U.S. patent application number 15/453972 was filed with the patent office on 2020-01-02 for binding of galectin-3 by low molecular weight pectin.
This patent application is currently assigned to ECONUGENICS, INC.. The applicant listed for this patent is ECONUGENICS, INC.. Invention is credited to Isaac Eliaz.
Application Number | 20200000841 15/453972 |
Document ID | / |
Family ID | 63446188 |
Filed Date | 2020-01-02 |
United States Patent
Application |
20200000841 |
Kind Code |
A9 |
Eliaz; Isaac |
January 2, 2020 |
Binding of Galectin-3 By Low Molecular Weight Pectin
Abstract
Administration of low molecular weight (10,000-20,000 Daltons,
or lower) pectins, particularly modified citrus pectins (MCP), like
PectaSol-C reduces galectins-3 levels in vivo. Reduction of
galectin-3 levels by MCP inhibits inflammation, inhibits fibrosis
formation in organs and tissues, and inhibits cancer formation,
progression, transformation and metastases. The reduction in
circulating, serum and cellular galectin-3, inherently resulting
from the administration of MCP, provides benefit over a spectrum of
biological conditions, as evidenced by in vivo trials.
Inventors: |
Eliaz; Isaac; (Sebastopol,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ECONUGENICS, INC. |
Santa Rosa |
CA |
US |
|
|
Assignee: |
ECONUGENICS, INC.
Santa Rosa
CA
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20180256632 A1 |
September 13, 2018 |
|
|
Family ID: |
63446188 |
Appl. No.: |
15/453972 |
Filed: |
March 9, 2017 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
15214514 |
Jul 20, 2016 |
9649329 |
|
|
15453972 |
|
|
|
|
13153648 |
Jun 6, 2011 |
9427449 |
|
|
15214514 |
|
|
|
|
11485955 |
Jul 14, 2006 |
8426567 |
|
|
13153648 |
|
|
|
|
60711415 |
Aug 26, 2005 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/732
20130101 |
International
Class: |
A61K 31/732 20060101
A61K031/732 |
Claims
1-6. (canceled)
7. A method of treating a mammal which benefits from a reduction in
available circulating galectin-3, comprising the steps of: a)
Selecting a mammal in need of treatment for chronic heart failure,
and b) Administering to said mammal an amount of modified pectin of
molecular weight of 3,000-13,000 Daltons, in an amount of 10-750
mg/kg/day, for a period of time sufficient such that said mammal
exhibits a reduction in active galectin-3 levels in said mammal and
thereby treat chronic heart failure in said mammal.
8. A method of treating a mammal which benefits from a reduction in
available galectin-3, comprising the steps of: a) Selecting a
mammal in need of treatment for chronic heart failure, and b)
Administering to said mammal modified pectin of low molecular
weight of 10,000-20,000 Daltons, in an amount of 5-1,500 mg/kg/day,
for a period of time sufficient for said mammal to exhibit a
reduction in active galectin-3 levels in said mammal and thereby
treat chronic heart failure in said mammal.
Description
PRIORITY DATA AND INCORPORATION BY REFERENCE
[0001] This application is a continuation-in-part of U.S. patent
application Ser. No. 11/485,955, filed Jul. 14, 2006, pending,
which claims the benefit under 35 U.S.C. .sctn. 119(e) of U.S.
Provisional Patent Application Ser. No. 60/711,415, filed on Aug.
26, 2005, both of which are incorporated by reference herein in
their entirety. This application also claims benefit of priority to
U.S. patent application Ser. No. 12/984,843, filed Jan. 5, 2011,
pending, and U.S. Provisional Patent Application Ser. No.
61/447,138 filed Feb. 28, 2011 both of which are incorporated by
reference in their entirety.
BACKGROUND OF THE INVENTION
Field of the Invention
[0002] The present invention relates to improvement of mammalian,
including human, biological conditions impacted by, or mediated by,
galectin-3. Galectin-3 is a member of the lectin family, of which
at least fourteen (14) mammalian galectins have been identified.
Galectin-3 is approximately 30 kDa and, like all galectins,
contains a carbohydrate-recognition-binding domain (CRD) of about
one hundred thirty (130) amino acids that enable the specific
binding of .beta.-galactosides. Galectin-3 is encoded by a single
gene, LGALS3, located on chromosome 14, locus q21-q22. It is
expressed in the nucleus, cytoplasm, mitochondrion, cell surface,
and extracellular space, and can circulate in the blood stream.
