COMPOSITIONS AND METHODS OF USE THEREOF
Described herein are methods for treating or preventing a disease or disorder of the pulmonary system (e.g., cystic fibrosis), respiratory or digestive system in a subject, the methods comprising administering compounds or compositions comprising water soluble polyglucosamine and derivatized polyglucosamine.
1 . A method for treating a subject suffering from a mucosal disease or disorder, comprising administering an effective amount of a poly (acetyl, arginyl) glucosamine (PAAG) comprising the following formula (I):
wherein:
n is an integer between 20 and 6000; and
each R 1 is independently selected for each occurrence from hydrogen, acetyl,
wherein at least 25% of R 1 substituents are H, at least 1% of R 1 substituents are acetyl, and at least 2% of R 1 substituents are
wherein the method improves (e.g., enhances, increases) mucociliary transport or clearance,
thereby treating a mucosal disease or disorder.
2 . The method of claim 1 , wherein the method reduces the viscosity of mucus.
3 . The method of claim 1 , wherein the method reduces the elasticity of mucus.
4 . The method of claim 1 , wherein the method reduces the adhesion of mucus to epithelia (e.g., gastrointestinal or pulmonary epithelia).
5 . The method of claim 1 , wherein the method reduces the adhesion of bacteria and biofilms to epithelia (e.g., gastrointestinal or pulmonary epithelia).
6 . A method for treating a subject suffering from a gastrointestinal disease or disorder, comprising administering an effective amount of a poly (acetyl, arginyl) glucosamine (PAAG) comprising the following formula (I):
wherein:
n is an integer between 20 and 6000; and
each R 1 is independently selected for each occurrence from hydrogen, acetyl,
wherein at least 25% of R 1 substituents are H, at least 1% of R 1 substituents are acetyl, and at least 2% of R 1 substituents are
wherein the method improves (e.g., enhances, increases) mucociliary transport or clearance,
thereby treating the gastrointestinal disease or disorder.
7 . The method of claim 6 , wherein the gastrointestinal disease is meconium ileus.
8 . The method of claim 6 , wherein the gastrointestinal disease is DIOS.
9 . A method for treating a subject suffering from a pulmonary disease or disorder (e.g., improving lung function (e.g., improving the forced expiratory volume in 1 second (FEV 1 ))), comprising administering an effective amount of a poly (acetyl, arginyl) glucosamine (PAAG) comprising the following formula (I):
wherein:
n is an integer between 20 and 6000; and
each R 1 is independently selected for each occurrence from hydrogen, acetyl,
wherein at least 25% of R 1 substituents are H, at least 1% of R 1 substituents are acetyl, and at least 2% of R 1 substituents an
wherein the method improves (e.g., enhances, increases) mucociliary transport or clearance,
thereby treating the pulmonary disease or disorder.
10 . The method of claim 9 , wherein the method reduces the viscosity of sputum.
11 . The method of claim 9 , wherein the method reduces the elasticity of sputum.
12 . The method of claim 9 , wherein the method improves (e.g., enhances, increases) the mobility of sputum.
13 . The method of claim 9 , wherein the method increases airway surface liquid thickness, increasing fluidity.
14 . The method of claim 9 , wherein the method improves (e.g., enhances, increases) ciliary beat frequency.
15 . The method of claim 9 , wherein the method improves resolution of pulmonary exacerbations.
16 . The method of claim 9 , wherein the method is mucolytic (e.g., removes mucus).
17 . The method of claim 16 , wherein the PAAG is mucoadhesive.
18 . The method of claim 17 , wherein the PAAG protects cells (e.g., epithelial cells) from bacterial attachment.
19 . The method of claim 18 , wherein the method reduces bacterial or biofilm cohesion (e.g., wherein the method reduces biofilm adhesion to the epithelial cell surface).
20 . The method of claim 9 , wherein the method reduces CF-specific biofilms.
21 . The method of claim 9 , wherein the method reduces mucus adhesion (e.g., to epithelial cell surfaces).
22 . The method of claim 9 , wherein the method improves lung function as compared to a subject that has not been treated with the PAAG of formula (I).
23 . The method of claim 22 , wherein the method improves the forced expiratory volume in 1 second (FEV 1 ).
