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Commentary: A promising gene therapy approach to treat disc degeneration
The Spine Journal 12 (2012) 21
Commentary
Commentary: A promising gene therapy approach to treat disc degeneration S. Timothy Yoon, MD, PhD* Department of Orthopedic Surgery, Emory University, 59 Executive Park South Suite 3000, Atlanta, GA 30033, USA Received 5 December 2011; accepted 5 January 2012
COMMENTARY ON: Leckie SK, Bechara BP, Hartman RA, et al. Injection of AAV2-BMP-2 and AAV2-TIMP-1 into the nucleus pulposus slows the course of intervertebral disc degeneration in an in vivo rabbit model. Spine J 2012;12:7–20 (in this issue).
Although there is a great deal of interest in biologic treatment for disc degeneration, developing a successful treatment strategy is a challenging task. This may be a reflection of the fact that disc tissue does not have the ability to heal on its own. This is in contrast to bone, which can heal and remodel without any external biologic intervention. Part of the challenge may be that disc cells survive in an avascular biologic environment of poor nutrition (low oxygen tension and low glucose concentration). This relatively harsh environment is even worse in the degenerated human disc. Disc degeneration is also a long-term process that is measured in years or decades. This combination of difficult biologic environment and chronicity of the situation suggest the need for a longterm biologic solution. At present, there are two different growth factors that are undergoing clinical trials in the United States. Both trials involve a single injection of growth factor. The growth factor is delivered as a protein that is expected to diffuse away and degrade relatively rapidly once it is injected. Although this may have transient effects, it is unclear that it will be sufficient to have a sustained effect measured in periods of years. Leckie et al. [1], in their 2011 Outstanding
DOI of original article: 10.1016/j.spinee.2011.09.011. FDA device/drug status: Investigational (AAV2-BMP-2, AAV2-TIMP-1). Author disclosures: STY: Stock Ownership: Phygen (A); Consulting: Meditech Advisors (B); Board of Directors: KASS (None); Trips/Travel: The Spine Journal (A); Other office: The Spine Journal (None, Deputy Editor); Grants: Biomet Spine (F, Paid directly to institution/employer); Relationships Outside the One-Year Requirement: Medtronic (06/2009, B, Consulting). The disclosure key can be found on the Table of Contents and at www. TheSpineJournalOnline.com. * Corresponding author. Department of Orthopedic Surgery, Emory University, 59 Executive Park South Suite 3000, Atlanta, GA 30033, USA. Tel.: (404) 778-7155; fax: (404) 778-7117. E-mail address: [email protected] (S.T. Yoon) 1529-9430/$ - see front matter Published by Elsevier Inc. doi:10.1016/j.spinee.2012.01.001
Paper in Basic Science, describe a strategy that could potentially provide long-term growth factor treatment in the disc. The authors report the first gene therapy approach for disc therapy using the adeno-associated virus (AAV) as the delivery agent. Adeno-associated virus is a virus that is replication deficient and is thought to be safer than the previously described adenovirus vector. They use the AAV coupled with either bone morphogenetic protein-2 (BMP-2) or tissue inhibitor of metalloproteinase-1 (TIMP-1) (both genes have been shown in other studies to help disc cells accumulate disc matrix in tissue culture experiments). They injected the AAV construct into a well-characterized animal model of disc degeneration (rabbit annulotomy model). The authors looked at multiple different outcome measures, including magnetic resonance imaging, histology, biomechanics, and serum biomarker of collagen breakdown; it is worth noting that this is a major strength of this article. The authors conclude that AAV with BMP-2 or TIMP-1 can ameliorate the course of disc degeneration over the course of 12 weeks. One weakness of the study is that the expression of the transferred genes (BMP-2 or TIMP-1) was not verified in the disc tissue at follow-up. This leaves open the question of whether the gene therapy approach they used with AAV can truly deliver the therapeutic gene for an extended period (the main theoretical advantage of gene therapy over protein injection). Regardless, the results are encouraging and should stimulate more research along similar lines. This is a landmark article in the field of biologic treatment of disc degeneration. Reference [1] Leckie SK, Bechara BP, Hartman RA, et al. Injection of AAV2-BMP2 and AAV2-TIMP1 into the nucleus pulposus slows the course of intervertebral disc degeneration in an in vivo rabbit model. Spine J 2012;12:7–20.