This protein has been shown to be involved in a large number of
biological processes, including cell adhesion, cell migration, cell
invasion, cell activation and chemoattraction, cell growth and
differentiation, cell cycle, and apoptosis. Given galectin-3's
broad biological functionality, it has been demonstrated to be
involved in a large number of disease states or medical
implications. Studies have also shown that the expression of
galectin-3 is implicated in a variety of processes associated with
heart failure, including myofibroblast proliferation, fibrogenesis,
tissue repair, inflammation, and ventricular and tissue remodeling.
Elevated levels of galectin-3 in the blood have been found to be
significantly associated with higher risk of death in both acute
decompensated heart failure and chronic heart failure populations,
as well as constituting a biomarker of cancer progression to a
metastatic stage.
Background of the Invention
[0003] In 2006, U.S. patent application Ser. No. 11/485,955 was
filed, a utility patent application claiming priority from a 2005
provisional application. This patent application, making reference
to earlier disclosures of administration of modified alginates and
pectins, such as those in U.S. Pat. Nos. 6,274,566 and 6,462,029,
disclosed for the first time the utility of using very specific low
molecular weight pectins, such as PectaSol-C MCP available from
EcoNugenics of Santa Rosa, Calif. This modified citrus pectin (MCP)
and similar very low molecular weight pectins (molecular weight of
20,000 Daltons or less, preferably about 10,000 Daltons) is shown
in U.S. patent application Ser. No. 11/485,955 to be effective in
stimulating a variety of immune responses in mammals.
[0004] In the years since the filing which first set forth the
administration of these low molecular weight modified citrus
pectins, and similar pectins, research has demonstrated that at
least one mode of action of MCP is the binding of galectin-3
molecules. This binding, an inherent feature of the inventions
disclosed in U.S. patent application Ser. No. 11/485,955, is also a
central mode of action in the later-filed U.S. patent application
Ser. No. 12/984,843, filed Jan. 5, 2011 directed to the inhibition
of certain cancers. In fact, it is now clear that administering
PectaSol-C MCP or other low molecular weight pectins at the dosage
levels of 5-1,500 mg/kg of body weight per day, a preferred range
of 10 mg/kg/day to 1,000 mg/kg/day inherently binds galectin-3
molecules in mammals in need of same in a variety of biological
systems, providing therapeutic benefit against many of the disease
conditions mentioned.
[0005] Thus, the activity of galectin-3 in aggravating or promoting
cancer, as well as the ability of a cancer to metastasize, is
widely commented on in the literature following the 2006 disclosure
of the effectiveness of low molecular weight pectins like
PectaSol-C in promoting immune systems. These literature findings
stress repeatedly the importance of binding or reducing the
circulating concentration or titer of galectin-3, and/or
inactivating glaectin-3 through galectin-3 binders such as
PectaSol-C. See, for example, Wang et al, Cell Death and Disease,
1-10 (2010) (galectin-3 inhibition promotes treatment) and Yu et
al, J. Biol. Chemistry, Vol. 282, 1, pp. 773-781 (2007)
establishing that galectin-3 interactions may enhance formation of
cancer or transformation of metastatic cancer.
[0006] Similar reports link acceleration of cancer formation and
transformation to circulating galectin-3 concentrations, and
suggest that reducing galectin-3 circulating concentrations,
reducing its free expression or otherwise reducing available
galectin-3 or galectin-3 interactions improve cancer prognosis.
Zhao et al, Cancer Res. 69, 6799-6806 (2009), Zhao et al, Molecular
Cancer 9, 154, 1-12 (2010) and Wang et al, Am. J. of Pathology,
174, 4, 1515-1523 (2009) wherein siRNA-induced reduction of
galectin-3 is shown to slow the course of prostate cancer. Clearly,
there is substantial literature that supports the conclusion that
reducing circulating galectin-3, either by blocking its expression,
or by binding it, as inherently disclosed in the 2006 filing of
U.S. patent application Ser. No. 11/485,955, is important in
controlling cancer.
[0007] Circulating galectin-3 is implicated in a wide variety of
biological conditions, however. Cardiac fibrosis is gaining
significant attention as a complicating risk factor in cardiac
disease, and in particular, chronic heart failure (CHF). Lok et al,
Clin. Res. Cardiol, 99, 323-328 (2010). DeFillipi et al, U.S.
