Long-Term Effect of Gene Therapy on Leber's Congenital Amaurosis

被引：579

作者：

Bainbridge, J. W. B. ^{[1
,3
]}

Mehat, M. S. ^{[1
,3
]}

Sundaram, V. ^{[1
,3
]}

Robbie, S. J. ^{[1
,3
]}

Barker, S. E. ^{[1
]}

Ripamonti, C. ^{[1
]}

Georgiadis, A. ^{[1
,3
]}

Mowat, F. M. ^{[1
,5
]}

Beattie, S. G. ^{[1
]}

Gardner, P. J. ^{[1
]}

Feathers, K. L. ^{[6
]}

Luong, V. A. ^{[1
]}

Yzer, S. ^{[9
]}

Balaggan, K. ^{[1
,3
]}

Viswanathan, A. ^{[1
]}

de Ravel, T. J. L. ^{[7
]}

Casteels, I. ^{[8
]}

Holder, G. E. ^{[1
,3
]}

Tyler, N. ^{[2
]}

Fitzke, F. W. ^{[1
]}

Weleber, R. G. ^{[10
]}

Nardini, M. ^{[1
,4
]}

Moore, A. T. ^{[1
,3
]}

Thompson, D. A. ^{[6
]}

Petersen-Jones, S. M. ^{[5
]}

Michaelides, M. ^{[1
,3
]}

van den Born, L. I. ^{[9
]}

Stockman, A. ^{[1
]}

Smith, A. J. ^{[1
]}

Rubin, G. ^{[1
]}

Ali, R. R. ^{[1
,6
]}

机构：

[1] UCL, Inst Ophthalmol, London EC1V 9EL, England

[2] UCL, Dept Civil Environm & Geomat Engn, London EC1V 9EL, England

[3] Moorfields Eye Hosp, London, England

[4] Univ Durham, Dept Psychol, Durham DH1 3LE, England

[5] Michigan State Univ, Coll Vet Med, E Lansing, MI 48824 USA

[6] Univ Michigan, Kellogg Eye Ctr, Sch Med, Ann Arbor, MI 48109 USA

[7] Katholieke Univ Leuven, Ctr Human Genet, Leuven, Belgium

[8] UZ Leuven, Dept Ophthalmol, Leuven, Belgium

[9] Rotterdam Eye Hosp, Rotterdam, Netherlands

[10] Oregon Hlth & Sci Univ, Casey Eye Inst, Oregon Retinal Degenerat Ctr, Ophthalm Genet Serv, Portland, OR 97201 USA

来源：

NEW ENGLAND JOURNAL OF MEDICINE | 2015年 / 372卷 / 20期

基金：

英国生物技术与生命科学研究理事会; 英国工程与自然科学研究理事会;

关键词：

ADENOASSOCIATED VIRUS; SUBRETINAL INJECTION; RETINAL-DETACHMENT; RPE65; MUTATIONS; VISION; MULLER; DEGENERATION; EXPRESSION; ISOMERASE; PROTEINS;

D O I：

10.1056/NEJMoa1414221

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

BACKGROUND Mutations in RPE65 cause Leber's congenital amaurosis, a progressive retinal degenerative disease that severely impairs sight in children. Gene therapy can result in modest improvements in night vision, but knowledge of its efficacy in humans is limited. METHODS We performed a phase 1-2 open-label trial involving 12 participants to evaluate the safety and efficacy of gene therapy with a recombinant adeno-associated virus 2/2 (rAAV2/2) vector carrying the RPE65 complementary DNA, and measured visual function over the course of 3 years. Four participants were administered a lower dose of the vector, and 8 were administered a higher dose. In a parallel study in dogs, we investigated the relationship among vector dose, visual function, and electroretinography (ERG) findings. RESULTS Improvements in retinal sensitivity were evident, to varying extents, in six participants for up to 3 years, peaking at 6 to 12 months after treatment and then declining. No associated improvement in retinal function was detected by means of ERG. Three participants had intraocular inflammation, and two had clinically significant deterioration of visual acuity. The reduction in central retinal thickness varied among participants. In dogs, RPE65 gene therapy with the same vector at lower doses improved vision-guided behavior, but only higher doses resulted in improvements in retinal function that were detectable with the use of ERG. CONCLUSIONS Gene therapy with rAAV2/2 RPE65 vector improved retinal sensitivity, albeit modestly and temporarily. Comparison with the results obtained in the dog model indicates that there is a species difference in the amount of RPE65 required to drive the visual cycle and that the demand for RPE65 in affected persons was not met to the extent required for a durable, robust effect.

引用

页码：1887 / 1897

页数：11

共 29 条

[1] Long-term restoration of rod and cone vision by single dose rAAV-mediated gene transfer to the retina in a canine model of childhood blindness [J].

Acland, GM ;

Aguirre, GD ;

Bennett, J ;

Aleman, TS ;

Cideciyan, AV ;

Bennicelli, J ;

Dejneka, NS ;

Pearce-Kelling, SE ;

Maguire, AM ;

Palczewski, K ;

Hauswirth, WW ;

Jacobson, SG .