24 . The method of claim 9 , wherein the subject has a complication of cystic fibrosis (e.g., lung infection or respiratory congestion) or a symptom thereof.
25 . The method of claim 24 , wherein the complication of cystic fibrosis is pulmonary exacerbations.
26 . The method of claim 24 , wherein the complication of cystic fibrosis is a gastrointestinal disease or disorder.
27 . The method of claim 26 , wherein the gastrointestinal disease is meconium ileus.
28 . The method of claim 26 , wherein the gastrointestinal disease is DIOS.
29 . The method of claim 9 , wherein the pulmonary disease or disorder is a chronic disease or disorder.
30 . The method of claim 29 , wherein the chronic disease is chronic obstructive pulmonary disease (COPD), emphysema, allergic damage, or pulmonary fibrosis.
31 . The method of claim 9 , wherein the disease is an acute disease.
32 . The method of claim 31 , wherein the acute disease is inhalation damage (e.g., from smoke, chemicals, or toxins), acute respiratory distress syndrome, or trauma induced respiratory failure.
33 . The method of claim 9 , further comprising administering an effective amount of an antibacterial agent (e.g., standard of care antibacterial agents to treat infections in CF patients).
34 . The method of claim 33 , wherein the antibacterial agent is tobramycin, vancomycin, or aztreonam (aztreonam-lysine).
35 . The method of claim 33 , wherein the method potentiates the efficacy of the antibacterial agent (e.g., antibiotics, e.g., pulmonary antibiotics).
36 . The method of claim 9 , wherein the administering delivers a composition comprising the PAAG of formula (I).
37 . The method of claim 36 , wherein the composition is a dry powder composition.
38 . The method of claim 37 , wherein the composition comprises a vacuum-dried, freeze-dried or spray-dried powder of PAAG.
39 . The method of claim 37 , wherein the composition is substantially free of impurities.
40 . The method of claim 36 , wherein the composition is a solution composition (e.g., an aqueous solution composition as described herein, e.g., an aqueous solution composition of neutral osmol).
41 . The method of claim 36 , wherein the composition is a nebulized composition.
42 . The method of claim 41 , wherein the nebulized composition comprises PAAG for pulmonary delivery.
43 . The method of claim 42 , wherein the nebulized composition comprises particles of 1-5 microns in mean particle size diameter.
44 . The method of claim 9 , wherein the method reduces infection (e.g., bacterial infection).
45 . The method of claim 44 , wherein the infection is from a bacterial infection (e.g., from a bacteria described herein).
46 . The method of claim 44 , wherein the bacterial infection is caused by Pseudomonas aeruginosa.
47 . The method of claim 44 , wherein the bacterial infection is caused by Staphylococcus aureus or methicillin resistant Staphylococcus aureus.
48 . The method of claim 44 , wherein the bacterial infection is caused by Burkholderia cepacia.
49 . The method of claim 9 , wherein the method prevents Burkholderia cepacia uptake into macrophages.
50 . The method of claim 9 , wherein the method reduces inflammatory cytokines from pathogenic or damage initiated sources.
51 . The method of claim 50 , wherein the method reduces inflammation (e.g., pulmonary inflammation).
52 . The method of claim 51 , wherein the method reduces LPS stimulated TNF-α secretion.
53 . The method of claim 51 , wherein the method reduces LPS stimulated IL-10 secretion.
54 . The method of claim 51 , wherein the method reduces LPS stimulated IL-8 secretion.
55 . The method of claim 51 , wherein the method reduces DNA stimulated IL-8 secretion.
56 . The method of claim 51 , wherein the method reduces bacterial stimulated IL-8 secretion.
57 . The method of claim 51 , wherein the method reduces inflammatory cytokine secretion compared to a subject treated with lactoferrin.
58 . The method of claim 9 , wherein the method reduces pulmonary fibrosis.
59 . The method of claim 9 , wherein the method increases the accessibility of other therapeutic agents (e.g., anti-bacterials) to bacteria in biofilms.
60 . The method of claim 9 , wherein the method potentiates the effectiveness of other therapeutic agents (e.g., anti-bacterials) for improving lung function.