Cardiology, 7,1, 3-6 (2010) clearly indicate that circulating
galectin-3 is an important factor in fibrosis of many organs and
organ systems, and that reducing circulating galectin-3 may have an
important role in remediating cardiac injury and progression to
heart failure (HF). Similarly, Psarras et al, Eur. Heart J., Apr.
26, 2011 demonstrate that reduction in galectin-3 levels in the
myocardium may reduce fibrosis in the heart and improve outlook. De
Boer et al, Ann. Med., 43,1, 60-68 (2011) identify galectin-3 as a
key indicator in cardiac health. Shash et al, Eur J. Heart Fail.,
12,8, 826-32 (2011) identify galectin-3 levels as a key agent in
heart failure through fibrosis. De Boer et al. Eur. J. Heart Fail.,
11, 9, 811-817 (2009) link an increase in galectin-3 expression and
presence to heightened fibrosis, and heart failure. The same
article links galectin-3 to inflammation. Inflammation is the
hallmark of arteriosclerosis and therefore galectin-3 levels also
contribute to coronary artery disease, peripheral artery disease,
strokes, and vascular dementia.
[0008] Fibrosis and inflammation, both mediated to some degree by
galectin-3 (cellular or circulating) are implicated in a variety of
conditions of the mammalian body, not just cardiac injury and heart
failure. The binding of galectin-3 achieved by administration of
low molecular weight pectins (at least, as reflected in U.S. patent
application Ser. No. 11/485,955 10,000-20,000 Daltons molecular
weight such as PectaSol MCP) is effective in reducing trauma due to
kidney injury. Kolatsi-Jannou et al, PlusOne, 6, 4, e18683 (2011).
The reduction in circulating galectin-3 levels is also indicated to
reduce inflammation associated with type 2 diabetics, and similar
metabolic diseases. Weigert et al, J. Endocrinol. Metab. 95,
3,1404-1411(2010). Thus, high levels of galectin-3 have been linked
to thyroid cancer, Sethi et al, J. Exp. Ther. Oncol., 8, 4,341-52
(2010) and reduction of galectin-3 expression and circulation may
delay or reduce tumor cell transformation. Chiu et al, Am J.
Pathol. 176, 5, 2067-81 (2010).
[0009] As noted, galectin-3 is implicated in a wide variety of
biological conditions, and a reduction in galectin-3 activity, such
as that which can be achieved by galectin-3 binding with PectaSol-C
MCP and similar low molecular weight pectins may be of value in
treating gastric ulcerative conditions. Srikanta, Biochimie, 92, 2,
194-203 (2010). Kim et al, Gastroenterology, 138, 1035-45 (2010)
indicate that reducing galectin-3 levels may be of therapeutic
value in reducing gastric cancer progression. By the same
methodology, reducing galectin-3 levels sensitizes gastric cancer
cells to conventional chemotherapeutic agents. Cheong et al, Cancer
Sci., 101, 1, 94-102 (2010). Galectin-3 is implicated in a wide
variety of gastrointestinal conditions. Reducing galectin-3, by
binding for example, may reduce inflammation in the gut mucosa,
making MCP an important agent for treatment of ulcerative colitis,
non-specific colitis and ileitis, Crohn's disease, Celiac disease,
and gluten sensitivity. Fowler et al, Cell Microbiol., 81,1,44-54
(2006).
[0010] Biliary artesia, a liver disease, is associated with
extensive fibrosis of the liver linked with elevated galectin-3
levels. Honsawek et al, Eur. J. Pediatr. Surg., Apr. 2011.
Reduction of galectin-3 levels resulted in a general improvement in
hepatic health, including reducing inflammation, hepatocyte injury
and fibrosis. Federici et al, J. Heptal., 54, 5, 975-83 (2011). See
also, Liu et al, World J. Gastroenterol. 14,48, 7386-91 (2008)
which reported, following Applicant's teaching in 2005 and 2006 to
administer low molecular weight MCP, that MCP inhibited liver
metastases of colon cancer and reduced galectin-3 concentrations.
MCP may be used for prevention of liver inflammation, liver
fibrosis and liver cirrhosis as well as post-disease liver damage,
including the various viral hepatitis disease (B, C, and others)
and may be used as well in the treatment of parasitic and chemical
hepatitis, chemical liver damage, and others.
