Injection of AAV2-BMP2 and AAV2-TIMP1 into the nucleus pulposus slows the course of intervertebral disc degeneration in an in vivo rabbit model.
BACKGROUND
Intervertebral disc degeneration (IDD) is a common cause of back pain. Patients who fail conservative management may face the morbidity of surgery. Alternative treatment modalities could have a significant impact on disease progression and patients' quality of life.


OBJECTIVE
To determine if the injection of a virus vector carrying a therapeutic gene directly into the nucleus pulposus improves the course of IDD.


METHODS
Prospective randomized controlled animal study.


METHODS
Thirty-four skeletally mature New Zealand white rabbits were used. In the treatment group, L2-L3, L3-L4, and L4-L5 discs were punctured in accordance with a previously validated rabbit annulotomy model for IDD and then subsequently treated with adeno-associated virus serotype 2 (AAV2) vector carrying genes for either bone morphogenetic protein 2 (BMP2) or tissue inhibitor of metalloproteinase 1 (TIMP1). A nonoperative control group, nonpunctured sham surgical group, and punctured control group were also evaluated. Serial magnetic resonance imaging (MRI) studies at 0, 6, and 12 weeks were obtained, and a validated MRI analysis program was used to quantify degeneration. The rabbits were sacrificed at 12 weeks, and L4-L5 discs were analyzed histologically. Viscoelastic properties of the L3-L4 discs were analyzed using uniaxial load-normalized displacement testing. Creep curves were mathematically modeled according to a previously validated two-phase exponential model. Serum samples obtained at 0, 6, and 12 weeks were assayed for biochemical evidence of degeneration.


RESULTS
The punctured group demonstrated MRI and histologic evidence of degeneration as expected. The treatment groups demonstrated less MRI and histologic evidence of degeneration than the punctured group. The serum biochemical marker C-telopeptide of collagen type II increased rapidly in the punctured group, but the treated groups returned to control values by 12 weeks. The treatment groups demonstrated several viscoelastic properties that were distinct from control and punctured values.


CONCLUSIONS
Treatment of punctured rabbit intervertebral discs with AAV2-BMP2 or AAV2-TIMP1 helps delay degenerative changes, as seen on MRI, histologic sampling, serum biochemical analysis, and biomechanical testing. Although data from animal models should be extrapolated to the human condition with caution, this study supports the potential use of gene therapy for the treatment of IDD.
Department of Orthopedic Surgery, University of Pittsburgh Medical Center, BST E1641, 200 Lothrop St, Pittsburgh, PA 15213, USA. leckiesk@upmc.edu
Steven K
SK
Leckie
Bernard P
BP
Bechara
Robert A
RA
Hartman
Gwendolyn A
GA
Sowa
Barrett I
BI
Woods
Joao P
JP
Coelho
William T
WT
Witt
Qing D
QD
Dong
Brent W
BW
Bowman
Kevin M
KM
Bell
Nam V
NV
Vo
Bing
B
Wang
James D
JD
Kang
D000818:Animals; D001696:Biomechanical Phenomena; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000627:therapeutic use*; D024043:Collagen Type II / Q000097:blood; D000229:Dependovirus; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007091:Image Processing, Computer-Assisted; D055959:Intervertebral Disc Degeneration / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D008279:Magnetic Resonance Imaging; D011817:Rabbits; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000627:therapeutic use*
D055396:Bone Morphogenetic Protein 2; D024043:Collagen Type II; D019715:Tissue Inhibitor of Metalloproteinase-1