Synthetic adenoviruses with tropism to damaged tissue for use in promoting wound repair and tissue regeneration
Synthetic adenoviruses having chimeric fiber proteins and liver detargeting mutations are described. The synthetic adenovirus vectors are capable of specifically infecting cells at wound sites or in regions of damaged tissue. The synthetic adenovirus vectors also are capable of expressing transgenes, such as wound healing factors, at sites of wounded or damaged tissue. Accordingly, the described vectors can be used to detect wounded or damaged tissue, and/or to promote wound healing and regeneration of damaged tissue, such as by expression of heterologous wound healing or tissue regeneration factors.
1. A method of promoting wound repair or tissue regeneration in a subject, comprising administering to the subject a synthetic adenovirus comprising:
a transgene encoding platelet-derived growth factor-β(PDGF-β), transforming growth factor (TGF)-β1, or TGF-β2;
a modified hexon protein comprising an E451Q mutation, numbered with reference to SEQ ID NO: 8; and
a chimeric fiber protein comprising an adenovirus type 5 (Ad5) shaft domain and an adenovirus type 34 (Ad34) knob domain.
2. The method of claim 1 , further comprising selecting a subject with a wound or damaged tissue.
3. The method of claim 2 , wherein:
the wound is a cutaneous wound; or
the damaged tissue is kidney, heart, liver or lung tissue.
4. The method of claim 1 , wherein the synthetic adenovirus further comprises one or more binding sites for a liver-specific microRNA.
5. The method of claim 4 , wherein the liver-specific microRNA is miR-122.
6. The method of claim 4 , wherein the one or more binding sites are in the 3‘UTR of the adenovirus E1 region.
7. The method of claim 1 , wherein the transgene encodes PDGF-β.
8. The method of claim 1 , wherein the synthetic adenovirus further comprises a deletion of the E1 region.
9. A method of promoting wound repair or tissue regeneration in a subject, comprising administering to the subject a synthetic adenovirus comprising:
a transgene encoding platelet-derived growth factor-β(PDGF-β);
a modified hexon protein comprising an E451Q mutation, numbered with reference to SEQ ID NO: 8;
a deletion of the E1 region;
one or more binding sites for liver-specific microRNA (miR)-122; and
a chimeric fiber protein comprising an adenovirus type 5 (Ad5) shaft domain and an adenovirus type 34 (Ad34) knob domain.
10. The method of claim 9 , wherein the synthetic adenovirus further comprises a reporter gene.
11. The method of claim 1 , wherein the synthetic adenovirus further comprises a reporter gene.