SUMMARY OF THE INVENTION
[0011] The invention lies in the recognition that the method
described in U.S. patent application Ser. No. 11/485,955 of
administering low molecular weight pectins, such as modified citrus
pectin, having a molecular weight of between 10,000-20,000 Daltons,
in a therapeutically effective dosage, has implications far beyond
stimulating the immune system. Because this administration,
particularly oral or intravenous, inherently hinds cellular, serum
and circulating galectin-3, it is implicated in a wide variety of
biological conditions and may be effective in ameliorating a wide
variety of disease states and conditions.
[0012] Further improvement can be obtained in selecting the MCP to
have a molecular weight of between 3,000-13,000 Daltons that is
mostly linear homogalacturonan with fewer than ten percent (10%)
esterification, and maintaining a percentage of
rhamnogalacturonan-I, II in the MCP to approximately ten percent
(10%), while reducing the amount of mono galacturonic acid to under
ten percent (10%). The reduction in molecular weight promotes
bioavailability (absorption into the circulatory system from the
gastrointestinal tract), the degree of esterification (bulky side
groups which contribute to cross bridging between pectin fibers)
decreased below ten percent (10%) in the MCP contributes to the
galectin-3 binding by fostering open fibers, allowing increased
accessibility to binding galectin-3, while the reduction in
mono-galacturonic acid (representative of inactive total breakdown
of the pectin fiber into its major single subunit) increases that
amount of MCP available for effectively binding galcetin-3.
Therapeutic properties in vivo are further improved by selecting a
modified citrus pectin with approximately ten percent (10%)
rhamnogalcturonan-I, II content. Pectic rhamnogalacturonan-1 has
been shown to induce apoptosis in melanoma cells by interacting
with Gal-3. Rhamnogalacturonan-II has demonstrated a strong binding
potential for heavy metal chelation. The modified citrus pectin,
prepared by enzymatic degradation, results in shorter chain
molecules of low esterification with enhanced bio-availability and
binding potential to galectin-3.
[0013] This modified citrus pectin can be used to improve or
enhance a mammal's immune reaction, as disclosed in U.S. patent
application Ser. No. 11/485,955. The power of binding galectin-3, a
ubiquitous molecule, without eliminating it from circulation, is
powerful beyond this limited indication, however. Galectin-3 is
implicated, as noted, in a wide variety of medical conditions. The
inhibition of the growth and transformation of various cancers, the
inhibition of fibrosis in a variety of organs and organ systems,
the reduction in inflammation associated with galectin-3, all
combine to provide a powerful method of treatment in a wide variety
of situations. The issue is more of patient selection than
treatment modification. In 2006, Applicant taught that MCP should
be administered in a range of low molecular weight pectins at the
dosage levels of 5-1,500 mg/kg of body weight per day, with a
preferred range of 10 mg/kg/day to 1,000 mg/kg/day to achieve the
desired results. This range inherently achieves binding or
inactivation of cellular, serum and circulating MCP. Particularly
for conditions characterized at least in part by fibrosis, a
reduced preferred range of 10 mg/kg/day-750 mg/kg/day may provide
even better effects.
[0014] PectaSol-C is only one modified pectin useful in this
invention. In general, pectins of reduced molecular weight (10,000
to 20,000 Daltons or lower) having a lower percentage of mono
galacturonic acid and having approximately ten percent (10%)
rhamnogalcturonan-I, II all exhibit a higher rate of forming
complexes with the multifunctional carbohydrate-binding protein,
galectin-3, and thus reducing the effective level of galectin-3 to
which a body, injured organs and threatened cells are exposed. In
addition to the available commercial sources of low molecular
weight pectins, their preparation is discussed in detail, Pienta et
al, J. Nat'l. Cancer Inst., 87, 348-352 (1995). In an alternative
embodiment, low molecular weight pectin can also be synthesized.
Specific molecular structures such as, for example,
polygalacturonic acid, side branches and neutral sugars in the
desired range as specified above can be synthesized to create a
more consistent, accurate and highly reproducible molecular weight.
