Treatment of pulmonary vascular remodeling with neprilysin
The present invention relates to agonists of Neprilysin and their use in preventing and treating pulmonary vascular remodeling. Also described are diagnostic and screening applications stemming from the inventor's discovery that Neprilysin is expressed at reduced levels in disease tissues.
1. A method of treating pulmonary vascular remodeling in a subject comprising the steps of:
(i) obtaining a tissue sample comprising lung tissue, pulmonary vascular muscle, endothelial cell tissue or fibroblast tissue from a subject;
(ii) assessing the expression of neprilysin in cells of said sample; and
(iii) providing to said subject neprilysin or a peptidase active fragment thereof when expression of neprilysin cells of said tissue sample is reduced as compared to a healthy cells.
2. The method of claim 1 , wherein an expression cassette comprising a polynucleotide encoding a neprilysin polypeptide, or a peptidase active fragment thereof, under the control of a promoter operable in eukaryotic cells, is administered.
3. The method of claim 2 , wherein said expression cassette is contained in a viral vector.
4. The method of claim 2 , wherein said expression cassette is contained in a non-viral vector.
5. The method of claim 1 , wherein neprilysin or a peptidase active fragment of neprilysin is administered.
6. The method of claim 1 , wherein neprilysin, a peptidase active fragment of neprilysin, or an expression cassette encoding the same under the control of a promoter operable in a eukaryotic cell is administered orally, intravenously, intraarterially, subcutaneously, transdermally or by inhalation.
7. The method of claim 1 , wherein said subject is a human.
8. The method of claim 1 , wherein said subject is or was a smoker.
9. The method of claim 1 , wherein said subject has emphysema.
10. The method of claim 1 , wherein said subject is administered a second therapy.
11. The method of claim 1 , wherein step (ii) comprises assessing neprilysin protein expression.
12. The method of claim 1 , wherein step (ii) comprises assessing neprilysin mRNA expression.
13. The method of claim 12 , further comprising subjecting said sample to conditions suitable to amplify said mRNA.
14. The method of claim 11 , wherein said assessing comprises contacting a cell lysate of said sample with an antibody that binds immunologically to neprilysin.
15. The method of claim 14 , further comprising subjecting proteins of said sample to ELISA or Western blot.
16. The method of claim 1 , wherein assessing comprising measuring zinc peptidase activity in cells of said sample.
17. The method of claim 1 , wherein said sample is a lung tissue homogenate.
18. The method of claim 1 , wherein said sample is pulmonary arterial smooth muscle.
19. The method of claim 1 , wherein said pulmonary vascular remodeling underlies pulmonary hypertension, idiopathic forms of pulmonary vascular disease, or a lung disorder that could include any form of acute and chronic lung injury and inflammation (ARDS, ILD, Pneumonia, COPD, Asthma), primary lung vascular disorders (Idiopathic, Collagen Vascular Associated, Liver Disease Associated, Drug Associated, HIV Associated, Blood Clot Induced Pulmonary Hypertension).
20. The method of claim 4 , wherein said non-viral vector is comprised within a lipid formulation.