COMPOSITIONS AND METHODS FOR PROTECTING TYPE 2 ALVEOLAR EPITHELIAL CELLS (AEC2)
Provided herein are compositions comprising caveolin-1 (Cav-1) peptides and methods of using said compositions to protect type 2 alveolar epithelial cells from injury- or disease-induced apoptosis as well as increase the expression of the ABCA3 and SpC proteins.
1 . A method of preventing injury- or disease-induced apoptosis of alveolar epithelial type 2 cells (AEC2) in a patient in need thereof, the method comprising administering to the patient in need thereof an effective amount of a pharmaceutical composition comprising a recombinant polypeptide consisting of the amino acid sequence FTTFTVT (SEQ ID NO: 2) and, optionally, including 1-5 amino acids of additional sequence at the N- and/or C-terminus of the sequence of SEQ ID NO: 2 to the subject.
2 . The method of claim 1 , wherein the injury or disease is pulmonary inflammation, acute lung injury, lung infection, or lung disease.
3 . A method of increasing the expression level of ATP-binding cassette sub-family A member 3 (ABCA3) protein in the lung epithelium in a patient in need thereof, the method comprising administering to the patient in need thereof an effective amount of a pharmaceutical composition comprising a recombinant polypeptide consisting of the amino acid sequence FTTFTVT (SEQ ID NO: 2) and, optionally, including 1-5 amino acids of additional sequence at the N- and/or C-terminus of the sequence of SEQ ID NO: 2 to the subject.
4 . A method of increasing the expression level of surfactant protein C (SpC) protein in the lung epithelium in a patient in need thereof, the method comprising administering to the patient in need thereof an effective amount of a pharmaceutical composition comprising a recombinant polypeptide consisting of the amino acid sequence FTTFTVT (SEQ ID NO: 2) and, optionally, including 1-5 amino acids of additional sequence at the N- and/or C-terminus of the sequence of SEQ ID NO: 2 to the subject.
5 . The method of claim 3 or 4 , wherein the patient has infant respiratory distress syndrome.
6 . The method of any one of claims 1-4 , wherein the patient has pulmonary inflammation.
7 . The method of any one of claims 1-4 , wherein the patient has chronic obstructive pulmonary disorder (COPD).
8 . The method of any one of claims 1-4 , wherein the patient is undergoing chemotherapy or radiation therapy.
9 . The method of any one of claims 1-4 , wherein the patient has an acute lung injury.
10 . The method of any one of claims 1-4 , wherein the patient has a lung infection.
11 . The method of any one of claims 1-4 , wherein the patient has a chemical-induced lung injury.
12 . The method of any one of claims 1-4 , wherein the patient has plastic bronchitis.
13 . The method of any one of claims 1-4 , wherein the patient has asthma.
14 . The method of any one of claims 1-4 , wherein the patient has acute respiratory distress syndrome (ARDS).
15 . The method of any one of claims 1-4 , wherein the patient has inhalational smoke induced acute lung injury (ISALI).
16 . The method of any one of claims 1-4 , wherein the patient has bronchiolitis.
17 . The method of any one of claims 1-4 , wherein the patient has bronchiolitis obliterans.
18 . The method of claim 2 , wherein the lung disease is a fibrotic condition of the lungs.
19 . The method of claim 2 , wherein the lung disease is not a fibrotic condition.
20 . The method of claim 2 , wherein the lung disease is interstitial lung disease.
21 . The method of claim 2 , wherein the lung disease is Idiopathic Pulmonary Fibrosis (IPF) or lung scarring.
22 . The method of any one of claims 1-21 , wherein administering comprises nebulizing a solution comprising the peptide.
23 . The method of any one of claims 1-22 , further comprising administering at least one additional therapeutic to the patient.
24 . The method of claim 23 , wherein the at least one additional therapeutic is an NSAID, steroid, DMARD, immunosuppressive, biologic response modulators, or bronchodilator.
25 . The method of any one of claims 1-24 , wherein the patient is a human.
26 . The method of any one of claims 1-25 , wherein the recombinant polypeptide consists of the amino acid sequence FTTFTVT (SEQ ID NO: 2).
27 . The method of claim 26 , wherein the recombinant polypeptide consists of the amino acid sequence FTTFTVT (SEQ ID NO: 2) and 1-5 amino acids of additional sequence at the N-terminus.
28 . The method of claim 26 , wherein the recombinant polypeptide consists of the amino acid sequence FTTFTVT (SEQ ID NO: 2) and 1-5 amino acids of additional sequence at the C-terminus.
