Inhibition of experimental liver cirrhosis in mice by telomerase gene delivery.
Accelerated telomere loss has been proposed to be a factor leading to end-stage organ failure in chronic diseases of high cellular turnover such as liver cirrhosis. To test this hypothesis directly, telomerase-deficient mice, null for the essential telomerase RNA (mTR) gene, were subjected to genetic, surgical, and chemical ablation of the liver. Telomere dysfunction was associated with defects in liver regeneration and accelerated the development of liver cirrhosis in response to chronic liver injury. Adenoviral delivery of mTR into the livers of mTR(-/-) mice with short dysfunctional telomeres restored telomerase activity and telomere function, alleviated cirrhotic pathology, and improved liver function. These studies indicate that telomere dysfunction contributes to chronic diseases of continual cellular loss-replacement and encourage the evaluation of "telomerase therapy" for such diseases.
Rudolph
K L
KL
Department of Adult Oncology, Medicine and Genetics, Dana-Farber Cancer Institute, 44 Binney Street (M413), and Harvard Medical School, Boston, MA 02115, USA.
Chang
S
S
Millard
M
M
Schreiber-Agus
N
N
DePinho
R A
RA
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D002251:Carbon Tetrachloride / Q000633:toxicity; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006498:Hepatectomy; D008099:Liver / Q000201:enzymology / Q000473:pathology*; D008106:Liver Cirrhosis, Experimental / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D008115:Liver Regeneration; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008938:Mitosis; D013154:Spleen / Q000201:enzymology; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D016615:Telomere / Q000502:physiology / Q000648:ultrastructure; D016212:Transforming Growth Factor beta / Q000378:metabolism
D016212:Transforming Growth Factor beta; D002251:Carbon Tetrachloride; D019098:Telomerase