MOLECULAR THERAPY, 2005, 12 (06) :1072-1082

[2] Gene therapy in the second eye of RPE65-deficient dogs improves retinal function [J].

Annear, M. J. ;

Bartoe, J. T. ;

Barker, S. E. ;

Smith, A. J. ;

Curran, P. G. ;

Bainbridge, J. W. ;

Ali, R. R. ;

Petersen-Jones, S. M. .

GENE THERAPY, 2011, 18 (01) :53-61

[3] Successful Gene Therapy in Older Rpe65-Deficient Dogs Following Subretinal Injection of an Adeno-Associated Vector Expressing RPE65 [J].

Annear, Matthew J. ;

Mowat, Freya M. ;

Bartoe, Joshua T. ;

Querubin, Janice ;

Azam, Selina A. ;

Basche, Mark ;

Curran, Paul G. ;

Smith, Alexander J. ;

Bainbridge, James W. B. ;

Ali, Robin R. ;

Petersen-Jones, Simon M. .

HUMAN GENE THERAPY, 2013, 24 (10) :883-893

[4] Effect of gene therapy on visual function in Leber's congenital amaurosis [J].

Bainbridge, James W. B. ;

Smith, Alexander J. ;

Barker, Susie S. ;

Robbie, Scott ;

Henderson, Robert ;

Balaggan, Kamaljit ;

Viswanathan, Ananth ;

Holder, Graham E. ;

Stockman, Andrew ;

Tyler, Nick ;

Petersen-Jones, Simon ;

Bhattacharya, Shomi S. ;

Thrasher, Adrian J. ;

Fitzke, Fred W. ;

Carter, Barrie J. ;

Rubin, Gary S. ;

Moore, Anthony T. ;

Ali, Robin R. .

NEW ENGLAND JOURNAL OF MEDICINE, 2008, 358 (21) :2231-2239

[5] Molecular Anthropology Meets Genetic Medicine to Treat Blindness in the North African Jewish Population: Human Gene Therapy Initiated in Israel [J].

Banin, Eyal ;

Bandah-Rozenfeld, Dikla ;

Obolensky, Alexey ;

Cideciyan, Artur V. ;

Aleman, Tomas S. ;

Marks-Ohana, Devora ;

Sela, Malka ;

Boye, Sanford ;

Sumaroka, Alexander ;

Roman, Alejandro J. ;

Schwartz, Sharon B. ;

Hauswirth, William W. ;

Jacobson, Samuel G. ;

Hemo, Itzhak ;

Sharon, Dror .

HUMAN GENE THERAPY, 2010, 21 (12) :1749-1757

[6] Lentiviral gene transfer of Rpe65 rescues survival and function of cones in a mouse model of Leber congenital amaurosis [J].

Bemelmans, Alexis-Pierre ;

Kostic, Corinne ;

Crippa, Sylvain V. ;

Hauswirth, William W. ;

Lem, Janis ;

Munier, Francis L. ;

Seeliger, Mathias W. ;

Wenzel, Andreas ;

Arsenijevic, Yvan .

PLOS MEDICINE, 2006, 3 (10) :1892-1903

[7]

Bland JM, 1996, BRIT MED J, V313, P744

[8] Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement [J].

Cideciyan, Artur V. ;

Jacobson, Samuel G. ;

Beltran, William A. ;

Sumaroka, Alexander ;

Swider, Malgorzata ;

Iwabe, Simone ;

Roman, Alejandro J. ;

Olivares, Melani B. ;

Schwartz, Sharon B. ;

Komaromy, Andras M. ;

Hauswirth, William W. ;

Aguirre, Gustavo D. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2013, 110 (06) :E517-E525

[9] Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics [J].

Cideciyan, Artur V. ;

Aleman, Tomas S. ;

Boye, Sanford L. ;

Schwartz, Sharon B. ;

Kaushal, Shalesh ;

Roman, Alejandro J. ;

Pang, Ji-Jing ;

Sumaroka, Alexander ;

Windsor, Elizabeth A. M. ;

Wilson, James M. ;

Flotte, Terence R. ;

Fishman, Gerald A. ;

Heon, Elise ;

Stone, Edwin M. ;

Byrne, Barry J. ;

Jacobson, Samuel G. ;

Hauswirth, William W. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2008, 105 (39) :15112-15117

[10] In utero gene therapy rescues vision in a murine model of congenital blindness [J].

Dejneka, NS ;

Surace, EM ;

Aleman, TS ;

Cideciyan, AV ;

Lyubarsky, A ;

Savchenko, A ;

Redmond, TM ;

Tang, WX ;

Wei, ZY ;

Rex, TS ;

Glover, E ;

Maguire, AM ;

Pugh, EN ;

Jacobson, SG ;

Bennett, J .

MOLECULAR THERAPY, 2004, 9 (02) :182-188

← 1 2 3 →