By synthesizing MCP, an optimal structure within the molecular
weight range of 10-20 KD, and more preferably 3-13 KD can be
produced. Whether derived from reduced natural starting materials,
or synthesized, administration of these lower molecular weight
pectins, 20,000-10,000 Daltons, or even lower, 13,000-3,000
Daltons, is a preferred method of practicing the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0015] The binding of galectin-3 by MCP is an event that will aid
medical conditions over a wide variety of indications. These
include cancer, inflammation and fibrosis, heart disease, kidney
damage, liver damage, bladder disease, thyroid disease, pulmonary
disease, immune response, stroke, persistent acute inflammation due
to non-degradable pathogens, persistent foreign bodies, or
autoimmune reactions, hypersensitivities and allergies, pesticides,
environmental toxins, and heavy metals, as well as heterogenic
conditions such as radiation (examples being medical procedures
such as various radiation therapies, exposure to ionizing
radiation, nuclear radiation, cosmic radiation, electromagnetic
radiation) and chemotherapy damage, and post radiation and
chemotherapy induced inflammation and fibrosis. As noted above,
elevated galectin-3 levels are associated with (1) growth,
transformation and metastatic migration of cancer cells across a
wide variety of cancers, including liver, breast, prostate, colon,
thyroid, gallbladder, nasopharyngeal, lymphocytic leukemia,
melanoma and lung cancers among others, as well as reducing
sensitivity in these cancers to conventional antineoplastic agents;
(2) development and extension of fibroses beyond normal and healthy
levels, in situations associated with cardiovascular disease and
heart failure, in tissue injury including brain, lungs, renal,
hepatic, heart and gastroenterologic situations as well as tissue
damage due to radiation and chemotherapy exposure and persistent
acute inflammation due to non-degradable pathogens, persistent
foreign bodies, or autoimmune reactions, hypersensitivities and
allergies; and (3) in inflammation that may be associated with
disease or organ failure modes, including diabetes (I and II),
heart disease and dysfunction, atherosclerosis, asthma (bronchial
inflammation), ulcers, intestinal inflammation in the bowels
(inflammatory bowel diseases), hepatic inflammation associated with
both alcohol and non-alcohol related cirrhosis and inflammation,
liver infections such as viral hepatitis among others. Other
indications associated with inflammation and susceptible to
treatment by administration of MCP include parasite-induced
conditions, such as trypanosomiasis, cerebral malaria, and
inflammation and resistance to various infections including
Paracoccidiosis brasilensis (fungal infection), schistosomiasis,
granulatomatous bronchopneumonia, and in inflammation associated
with arthritis and other diseases of the skeletomuscular and skin
systems, including inflammation and fibrosis related conditions
such as psoriasis and aging of the skin.
[0016] Reference is made herein to the binding of galectin-3 by MPC
of the invention. Binding occurs between the two molecules in in
vitro assays and there is a natural chemical bond possible between
the reactive moieties of the two compounds. In vitro assays rarely
reflect, at a microscopic and chemical level, the actual mechanisms
that occur in vivo. Binding of galectin-3 by MCP in vivo is an
event that may be reversible to some degree--in the same fashion
that an antibody may bind and then release a poorly held antigen.
Galectin-3 is ubiquitous in mammals, found in many different
tissues and spaces. Administration of MCP does not appear to result
in removal of all galectin-3 from the body. By the term binding,
Applicant intends to describe the formation of a complex between
galectin-3 and MCP that removes the galectin-3 from active
involvement in the metabolic and biological processes of the body.
Whether that complex is permanent and eliminated from the body over
time, or reversible, does not appear to impact the relief
obtained.
[0017] It is to be understood that MCP rarely mediates only
inhibition of cancer progression, fibrosis or inflammation. These
are conditions that are closely related, and tumor growth is
frequently combined with inflammation and development of fibroses.
Inflammation enhances the speed with which a cancer progresses, so
treatment of one may include treatment of the other. Certainly,
non-cancerous diseases, particularly heart disease and
atherosclerosis, arthritis and diabetes are associated with
inflammation and fibrosis. There will be patients in need of
treatment primarily for inhibition of inflammation, patients in
need of treatment primarily for suppression of fibrosis, and
patients whose primary indication is the progression or
transformation of cancer. While patient selection is a critical
step in the methods embraced by this invention, it does not alter
the fact that the patients receiving MCP in amounts of 5-1,500
mg/kg/day will receive the full benefit of MCP, independent of
their primary indication.
[0018] The MCP of this invention may be the MCP of 10,000-20,000
Daltons, with a degree of etherification of less than about ten
percent (10%). Further research has demonstrated that even lower
molecular weight MCP may be more efficacious, identifying a
preferred range of 3,000-13,000 Daltons molecular weight. With this
newer formulation has come a small revision in the preferred range
of administration. While 5-1,500 mg/kg/day remains an effective
range, more effective MCP may be administered in a more preferred
range of 10 mg/kg/day to 750 mg/kg/day. The MCPs of this invention
may be administered over a prolonged period of time, as many
disease conditions associated with inflammation and fibrotic
complications are chronic in nature. Extended administration of MCP
has not shown toxicity or presented issues of tolerance in any way.
