Prävention von Fibrose und Organschäden
Prävention von Fibrose und Organschäden bzw. Schutz durch Vorbehandlung mittels ARNT Regulationsachse, z.B. mit geringer Dosis von Tacrolimus (FK506), GPI-1046, LB100 or mittels Gentherapie.
Novel therapeutic approaches and agents for the prevention, treatment and/or delaying progression of chronic injury, progressive loss of functional parenchymal cells, or fibrosis of an organ. The technology is based on a novel signaling axis.
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Injury in an organ triggers a complex signaling cascade that involves various cellular and molecular responses, ultimately culminating in tissue fibrosis, loss of functional parenchyma and organ failure. Progressive fibrosis and impaired regenerative capacity is still an unmet biomedical challenge, because once chronic lesions have manifested, no effective therapies are available as of yet for clinical use. (i.e. progression of chronic kidney disease (CKD) towards end-stage renal disease (ESRD)). It has been known that parenchymal organs including the kidney can be preconditioned to resist later acute ensuring tissue injuries, preventing both progressive loss of functional epithelium and kidney fibrosis.
Novel therapeutic approaches and agents for the prevention, treatment and/or delaying progression of chronic injury, progressive loss of functional parenchymal cells, or fibrosis of an organ. The technology is based on a novel signaling axis, which through the increase of the expression of ALK3 controls the BMP signaling response, which ultimately has an anti-fibrotic and pro-regenerative action. These effects protect an organ against chronic injury, progressive loss of functional parenchymal cells, or fibrosis.
The novel agents may be:
- an inhibitor of protein phasphatase 2A (PP2A), i.e. LB-100; or
- an inhibitor of the transcriptional repressor complex FKBP12/YY1, i.e. tacrolimus (=FK506, at sub-immunosuppresant low-dose, GPI-1046); or
- an expression construct, which is capable of over-expressing ARNT in said organ, i.e. in vivo morpholinos.
Several in vivo experimental results have been achieved:
- In vivo low-dose tacrolimus (FK506) protects kidney from chronic kidney injury in UUO mice.
- GPI-1046 protects from chronic renal failure in UUO mice.
- Modulation with in vivo morpholinos (VMO) achieved in UUO mice.
- Selective PP2A inhibition with LB-100 reduced tubulointerstitial fibrosis and attenuated chronic kidney failure in UUO mice.
- Synergistic effect observed in vivo for tacrolimus and LB-100.
- Kidney protection in diabetic model of chronic kidney injury with low-dose tacrolimus or GPI-1046.
- Modulation of new signaling axis.
- Several pharmacologicall approaches possible.
- Some drugs already in clinics.
- In vivo proof of concept achieved.
- Prevention and delay of organ injury.
- Prevention and delay of fibrosis progression.
Organ protection against chronic injury through (1.) preventive preconditioning (administered before organ injury), or (2.) interventional treatment (initiated when injury had already been established).
StichworteMBM ScienceBridge GmbH, Technologieangebot/technology offer, Technologietransfer/ technology transfer, Georg-August-Universität Göttingen/ oder anderer Verbundspartner, michael zeisberg, elisabetz zeisberg, zeisberg, björn tampe, tampe, raghu kalluri, kalluri, universitätsmedizin göttingen, fibrose, organschaden, FK506, LB100, GPI-1046, tacrolimus