29 . The method of any one of claims 1-28 , wherein the recombinant polypeptide comprises the amino acid sequence ASFTTFTVT (SEQ ID NO: 3), wherein the peptide comprises at least one N- or C-terminal addition lacking identity to SEQ ID NO: 2.
30 . The method of claim 29 , wherein the recombinant polypeptide comprises at least one amino acid added to the N-terminus.
31 . The method of claim 29 , wherein the recombinant polypeptide comprises at least one amino acid added to the C-terminus.
32 . The method of claim 29 , wherein the recombinant polypeptide comprises at least one amino acid added to the N-terminus and the C-terminus.
33 . The method of any one of claims 1-32 , wherein the recombinant polypeptide comprises at least one non-standard amino acid.
34 . The method of claim 33 , wherein the recombinant polypeptide comprises 2 non-standard amino acids.
35 . The method of claim 33 , wherein the non-standard amino acid is ornithine.
36 . The method of any of claims 1-35 , wherein the recombinant polypeptide comprises a N-terminal modification.
37 . The method of any of claims 1-35 , wherein the recombinant polypeptide comprises a C-terminal modification.
38 . The method of any of claims 1-35 , wherein the recombinant polypeptide comprises a N- and C-terminal modification.
39 . The method of claim 36 or 38 , wherein the N-terminal modification is acylation.
40 . The method of claim 37 or 38 , wherein the C-terminal modification is amidation.
41 . The method of claim 32 , wherein the recombinant polypeptide comprises the amino acid sequence KASFTTFTVTKGS (SEQ ID NO: 4).
42 . The method of claim 32 , wherein the recombinant polypeptide comprises the amino acid sequence aaEGKASFTTFTVTKGSaa (SEQ ID NO: 6).
43 . The method of claim 35 , wherein the recombinant polypeptide comprises the amino acid sequence OASFTTFTVTOS (SEQ ID NO: 9).
44 . The method of claim 40 , wherein the recombinant polypeptide comprises the amino acid sequence KASFTTFTVTKGS-NH2 (SEQ ID NO: 5).
45 . The method of claim 40 , wherein the recombinant polypeptide comprises the amino acid sequence aaEGKASFTTFTVTKGSaa-NH2 (SEQ ID NO: 7).
46 . The method of claim 38 , wherein the recombinant polypeptide comprises the amino acid sequence Ac-aaEGKASFTTFTVTKGSaa-NH2 (SEQ ID NO: 8).
47 . The method of claim 40 , wherein the recombinant polypeptide comprises the amino acid sequence OASFTTFTVTOS-NH2 (SEQ ID NO: 10).
48 . The method of any one of claim 1-47 , wherein the recombinant polypeptide further comprises a cell-penetrating peptide (CPP).
49 . The method of claim 48 , wherein the CPP comprises an amino acid sequence selected from the group consisting of GRKKRRQRRRPPQ (SEQ ID NO: 21), RQIKIWFQNRRMKWKK (SEQ ID NO:22), and GIGAVLKVLTTGLPALISWIKRKRQQ (SEQ ID NO:23).
50 . The method of any one of claims 1-49 , wherein the recombinant polypeptide maintains the biological activity of caveolin-1 (Cav-1).
51 . The method of any one of claims 1-50 , wherein the recombinant polypeptide is a peptide multimer comprising at least two peptides according to any one of claims 26-50 .
52 . The method of claim 51 , wherein a first peptide of the at least two peptides is essentially identical to a second peptide of the at least two peptides.
53 . The method of claim 51 , wherein a first peptide of the at least two peptides is not identical to a second peptide of the at least two peptides.
54 . The method of any one of claims 1-53 , wherein the recombinant polypeptide comprises L-amino acids.
55 . The method of any one of claims 1-54 , wherein the recombinant polypeptide comprises at least one D-amino acid.
56 . The method of any one of claims 1-55 , wherein the recombinant polypeptide is capped at its N and/or C termini.
57 . The method of any one of claims 1-56 , wherein the pharmaceutical composition is formulated for injection or lung instillation.
58 . The method of claim 57 , wherein the pharmaceutical composition is formulated for lung instillation.
59 . The method of claim 57 , wherein the recombinant polypeptide is micronized using air-jet milling.
60 . The method of claim 57 , wherein the pharmaceutical composition is formulated as a nebulized solution.
61 . The method of claim 57 , wherein the pharmaceutical composition is administered intranasally, intrabronchially, intrapleurally or by instillation into lungs of the subject.
62 . The method of any one of claims 1-56 , wherein the pharmaceutical composition is formulated for systemic administration.
63 . The method of claim 62 , wherein the pharmaceutical composition is administered systemically.