No cytopathic or toxicologic complications are associated with the
administration of MCP in this range either orally or intravenously.
These MCP are readily absorbed intrabucally or through the
intestinal mucosa into the bloodstream. In one alternative
embodiment, the MCP may be encapsulated, as a powder, into gelatin
capsules which may, for example, include 500-800 mg/capsule.
Alternatively, a water-based preparation may be used, for example,
six (6) capsules taken three (3) times a day with a full eight (8)
ounces of water or juice. Controlled dosage formulations are
preferred to ensure adequate, constant dosage over time.
[0019] MCPs may be combined with a wide variety of pharmaceutically
acceptable carriers, conventional excipients, flavorings and the
like that are suitable for oral or intravenous administration,
depending on the protocol desired. The modified pectins may also be
administered together with agents that will enhance complexation
with galectin-3, such as glutathione-rich why protein and other
binding adjuvants. Chelating agents, such as 2,3
dimercapto-1-propane sulphonic acid and DL-2,3-dimercapto-succinic
acid, EDTA may also be useful. MCP can be added to formulations
that include pharmaceuticals, botanicals, mineral and vitamins, to
create additional effects, as needed. Absorption may be enhanced by
using intrabuccal and transdermal delivery systems.
[0020] It should be noted that commonly, inflammation and fibrosis
can be induced by human agency, not just trauma or disease
condition. The administration of MCP and its binding of galectin-3
can be effective in reducing or preventing organ damage induced by
chemotherapy and other pharmaceuticals. Some examples include
bleomycin, which induces lung fibroses, and a wide variety of
cardiac drugs such as amiodarone. Adriamycin and doxorubicin are
widely prescribed and present cardiac inflammation and fibroses
issues. Bacillus Calmette-Guerin washes to treat bladder cancer
induce systemic inflammation and cyclophosphamide also induces
bladder damage. Ciclosporine, a widely used immunosuppressant drug,
and the active agent in Restasis.TM., induces kidney toxicity and
inflammation. Studies indicate that the vast array of organ damage
caused by prescribed pharmaceuticals is mediated, at least in part,
by elevated galectin-3 levels, and can be limited if not eliminated
by administration of MCP.
EXAMPLES
Renal Injury
[0021] Renal insult is simulated in mice with folic acid. Folic
acid induced renal injury candidates were pretreated with either
water, or water supplemented with one percent (1%) PectaSol-C one
(1) week before injection of folic acid. The gross changes
associated with the renal insult, including enlarged kidneys and
weight loss, were reduced in mice receiving MCP. In the recovery
phase, MCP-receiving mice demonstrated reduced galectin-3 and
decreased renal fibrosis, macrophages, pro-inflammatory cytokine
expression and apoptosis. The levels of other renal-associated
galectins, including galectin-1 and galectin-9, were unchanged.
Clearly, MCP was of value in suppressing both inflammation and
fibrosis relative to organ injury. Kolatsi-Joannou, PLoS One,
8,6(4), e18683 (2011).
Thyroid Cancer Treatment
[0022] Patients with papillary thyroid cancer were administered a
galectin-3 binding molecule, inhibiting galectin-3 concentrations
in the patients so studied. Patients with reduced galectin-3
concentrations exhibited improved apoptotic activity, and improved
sensitivity to both radiation and chemotherapeutic treatment
(doxorubicin). Galectin-3 inhibition by administration of a
molecule that binds to galectin-3 offers a promising therapeutic
treatment to both inhibit cancer, and elevate the utility of
conventional antineoplastic agents and treatments. Mol. Cancer
Res., 7,10, 1655-62 (2009).
Lung Cancer Treatment
[0023] In patients with pulmonary adenocarcinoma, the test group
was administered polyclonal antibodies which bind galectin-3 in
much the same fashion as MCP does. The tissues of these patients
exhibited a significant inhibition of cancer cell growth, the
galectin-3 clearly playing a role in oncogenesis. Binding of
galectin-3, as a means of reducing its effective local
concentration, whether by antibody or MCP offers a therapeutic
target for cancer intervention. Li et al, Clin. Invest. Med., 33,
1, e44-53 (2010).
