TY - JOUR
T1 - Transgene persistence and cell turnover in the diarthrodial joint
T2 - Implications for gene therapy of chronic joint diseases
AU - Gouze, Elvire
AU - Gouze, Jean Noel
AU - Palmer, Glyn D.
AU - Pilapil, Carmencita
AU - Evans, Christopher H.
AU - Ghivizzani, Steven C.
N1 - Funding Information:
We thank John Daley from the Flow Cytometry Facility of the Hematologic Malignancies Core at the Dana Farber Cancer Institute for his assistance with the flow cytometry experiments. This work was supported by grants AR48566 and AR050249 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health.
PY - 2007/6
Y1 - 2007/6
N2 - Local gene therapy for chronic joint diseases requires prolonged transgenic expression, but this has not been reliably achieved in animal models. Using normal and immunocompromised animals, we examined the capacity of various cell types in joint tissues to maintain and express exogenous transgenes after direct intra-articular gene delivery. We found that transgenic expression could persist for the lifetime of the animal but required precise immunological compatibility between the vector, transgene product, and host. It was not dependent on vector integration or promoter origin. We identified two phenotypically distinct sub-populations of genetically modified cells within the joint: (i) transient cells, with a half-life of a few weeks, and (ii) stable cells that reside in the joint tissues indefinitely. Contrary to the prevailing assumption, the transient sub-population was composed almost exclusively of synovial fibroblasts, indicating that the synovium is not an appropriate tissue upon which to base a long-term therapy. Instead, fibroblasts in the ligaments, tendons, and capsule emerged as the primary cell types capable of sustained therapeutic transgene expression. This study sheds new light on the cellular dynamics of articular tissues and suggests that cell turnover and immune reactivity are the key determinants in achieving sustained transgenic expression intra-articularly.
AB - Local gene therapy for chronic joint diseases requires prolonged transgenic expression, but this has not been reliably achieved in animal models. Using normal and immunocompromised animals, we examined the capacity of various cell types in joint tissues to maintain and express exogenous transgenes after direct intra-articular gene delivery. We found that transgenic expression could persist for the lifetime of the animal but required precise immunological compatibility between the vector, transgene product, and host. It was not dependent on vector integration or promoter origin. We identified two phenotypically distinct sub-populations of genetically modified cells within the joint: (i) transient cells, with a half-life of a few weeks, and (ii) stable cells that reside in the joint tissues indefinitely. Contrary to the prevailing assumption, the transient sub-population was composed almost exclusively of synovial fibroblasts, indicating that the synovium is not an appropriate tissue upon which to base a long-term therapy. Instead, fibroblasts in the ligaments, tendons, and capsule emerged as the primary cell types capable of sustained therapeutic transgene expression. This study sheds new light on the cellular dynamics of articular tissues and suggests that cell turnover and immune reactivity are the key determinants in achieving sustained transgenic expression intra-articularly.
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U2 - 10.1038/sj.mt.6300151
DO - 10.1038/sj.mt.6300151
M3 - Article
C2 - 17440444
AN - SCOPUS:34249334647
SN - 1525-0016
VL - 15
SP - 1114
EP - 1120
JO - Molecular Therapy
JF - Molecular Therapy
IS - 6
ER -