Positive Signs for Gene Therapy in Slowing the Course of Disc Degeneration

Spinal News International - Issue 22, March 2012 -- view as PDF

A new study, which was presented at the annual meeting of the North American Spine Society (NASS; 2–5 November 2011, Chicago, USA) and subsequently published online in The Spine Journal, has found that gene therapy has the potential to delay disc degeneration.

Lead author Steven Leckie, Department of Orthopedic Surgery, University of Pittsburgh Medical Center, Pennsylvania, USA, and co-investigators reviewed the use of the adeno-associated virus sero-type 2 (AAV2) vector carrying genes for either bone morphogenetic protein 2 (BMP2) or tissue inhibitor of metalloproteinase 1 (TIMP1) to manage degenerative disc disease in New Zealand white rabbits. Explaining the purpose of the study, Leckie, who presented the data at NASS, said: “BMP2 is known to induce proteoglycan production in the intervertebral disc and TIMP1 is anti-anabolic in that it prevents the breakdown of proteoglycan. The problem with growth factors is that they are transient, so the philosophy of gene therapy is that we might be able to induce a sustained response from the host.” He added that, in their study, which won the 2011 outstanding Paper: Basic Science award at NASS, they used AAV2 because it has been shown to be safer than other vectors used in previous studies.

The 34 skeletally mature rabbits used in the study were divided into five groups: non-surgical (negative controls; six), sham procedure (negative controls; four), puncture surgery (underwent puncture surgery but did not receive any subsequent therapy, positive controls; eight), puncture surgery followed by treatment with AAV2-BMP2 (eight), and puncture surgery followed by treatment with AAV2- TIMP1 (eight). Puncture surgery was performed with a 16-gauge needle, which has been reliably shown to induce degeneration, in L2-L3, L3-L4, and L4-L5 discs. Leckie said: “The outcomes that we measured included MRI, histology, biomechanics, and biochemistry.”

After 12 weeks, rabbits in the non-surgical and the sham procedure groups did not show any evidence of disc degeneration on MRI but all rabbits in the puncture surgery group did have evidence of disc degeneration (on MRI, images of nucleus pulpous in the affected area darkened and decreased over the 12 weeks of the study). About the treatment groups, Leckie said: “Although they did have some degree of
disc degeneration, they appeared to have less degeneration than the puncture group.” In The Spine Journal paper, Leckie et al reported that the nucleus pulpous of the treated groups “retained their size and did not darken as much as the punctured discs.”

Leckie said that he and his fellow investigators also collected serum biomarkers for C-telopeptide II, which he explained is the breakdown product of C-terminus of collagen II and could be measured in the serum. He added: “At 12 weeks, the control rabbits had a slight increase [the rabbits in the non-surgical group], the
puncture rabbits had significantly higher serum values, and the treatment groups had values that fell well below those of the puncture group.”

As well as the MRI data and the biomarker data, there was also histological data. Leckie said: “The discs of the control and sham rabbits appeared to be normal. The punctured discs appeared relatively acellular and more fibrotic, and the discs that were treated with AAV2-BMP2 or AAV2-TIMP1 gene therapy had a relative maintenance of cellularity and relative preservation of their architecture.”

Leckie concluded by saying: “We have MRI evidence, serum biomarker evidence, biomechanics evidence, and histology evidence that gene therapy treatment with AAV2-BMP2 or AAV2-TIMP1 might help slow the course of disc degeneration in a rabbit model.”