61 . The method of claim 59 , wherein the anti-bacterial agent and PAAG are present at a concentration, or administered at a dose or doses, which result in a bactericidal activity at least 2 logs more effective than the most effective activity in the absence of the PAAG or anti-bacterial agent.
62 . The method of claim 9 , the method comprising administering a nebulizer solution composition configured for inhaled administration (e.g., a composition as described herein, e.g., a composition comprising PAAG), further comprising a neutral osmol agent (i.e., an agent for achieving neutral osmotic balance).
63 . The method of claim 62 , wherein the subject is suffering from cystic fibrosis.
64 . The method of claim 62 , wherein the method provides mucosal clearance in the absence of infection (e.g., relative to a subject that is not treated with the method).
65 . The method of claim 62 , wherein the composition is administered at about 1 mL to about 3 mL.
66 . The method of claim 62 , wherein the composition is administered in an amount (e.g, a volume, e.g., nebulized solution volume) sufficient to provide about 0.2 mg to about 3 mg to the subject.
67 . The method of claim 62 , wherein the composition is administered once daily.
68 . The method of claim 62 , wherein the composition is administered every other day.
69 . The method of claim 62 , wherein the composition is administered twice a week.
70 . The method of claim 62 , wherein the composition is administered once a week.
71 . The method of claim 62 , further comprising administration of an antibiotic.
72 . The method of claim 71 , wherein the composition (e.g., a composition as described herein, e.g., a composition comprising PAAG) is administered prior to administration of the antibiotic.
73 . The method of claim 71 , wherein the composition (e.g., a composition as described herein, e.g., a composition comprising PAAG) is administered concurrently with administration of the antibiotic.
74 . The method of claim 62 , wherein the average molecular weight of the PAAG is from 20 to 150 kDa.
75 . The method of claim 74 , wherein the average molecular weight of the PAAG is from 20 to 120 kDa.
76 . The method of claim 74 , wherein the average molecular weight of the PAAG is from 40 to 100 kDa.
77 . The method of claim 74 , wherein the average molecular weight of the PAAG is from 70-120 kDa.
78 . The method of claim 74 , wherein the average molecular weight of the PAAG is from 50-90 kDa.
79 . The method of claim 62 , wherein the polydispersity index of the PAAG is from 1.0 to 2.5.
80 . The method of claim 62 , wherein the polydispersity index of the PAAG is from 1.0 to 1.8.
81 . The method of claim 62 , wherein the pH is about 7 to about 8.
82 . The method of claim 62 , wherein the PAAG is arginine-functionalized at least 18%.
83 . The method of claim 82 , wherein the PAAG is arginine-functionalized at between 18% and 30%.
84 . The method of claim 82 , wherein the PAAG is arginine-functionalized at between 20%-30%.
85 . The method of claim 82 , wherein the PAAG is greater than 18% arginine-functionalized.
86 . The method of claim 62 , wherein the neutral osmol agent is a non-fermentable sugar.
87 . The method of claim 86 , wherein the neutral osmol agent is glycerol, sorbitol, mannitol, xylitol, erythritol or another non-fermentable sugar.
88 . The method of claim 86 , wherein the non fermenatable sugar is glycerol.
89 . The method of claim 88 , wherein the glycerol is present in the composition at between 1.2-2.0% v/v.
90 . The method of claim 88 , wherein the glycerol is present in the composition at between 1.2-1.8% v/v.
91 . The method of claim 88 , wherein the glycerol is present in the composition at between 1.2-1.6% v/v.
92 . The method of claim 88 , wherein the glycerol is present in the composition at between 1.2-1.4% v/v.
93 . The method of claim 88 , wherein the glycerol is present in the composition at between 1.3-1.4% v/v.
94 . The method of claim 88 , wherein the glycerol is around 1.38% v/v.
95 . The method of claim 88 , wherein the PAAG is present in the composition at between 0.1-2 mg/ml (i.e., 0.01 to 0.2% w/v).
96 . The method of claim 88 , wherein the PAAG is present in the composition at between 0.2-1 mg/ml (i.e., 0.02 to 0.1% w/v).