Asthma and Related Inflammation
[0024] Mice with reduced galectin-3 concentrations were compared
with mice with normal galectin-3 levels in mice with induced asthma
(ovalbumin induced). Mice with lower levels of galectin-3 exhibited
fewer eosinophils and lower goblet metaplasia, less airway
hyperressponsiveness and a different Th1/Th2 response.
Administration of MCP is an effective means of reducing the
concentration of galectin-3 to which cells, organs and systems
sensitive to inflammation are exposed. This reduction provides
benefits in treatment to intractable disease states. Zuberi et al,
Am J. Pathol. 165, 6, 2045-53 (2004).
Inflammation of the Gastrointestinal Tract
[0025] Inflammation is a normal mammalian response to cellular
stress in a wide variety of environments. In gastric ulcers,
inflammation can often represent an imbalance in mucosal defense.
Wistar albino rats with induced gastric ulcers with a 3-fold
reduction in galectin-3 concentration exhibited improved protection
against inflammation and gastric wall damage. Galectin-3 is,
generally, an inflammation modulator, and wherever that
inflammation is a response to a condition that is injurious or
imbalanced, MCP may be administered to reduce galectin-3
concentration locally and inhibit associated inflammation. Srikanta
et al, Biochimie, 92, 2, 194-203 (2010).
Inflammation and Fibrosis of the Liver
[0026] Normal mice and galectin-3 deficient mice were compared
after being fed a diet that results in the formation of advanced
lipoxidation endproducts or ALEs associated with inflammation and
fibrosis. Galectin-3 deficient mice exhibited significantly reduced
hepatic inflammation and fibrosis together with reduced hepatocyte
injury. Reduced concentration of galectin-3 may also lead to
reduced insulin resistance. MCP reduces effective concentration of
galectin-3 in tissues threatened by inflammation and fibrosis.
Reducing galectin-3 concentration may be an effective therapeutic
measure in addressing liver disease. Federici, J. Hepatol.
54,5,975-83 (2011).
Treatment of Liver Cancer
[0027] Balb/C mice were divided into a control group, and test
groups that received varying levels of MCP following administration
of colon cancer cells to the spleen to set up a colon cancer liver
metastasis model. The MCP was delivered in varying levels through
the drinking water. The concentration of serum galectin-3 was
significantly higher in the control group. Expression of galectin-3
was found to significantly increase liver metastases of colon
cancer. The administration of MCP to reduce the concentration of
galectin-3 resulted in a significant reduction in liver metastases
that varied directly with the concentration of MCP in the drinking
water (the higher the concentration, the more dramatic the
reduction in liver metastases.) Liu et al, World J. Gastroenterol.
14, 48, 7386-91 (2008).
Inflammation to Due Parasite Invasion
[0028] In mammals infected with Trypanasoma brucei, chronic
inflammation is a key factor in the development of ACD. In mice
with a reduced galectin-3 concentration, significantly lower levels
of anemia during infection were observed, and the mice survived
twice as long as untreated mice. The mice with a reduced galectin-3
concentration reflected reduced liver pathology as well. Reduced
inflammation was accompanied by reduced anemia and better survival,
indicating reduction of galectin-3 levels is a potential
therapeutic avenue for liver malfunction. MCP may be administered
to reduce effective galectin-3 levels. Vankrunkelsven,
Immunobiology, 215, 9-10, 833-841 (2010). In a related study,
galectin-3 deficient mice demonstrated lower bacterial count when
challenged with a sublethal dose of Rhodococcus equi, together with
a decreased frequency of bacterial replication and survival. Ferraz
et al, Eur. J. Immunol. 38, 10, 2762-75 (2008). Reduced levels of
galectin-3 in mice were also associated with reduced inflammation
in mice infected with Schistosoma mansoni. Breuilh et al, Infect.
Immun.75, 11, 5148-57 (2007).
Diabetes Resistance
[0029] Mice were exposed to conditions that induce hyperglycemia
and similar diabetic traits. In mice with reduced galectin-3
levels, measurements of glycemia, quantitative histology and
insulin content showed these mice to be resistant to the
development of diabetes, as compared with nice with normal levels
of galectin-3. The same mice showed a reduction in inflammation.
One method of reducing the galectin-3 levels to which challenged
tissues and organs are exposed is by systemic administration of
MCP, orally or intravenously. Reduction in galectin-3 levels is
associated with resistance to diabetogenesis. Mensah-Brown, Ann N.
