Ectopic PDX-1 expression in liver ameliorates type 1 diabetes
, Francisco J. Quintana
, Shira Perl
, Irit Meivar-Levy
, Irun R. Cohen
, Sarah Ferber
The Endocrine Institute, Sheba Medical Ctr., Tel-Hashomer 52621, Israel
Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel
Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel
The Institute for Pathology, Sheba Medical Ctr., Tel-Hashomer 52621, Israel
Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv 69978, Israel
Type 1 diabetes mellitus (T1DM) results from a speciﬁc autoimmune mediated destruction of the pancreatic b-cells. PDX-1 induced
developmentally redirected liver cells were suggested to restore the ablated pancreatic function in chemically induced diabetes. However,
developmentally redirected liver cells, may have acquired along with the desired b-cell characteristics and functions, also undesired sensitivity
to autoimmune attack and therefore may be inefﬁcient in ameliorating T1DM.
This study analyzes whether subjects with b-cell autoimmunity could beneﬁt from Ad-CMV-PDX-1 gene therapy. Using the model of
cyclophosphamide-accelerated diabetes in non-obese diabetic (CAD-NOD) mice, we report that recombinant adenovirus mediated PDX-1
gene therapy, ameliorates hyperglycemia in CAD-NOD mice.
Our data demonstrate that 43% of the overtly diabetic CAD-NOD mice treated with Ad-CMV-PDX-1 became normoglycemic and maintained
a stable body weight. Ectopic PDX-1 expression induced pancreatic gene expression and insulin production in the mice livers. The amelioration
of hyperglycemia, in PDX-1 treated diabetic mice was associated with an immune modulation manifested by Th1 to Th2 shift in the autoimmune
T-cell response to antigens associated with NOD diabetes. Thus, liver-to-pancreas transdifferentiation ameliorates T1DM in a process which is
associated with a concomitant modulation of the autoimmune attack. Our ﬁndings suggest a beneﬁcial therapeutic effect of the PDX-1 gene
therapy for treating autoimmune type 1 diabetes mellitus (T1DM).
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Autoimmune diabetes; Developmental redirection; Gene therapy; Immune modulation
Type 1 diabetes mellitus (T1DM) results from autoimmune
destruction of the insulin-producing b-cells of the pancreatic
islets . Pancreas transplantation and islet cell implantation
are being explored as replacement therapies for T1DM.
Several factors limit their use; vulnerability to reoccurring
autoimmune attack, the life-long immunosuppression needed
to prevent the allogeneic transplants and the shortage of tissue
from cadaver donors .
Insulin gene therapy was suggested as a potential approach
for treating T1DM in a mode that might overcome these lim-
itations. However, the simple replacement of the insulin gene
expression by genetic engineering is not likely to result in
continuous normoglycemia, unless the hormone secretion is
tightly regulated by glucose within a narrow physiological
A novel approach for generating an autologous insulin
producing tissue is the induction of developmental redirection
of liver to pancreas. This approach has been demonstrated in
mice, xenopus and human tissues [5e17]. In this approach,
* Corresponding author. The Endocrine Institute, Sheba Medical Ctr., Tel-
Hashomer 52621, Israel. Tel.: þ972 3 530 3152; fax: þ972 3 530 2083.
E-mail address: firstname.lastname@example.org (S. Ferber).
This work was performed in partial fulﬁllment of the requirements for
Both the authors contributed equally to this work.
0896-8411/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
Journal of Autoimmunity 28 (2007) 134e142