A systematic review and meta-analysis of gene therapy in animal models of cerebral glioma: why did promise not translate to human therapy?
The development of therapeutics is often characterized by promising animal research that fails to translate into clinical efficacy; this holds for the development of gene therapy in glioma. We tested the hypothesis that this is because of limitations in the internal and external validity of studies reporting the use of gene therapy in experimental glioma.



We systematically identified studies testing gene therapy in rodent glioma models by searching three online databases. The number of animals treated and median survival were extracted and studies graded using a quality checklist. We calculated median survival ratios and used random effects meta-analysis to estimate efficacy. We explored effects of study design and quality and searched for evidence of publication bias.



We identified 193 publications using gene therapy in experimental glioma, including 6,366 animals. Overall, gene therapy improved median survival by a factor of 1.60 (95% CI 1.53-1.67). Study quality was low and the type of gene therapy did not account for differences in outcome. Study design characteristics accounted for a significant proportion of between-study heterogeneity. We observed similar findings in a data subset limited to the most common gene therapy.



As the dysregulation of key molecular pathways is characteristic of gliomas, gene therapy remains a promising treatment for glioma. Nevertheless, we have identified areas for improvement in conduct and reporting of studies, and we provide a basis for sample size calculations. Further work should focus on genes of interest in paradigms recapitulating human disease. This might improve the translation of such therapies into the clinic.
Centre for Clinical Brain Sciences Chancellors Building University of Edinburgh Edinburgh UK.
T C
TC
Hirst
Centre for Clinical Brain Sciences Chancellors Building University of Edinburgh Edinburgh UK.
H M
HM
Vesterinen
Centre for Clinical Brain Sciences Chancellors Building University of Edinburgh Edinburgh UK.
S
S
Conlin
Centre for Clinical Brain Sciences Chancellors Building University of Edinburgh Edinburgh UK.
K J
KJ
Egan
Florey Neuroscience and Mental Health Institute University of Melbourne Victoria Australia.
A
A
Antonic
Centre for Clinical Brain Sciences Chancellors Building University of Edinburgh Edinburgh UK.
A
A
Lawson McLean
Division of Clinical Neurosciences University of Edinburgh Western General Hospital Edinburgh UK.
M R
MR
Macleod
Division of Clinical Neurosciences University of Edinburgh Western General Hospital Edinburgh UK.
R
R
Grant
Division of Clinical Neurosciences University of Edinburgh Western General Hospital Edinburgh UK.
P M
PM
Brennan
Centre for Clinical Brain Sciences Chancellors Building University of Edinburgh Edinburgh UK; Florey Neuroscience and Mental Health Institute University of Melbourne Victoria Australia.
E S
ES
Sena
Division of Clinical Neurosciences University of Edinburgh Western General Hospital Edinburgh UK.
I R
IR
Whittle
gene therapy; glioma; rodent models; systematic review
Ann Neurol. 2011 Feb;69(2):389-99
21387381
Cell Rep. 2013 Jan 31;3(1):260-73
23333277
Lancet Oncol. 2013 Aug;14(9):823-33
23850491
Stat Med. 1987 Jan-Feb;6(1):11-29
3576013
J Cereb Blood Flow Metab. 2010 Dec;30(12):1905-13
20648038
Stroke. 2009 Jul;40(7):e497
19498189
J Neurosci Methods. 2014 Jan 15;221:92-102
24099992
Nat Med. 1997 Dec;3(12):1354-61
9396605
Control Clin Trials. 1986 Sep;7(3):177-88
3802833
Transl Res. 2013 Apr;161(4):339-54
23246627
Science. 1991 May 10;252(5007):854-6
1851332
Cancer Res. 1970 Sep;30(9):2394-400
5475483
Neuro Oncol. 2014 Mar;16(3):334-51
24470549
J Natl Cancer Inst. 2004 Mar 17;96(6):434-42
15026468
Stroke. 2008 Oct;39(10):2824-9
18635842
Cancer Immunol Immunother. 2011 Feb;60(2):153-60
21120655
Stroke. 2004 May;35(5):1203-8
15060322
Mol Ther. 2005 Oct;12(4):585-98
16095972
PLoS Med. 2005 Aug;2(8):e124
16060722
Neurosci Lett. 2012 Oct 11;527(2):71-7
22906921
Jt Comm J Qual Improv. 1999 Sep;25(9):462-9
10481815
Int J Radiat Oncol Biol Phys. 1979 Oct;5(10):1725-31
231022
Br J Neurosurg. 1995;9(6):717-20
8719825
Biometrics. 2000 Jun;56(2):455-63
10877304
Acta Radiol Oncol Radiat Phys Biol. 1978;17(6):475-84
216238
PLoS Biol. 2010 Jun 29;8(6):e1000412
20613859
J Clin Oncol. 2003 Jul 1;21(13):2508-18
12839017
Trends Neurosci. 2007 Sep;30(9):433-9
17765332
Nature. 2004 Nov 18;432(7015):396-401
15549107
Evid Based Preclin Med. 2014 Dec;1(1):e00006
27668084
PLoS Biol. 2010 Mar 30;8(3):e1000344
20361022
Acta Neurochir (Wien). 1978;42(1-2):5-32
211808
Adv Exp Med Biol. 2012;746:42-52
22639158
J Neurosurg. 1992 Oct;77(4):590-4
1326612
J Neurooncol. 2009 Jan;91(2):117-25
18813876
Cancer Res. 1986 Mar;46(3):1367-73
3943101
Brain. 2007 Dec;130(Pt 12):3063-74
17478443
Mult Scler. 2010 Sep;16(9):1044-55
20685763
BMJ. 1997 Sep 13;315(7109):629-34
9310563
Br J Neurosurg. 2008 Jun;22(3):339-49
18568722
PLoS Med. 2010 Mar 30;7(3):e1000245
20361020
Hum Gene Ther. 2000 Nov 20;11(17):2389-401
11096443
Oncologist. 2009 Jun;14(6):621-36
19487335
J Neurooncol. 2009 Sep;94(3):299-312
19381449
Lancet. 2002 Mar 23;359(9311):1011-8
11937180
Int J Technol Assess Health Care. 2005 Winter;21(1):119-25
15736523
J Neurooncol. 2014 Sep;119(2):297-306
24990826
Neurosurgery. 1980 Aug;7(2):204
6252507
Hum Gene Ther. 1999 Sep 20;10(14):2325-35
10515452
Cancer Sci. 2006 Jun;97(6):546-53
16734735
Mol Ther. 2003 Jun;7(6):851-8
12788659
Br J Cancer. 2013 Jan 15;108(1):64-71
23321511
J Neurol Neurosurg Psychiatry. 2013 Feb;84(2):213-22
22993449
Anticancer Res. 2006 Jul-Aug;26(4B):2887-900
16886610
Biochim Biophys Acta. 2013 Aug;1836(1):158-65
23618720
Cell Adh Migr. 2008 Jul-Sep;2(3):186-91
19262115
Curr Gene Ther. 2009 Oct;9(5):368-74
19860651
Ann Oncol. 1998 Nov;9(11):1155-66
9862044
Stroke. 2007 Feb;38(2):388-94
17204689
N Engl J Med. 2005 Mar 10;352(10):987-96
15758009
Parkinsonism Relat Disord. 2011 Jun;17(5):313-20
21376651
Hum Gene Ther. 2000 Nov 1;11(16):2197-205
11084677