Y. Acad. Sci. 1084, 49-57 (2006). Related research has demonstrated
that reduction in galectin-3 levels slows the breakdown of the
inner blood-retinal barrier (iBRB) that typically occurs early in
diabetes. Galectin-3 deficient mice demonstrated a significant
reduction in diabetes-mediated iBRB and reduced junctional
disruption when compared with mice with normal galectin-3 levels.
Canning et al, Exp. Diabetes Res., 2007:51837 (2007). Among the
methods available to effectively reduce active galectin-3
concentrations to inhibit the development and progression of
diabetes and its symptoms is the administration of low molecular
weight MCP over a long term. No toxicity has been demonstrated for
such administration.
Arthritis and Inflammation
[0030] A model of arthritis may be induced in mice by immunization
with methylated. bovine serum albumin. Referred to as AIA, this
condition mimics arthritis and the inflammation associated with it.
Inflammation was shown to be markedly reduced, together with a
reduction in bone erosion, in mice with reduced galectin-3 levels.
The reduction in arthritis was accompanied by decreased levels of
proinflammatory cytokines. Confirming that the nature or the
galectin-3 level alteration can be genetic or chemical, exogenously
added glaectin-3 restored the level of arthritis in galectin-3
deficient mice to wild-type levels. Forsman et al, Arthritis
Rheum., 63, 2, 445-54 (2011). Reduction in galectin-3 levels as a
means of addressing arthritis and related inflammation was also
shown in rats where an artificial reduction in galectin-3 levels
via genetic modification substantially suppressed arthritis
indices. Wang et al, Gene Ther., 17. 10. 1225-33 (2010).
Administering low molecular weight MCP provides an effective in
vivo method of achieving this reduction of inflammation and
treating arthritis, including autoimmune arthritis such as
rheumatoid arthritis.
Skin Inflammation
[0031] The development of inflammation in connection with allergic
responses presents a vast panorama of patient discomfort. A
reduction in galectin-3 levels in galectin-3 deficient mice was
shown to reduce epidermal thickening, lower eosinophil infiltration
and significantly reduced dermatitis. Saegusa et al., Am. J.
Pathol., 174, 3, 922-31 (2009). Inflammation in a wide variety of
tissues, as described above, is mediated by galectin-3, at least in
part. Reducing the level of active galectin-3 by administration of
MCP of molecular weight below 20,000 Daltons down to 10,000 Daltons
or lower, and preferably about 3-13,000 Daltons, provides an
effective, easily tolerated method of reducing galectin-3 levels to
achieve this goal. MCP can also be applied trans-dermally for such
purposes.
Cardiac Disease and Fibrosis
[0032] As noted, MCP mediated reduction of galectin-3 levels may
provide an important treatment for cardiac diseases, particularly
by reducing cardiac fibrosis. Reducing galectin-3 levels in the
myocardium in osteopontin-deficient mice resulted in diminished
fibrotic response and inflammation. Psarras et al, Eur. Heart. J.
Apr. 2011. Galectin-3 levels associated with mediated fibrosis are
much higher than post-fibrotic recovery values. De Boer et al, Eur.
J. Heart Fail., 11, 9, 811-17 (2009) suggesting that lowering
galactin-3 levels temporarily following heart insult may reduce or
suppress fibrosis and heart disease and failure associated
therewith.
[0033] What has been clearly demonstrated is that reducing
galectins-3 levels in serum, cell and particularly in circulation
may beneficially affect tissues and organs in mammals. It may also
confer protection in mammalian patients presented with challenge
from cancer cells, or cells that may develop into cancerous cells.
Galectin-3 is a powerful mediator of the development of
inflammation and fibrosis and diseases and conditions associated
therewith in a wide variety of tissue types, from cardiac to kidney
to liver, to lung, to skin. Further, administration of MCP to a
mammal in amounts of from 5 mg/kg/day on up to 1,500 mg/kg/day may
be effective in reducing and controlling inflammation throughout
the body.
[0034] While the present invention has been disclosed both
generically and with reference to specific alternatives, those
alternatives are not intended to be limiting unless reflected in
the claims set forth below. The invention is limited only by the
provisions of those claims, and their equivalents, as would be
recognized by one of skill in the art to which this application is
directed, in general, a medical doctor of at least five (5) years
experience.
* * * * *