Immune responses to dystrophin: implications for gene therapy of Duchenne muscular dystrophy

被引:72
作者
Ferrer, A [1 ]
Wells, KE [1 ]
Wells, DJ [1 ]
机构
[1] Univ London Imperial Coll Sci Technol & Med, Sch Med, Charing Cross Hosp,Div Neurosci & Psychol Med, Gene Targeting Unit,Dept Neuromuscular Dis, London W6 8RP, England
基金
英国惠康基金; 英国医学研究理事会;
关键词
CD8; dystrophin; mdx; immunology; tolerance; Duchenne;
D O I
10.1038/sj.gt.3301259
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Introduction of dystrophin by gene transfer into the dystrophic muscles of Duchenne muscular dystrophy (DMD) patients has the possibility of triggering an immune response as many patients will not have been exposed to some (or ail) of the epitopes of dystrophin. This could in turn lead to cytotoxic destruction of transfected muscle fibres. We assessed such concerns in the dystrophin-deficient mdx mouse using plasmid DNA as the gene transfer system. This avoids complications associated with the administration of viral proteins. Gene transfer of cDNAs encoding mouse full-length or a truncated minidystrophin did not evoke either a humoral or cytotoxic immune response. Mdx mice may be tolerant due to the presence of rare 'revertant' dystrophin-positive fibres in their skeletal muscles. In contrast, gene transfer of human full-length or minidystrophin provoked both humoral and cytotoxic responses leading to destruction of the transfected fibres. These experiments demonstrate the potential risk of deleterious effects following gene therapy in DMD patients and lead us to suggest that patients enrolled in gene therapy trials should ideally have small, preferably point, mutations and evidence of 'revertant' dystrophin-positive muscle fibres.
引用
收藏
页码:1439 / 1446
页数:8
相关论文
共 40 条
[1]   HUMAN DYSTROPHIN EXPRESSION IN MDX MICE AFTER INTRAMUSCULAR INJECTION OF DNA CONSTRUCTS [J].
ACSADI, G ;
DICKSON, G ;
LOVE, DR ;
JANI, A ;
WALSH, FS ;
GURUSINGHE, A ;
WOLFF, JA ;
DAVIES, KE .
NATURE, 1991, 352 (6338) :815-818
[2]  
BAKKER E, 1998, NEUROMUSCULAR DISORD, P59
[3]   COISOGENIC ALL-PLUS-ONE IMMUNIZATION - A MODEL FOR IDENTIFYING MISSING PROTEINS IN NULL-MUTANT CONDITIONS - ANTIBODIES TO DYSTROPHIN IN MDX MOUSE AFTER TRANSPLANTATION OF MUSCLE FROM NORMAL COISOGENIC DONOR [J].
BITTNER, RE ;
STREUBEL, B ;
SHORNY, S ;
SCHADEN, G ;
VOIT, T ;
HOGER, H .
NEUROPEDIATRICS, 1994, 25 (04) :176-182
[4]   SERUM ANTIBODIES TO THE DELETED DYSTROPHIN SEQUENCE AFTER CARDIAC TRANSPLANTATION IN A PATIENT WITH BECKERS MUSCULAR-DYSTROPHY [J].
BITTNER, RE ;
SHORNY, S ;
STREUBEL, B ;
HUBNER, C ;
VOIT, T ;
KRESS, W .
NEW ENGLAND JOURNAL OF MEDICINE, 1995, 333 (11) :732-733
[5]  
BRENNAN KJ, 1993, J BIOL CHEM, V268, P719
[6]   X-CHROMOSOME-LINKED MUSCULAR-DYSTROPHY (MDX) IN THE MOUSE [J].
BULFIELD, G ;
SILLER, WG ;
WIGHT, PAL ;
MOORE, KJ .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES, 1984, 81 (04) :1189-1192
[7]   DYSTROPHIN EXPRESSION AND SOMATIC REVERSION IN PREDNISONE-TREATED AND UNTREATED DUCHENNE DYSTROPHY [J].
BURROW, KL ;
COOVERT, DD ;
KLEIN, CJ ;
BULMAN, DE ;
KISSEL, JT ;
RAMMOHAN, KW ;
BURGHES, AHM ;
MENDELL, JR .
NEUROLOGY, 1991, 41 (05) :661-666
[8]   EFFECT OF DYSTROPHIN GENE DELETIONS ON MESSENGER-RNA LEVELS AND PROCESSING IN DUCHENNE AND BECKER MUSCULAR-DYSTROPHIES [J].
CHELLY, J ;
GILGENKRANTZ, H ;
LAMBERT, M ;
HAMARD, G ;
CHAFEY, P ;
RECAN, D ;
KATZ, P ;
DELACHAPELLE, A ;
KOENIG, M ;
GINJAAR, IB ;
FARDEAU, M ;
TOME, F ;
KAHN, A ;
KAPLAN, JC .
CELL, 1990, 63 (06) :1239-1248
[9]   OVEREXPRESSION OF DYSTROPHIN IN TRANSGENIC MDX MICE ELIMINATES DYSTROPHIC SYMPTOMS WITHOUT TOXICITY [J].
COX, GA ;
COLE, NM ;
MATSUMURA, K ;
PHELPS, SF ;
HAUSCHKA, SD ;
CAMPBELL, KP ;
FAULKNER, JA ;
CHAMBERLAIN, JS .
NATURE, 1993, 364 (6439) :725-729
[10]  
EMERY AEH, 1987, OXFORD MONOG MED GEN, V15