Commentary
Commentary: A promising gene therapy approach to treat disc degeneration S. Timothy Yoon, MD, PhD* Department of Orthopedic Surgery, Emory University, 59 Executive Park South Suite 3000, Atlanta, GA 30033, USA Received 5 December 2011; accepted 5 January 2012
COMMENTARY ON: Leckie SK, Bechara BP, Hartman RA, et al. Injection of AAV2-BMP-2 and AAV2-TIMP-1 into the nucleus pulposus slows the course of intervertebral disc degeneration in an in vivo rabbit model. Spine J 2012;12:7–20 (in this issue).
Although there is a great deal of interest in biologic treatment for disc degeneration, developing a successful treatment strategy is a challenging task. This may be a reflection of the fact that disc tissue does not have the ability to heal on its own. This is in contrast to bone, which can heal and remodel without any external biologic intervention. Part of the challenge may be that disc cells survive in an avascular biologic environment of poor nutrition (low oxygen tension and low glucose concentration). This relatively harsh environment is even worse in the degenerated human disc. Disc degeneration is also a long-term process that is measured in years or decades. This combination of difficult biologic environment and chronicity of the situation suggest the need for a longterm biologic solution. At present, there are two different growth factors that are undergoing clinical trials in the United States. Both trials involve a single injection of growth factor. The growth factor is delivered as a protein that is expected to diffuse away and degrade relatively rapidly once it is injected. Although this may have transient effects, it is unclear that it will be sufficient to have a sustained effect measured in periods of years. Leckie et al. [1], in their 2011 Outstanding
DOI of original article: 10.1016/j.spinee.2011.09.011. FDA device/drug status: Investigational (AAV2-BMP-2, AAV2-TIMP-1). Author disclosures: STY: Stock Ownership: Phygen (A); Consulting: Meditech Advisors (B); Board of Directors: KASS (None); Trips/Travel: The Spine Journal (A); Other office: The Spine Journal (None, Deputy Editor); Grants: Biomet Spine (F, Paid directly to institution/employer); Relationships Outside the One-Year Requirement: Medtronic (06/2009, B, Consulting). The disclosure key can be found on the Table of Contents and at www. TheSpineJournalOnline.com. * Corresponding author. Department of Orthopedic Surgery, Emory University, 59 Executive Park South Suite 3000, Atlanta, GA 30033, USA. Tel.: (404) 778-7155; fax: (404) 778-7117. E-mail address: [email protected] (S.T. Yoon) 1529-9430/$ - see front matter Published by Elsevier Inc. doi:10.1016/j.spinee.2012.01.001
Paper in Basic Science, describe a strategy that could potentially provide long-term growth factor treatment in the disc. The authors report the first gene therapy approach for disc therapy using the adeno-associated virus (AAV) as the delivery agent. Adeno-associated virus is a virus that is replication deficient and is thought to be safer than the previously described adenovirus vector. They use the AAV coupled with either bone morphogenetic protein-2 (BMP-2) or tissue inhibitor of metalloproteinase-1 (TIMP-1) (both genes have been shown in other studies to help disc cells accumulate disc matrix in tissue culture experiments). They injected the AAV construct into a well-characterized animal model of disc degeneration (rabbit annulotomy model). The authors looked at multiple different outcome measures, including magnetic resonance imaging, histology, biomechanics, and serum biomarker of collagen breakdown; it is worth noting that this is a major strength of this article. The authors conclude that AAV with BMP-2 or TIMP-1 can ameliorate the course of disc degeneration over the course of 12 weeks. One weakness of the study is that the expression of the transferred genes (BMP-2 or TIMP-1) was not verified in the disc tissue at follow-up. This leaves open the question of whether the gene therapy approach they used with AAV can truly deliver the therapeutic gene for an extended period (the main theoretical advantage of gene therapy over protein injection). Regardless, the results are encouraging and should stimulate more research along similar lines. This is a landmark article in the field of biologic treatment of disc degeneration. Reference [1] Leckie SK, Bechara BP, Hartman RA, et al. Injection of AAV2-BMP2 and AAV2-TIMP1 into the nucleus pulposus slows the course of intervertebral disc degeneration in an in vivo rabbit model. Spine J 2012;12:7–20.