-7. DOI: 10.1056/NEJM198906153202405. View

15.

Lin J, Calcedo R, Vandenberghe L, Figueredo J, Wilson J . Impact of preexisting vector immunity on the efficacy of adeno-associated virus-based HIV-1 Gag vaccines. Hum Gene Ther. 2008; 19(7):663-9. PMC: 2940634. DOI: 10.1089/hum.2008.033. View

16.

Mendell J, Campbell K, Rodino-Klapac L, Sahenk Z, Shilling C, Lewis S . Dystrophin immunity in Duchenne's muscular dystrophy. N Engl J Med. 2010; 363(15):1429-37. PMC: 3014106. DOI: 10.1056/NEJMoa1000228. View

17.

Watchko J, ODay T, Wang B, Zhou L, Tang Y, Li J . Adeno-associated virus vector-mediated minidystrophin gene therapy improves dystrophic muscle contractile function in mdx mice. Hum Gene Ther. 2002; 13(12):1451-60. DOI: 10.1089/10430340260185085. View

18.

Salva M, Himeda C, Tai P, Nishiuchi E, Gregorevic P, Allen J . Design of tissue-specific regulatory cassettes for high-level rAAV-mediated expression in skeletal and cardiac muscle. Mol Ther. 2007; 15(2):320-9. DOI: 10.1038/sj.mt.6300027. View

19.

Yue Y, Ghosh A, Long C, Bostick B, Smith B, Kornegay J . A single intravenous injection of adeno-associated virus serotype-9 leads to whole body skeletal muscle transduction in dogs. Mol Ther. 2008; 16(12):1944-52. PMC: 2703820. DOI: 10.1038/mt.2008.207. View

20.

Mendell J, Rodino-Klapac L, Rosales X, Coley B, Galloway G, Lewis S . Sustained alpha-sarcoglycan gene expression after gene transfer in limb-girdle muscular dystrophy, type 2D. Ann Neurol. 2010; 68(5):629-38. PMC: 2970162. DOI: 10.1002/ana.22251. View