97 . The method of claim 88 , wherein the PAAG is present in the composition at between 0.2-0.5 mg/ml (i.e., 0.02 to 0.05% w/v).
98 . The method of claim 88 , wherein the composition comprises a mean particle size diameter of between 1 and 5 microns.
99 . The method of claim 88 , wherein the osmolality is between 150-550 mOsmol/kg
100 . A dosage form configured for oral administration, comprising: a PAAG comprising the following formula (I):
wherein:
n is an integer between 20 and 6000; and
each R 1 is independently selected for each occurrence from hydrogen, acetyl,
wherein at least 25% of R 1 substituents are H, at least 1% of R 1 substituents are acetyl, and at least 2% of R 1 substituents are
further comprising a neutral osmol agent (i.e., an agent for achieving neutral osmotic balance).
101 . The dosage form of claim 100 , wherein the dosage form is a capsule or gel-capsule.
102 . A nebulizer solution composition configured for inhaled administration, comprising: a PAAG comprising the following formula (I):
wherein:
n is an integer between 20 and 6000; and
each R 1 is independently selected for each occurrence from hydrogen, acetyl,
wherein at least 25% of R 1 substituents are H, at least 1% of R 1 substituents are acetyl, and at least 2% of R 1 substituents are
further comprising a neutral osmol agent (i.e., an agent for achieving neutral osmotic balance).
103 . The composition of claim 102 , wherein the average molecular weight of the PAAG is from 20 to 150 kDa.
104 . The composition of claim 103 , wherein the average molecular weight of the PAAG is from 20 to 120 kDa.
105 . The composition of claim 103 , wherein the average molecular weight of the PAAG is from 40 to 100 kDa
106 . The composition of claim 103 , wherein the average molecular weight of the PAAG is from 70-120 kDa
107 . The composition of claim 103 , wherein the average molecular weight of the PAAG is from 50-90 kDa
108 . The composition of claim 102 , wherein the polydispersity index of the PAAG is from 1.0 to 2.5.
109 . The composition of claim 102 , wherein the polydispersity index of the PAAG is from 1.0 to 1.8.
110 . The composition of claim 102 , wherein the pH is about 7 to about 8.
111 . The composition of claim 102 , wherein the PAAG is arginine-functionalized at least 18%.
112 . The composition of claim 111 , wherein the PAAG is arginine-functionalized at between 18% and 30%.
113 . The composition of claim 111 , wherein the PAAG is arginine-functionalized at between 20%-30%.
114 . The composition of claim 111 , wherein the PAAG is greater than 18% arginine-functionalized.
115 . The composition of claim 102 , wherein the neutral osmol agent is a non-fermentable sugar.
116 . The composition of claim 115 , wherein the neutral osmol agent is glycerol, sorbitol, mannitol, xylitol, erythritol or another non-fermentable sugar.
117 . The composition of claim 115 , wherein the non fermenatable sugar is glycerol.
118 . The composition of claim 115 , wherein the glycerol is present in the composition at between 1.2-2.0% v/v.
119 . The composition of claim 115 , wherein the glycerol is present in the composition at between 1.2-1.8% v/v.
120 . The composition of claim 115 , wherein the glycerol is present in the composition at between 1.2-1.6% v/v.
121 . The composition of claim 115 , wherein the glycerol is present in the composition at between 1.2-1.4% v/v.
122 . The composition of claim 115 , wherein the glycerol is present in the composition at between 1.3-1.4% v/v.
123 . The composition of claim 115 , wherein the glycerol is around 1.38% v/v.
124 . The composition of claim 115 , wherein the PAAG is present in the composition at between 0.1-2 mg/ml (i.e., 0.01 to 0.2% w/v).
125 . The composition of claim 115 , wherein the PAAG is present in the composition at between 0.2-1 mg/ml (i.e., 0.02 to 0.1% w/v).
126 . The composition of claim 115 , wherein the PAAG is present in the composition at between 0.2-0.5 mg/ml (i.e., 0.02 to 0.05% w/v).
127 . The composition of claim 115 , wherein the composition comprises a mean particle size diameter of between 1 and 5 microns.
128 . The composition of claim 115 , wherein the osmolality is between 150-550 mOsmol/kg