Download Periostin induces proliferation of cardiomyocytes and promotes

USOO8936806B2
(12) United States Patent
Kuhn
(54)
PERIOSTIN INDUCES PROLIFERATION OF
CARDIOMYOCYTES AND PROMOTES
CARDIAC REGENERATION
(75) Inventor:
Bernhard Kuhn, Brookline, MA (US)
(73) Assignee: Children’s Medical Center
Corporation, Boston, MA (US)
(*)
Notice:
Subject to any disclaimer, the term of this
patent is extended or adjusted under 35
U.S.C. 154(b) by 707 days.
(10) Patent N0.:
(45) Date of Patent:
US 8,936,806 B2
Jan. 20, 2015
Litvin J, S Zhu, R Norris, and R Markwald. 2006. Perio stin Family of
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6,444,642 B1
2005/0042254 A1*
2007/0264254 A1
Primary Examiner * Carlos Azpuru
Assistant Examiner * David Browe
(74) Attorney, Agent, 0rFirm * Nixon Peabody LLP; David
S. Resnick; Leena H. Karttunen Contarino
9/2002 Sklar et al.
2/2005
Freyman et al. ............ .. 424/426
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the Postnatal Heart: Potential Modi?cation of Phenotype by
Periostin. Ann NYAcad Sci. 1080: 19-33.*
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ure. Circ Res. 92: 139-150.*
(57)
ABSTRACT
The present invention provides compositions and methods for
increasing proliferation, increasing cell cycle activity, and/or
proliferation of postmitotic mammalian differentiated cardi
omyocytes. The invention can be used to slow, reduce, or
prevent the onset of cardiac damage caused by, for example,
myocardial ischemia, hypoxia, stroke, or myocardial infarc
tion in vivo. In addition, the methods and compositions of the
invention can be used to enhance proliferation of differenti
ated cardiomyocytes in vitro and/ or ex vivo, which can then
be used in tissue grafting.
9 Claims, 17 Drawing Sheets
US 8,936,806 B2
Page 2
(56)
International Preliminary Report on Patentability mailed Feb. 2, 20 12
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Mack Publishing Co., Easton, Pennsylvania Table of Contents. 3
pages.
* cited by examiner
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US 8,936,806 B2
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1
2
PERIOSTIN INDUCES PROLIFERATION OF
CARDIOMYOCYTES AND PROMOTES
CARDIAC REGENERATION
and/or proliferation of postmitotic mammalian differentiated
prevent the onset of cardiac damage caused by, for example,
RELATED APPLICATIONS
tion in vivo. In addition, the methods and compositions of the
cardiomyocytes. The invention canbe used to slow, reduce, or
myocardial ischemia, hypoxia, stroke, or myocardial infarc
invention can be used to enhance proliferation of differenti
ated cardiomyocytes in vitro and/ or ex vivo, which can then
This application claims priority of Us. Provisional Appli
cation No. 60/881,938 ?led Jan. 22, 2007, which is incorpo
rated by reference in its entirety.
be used in tissue grafting.
The invention is based, in part, on the discovery that peri
ostin, a component of the extracellular matrix, and fragments
GOVERNMENT SUPPORT
thereof promote cardiomyocyte proliferation and myocardial
This invention was made with government support under
Grant No. AHA 0425772T awarded by the American Heart
with scar formation, not with proliferation, the cellular basis
regeneration. The adult mammalian heart responds to injury
for regeneration. The insuf?cient regeneration of mammalian
hearts is explained by the contractile apparatus impinging on
cardiomyocyte division. The invention demonstrates that
extracellular periostin can induce cell cycle re-entry of dif
ferentiated mammalian cardiomyocytes. Perio stin stimulates
Association. The U.S. government has certain rights in this
invention.
BACKGROUND OF THE INVENTION
Cardiovascular diseases are a leading cause of death result
20
mononuclear cardiomyocytes, present in the adult mamma
ing in almost 40% of deaths annually in the United States.
lian heart, to undergo the full mitotic cell cycle. Periostin
Inadequate human myocardial regeneration poses a signi?
activates 0tV[31/3/5 integrins located in the cardiomyocyte
cell membrane. Periostin-induced cardiomyocyte prolifera
cant public health problem. It is estimated that 13 million
tion results from activation the ERK1/2 and Akt signaling
Americans have coronary artery disease, and more than half a
million experience a myocardial infarction every year.
25
Human cardiac tissue responds to injury, e.g. myocardial
remodeling and function, reduces ?brosis and infarct size,
and increases angiogenesis. These results demonstrate that
infarction, with scar formation. Because the human heart is
incapable of adequate muscle regeneration, survivors of a
myocardial infarction typically develop heart failure, arrhyth
mias, thrombosis, and other complications.
30
Adult human hearts do not regenerate after injury; instead,
the defect is replaced by ?brotic tissue. Most evidence to date
indicates that cardiomyocyte proliferation, the cellular basis
of regeneration, is not a signi?cant component of the mam
malian response to acute injury. In contrast to adult cardi
periostin and the pathway it regulates is a new target for
innovative strategies to treat heart failure.
The invention identi?es pathways that can induce prolif
eration of differentiated cardiomyocytes as a potential route
to restore cardiac function. In another aspect of the invention,
agents are disclosed that activate the signal transduction cas
35
omyocytes, fetal cardiomyocytes do proliferate during devel
opment.
cade consisting of extracellular periostin, integrins, and the
ERK1/2 and the PI3-kinase/Akt pathways. Such agents
include periostin, truncated biologically active constructs of
periostin, functional analogs of periostin and pharmaceuti
Heart disease results in the loss of cardiomyocytes. It has
been a signi?cant challenge to develop effective treatments
for cardiac repair because adult mammalian cardiomyocytes
pathways. After myocardial infarction, recombinant perio stin
induces cardiomyocyte cell cycle re-entry, improves cardiac
cally acceptable derivatives of periostin or its functional ana
40
logs, and combinations thereof.
are highly differentiated cells and have been believed to be
In another aspect, the invention discloses methods of
unable to proliferate. Mammalian cardiomyocytes withdraw
stimulating proliferation of post-mitotic cells using com
pounds comprising periostin, fragments or variants thereof,
from the cell cycle soon after birth and have lowered levels of
or pharmaceutically acceptable derivatives thereof. The post
cyclin A (Yoshizumi, M., et. al. (1995). J Clin Invest 95,
2275-2280). The fact that primary cardiac tumors occur
rarely supports the notion that adult cardiomyocytes are
highly restricted in their ability to divide. Because of its lack
of proliferative potential, the primary response of the mam
malian heart to injury is scar formation, which prevents car
45
diac repair. Thus the loss of cardiomyocytes after damage
caused by events such as myocardial infarction generally
50
lian cardiomyocytes. In some embodiments, proliferation
comprises at least one of cell cycle reentry, increased cardi
omyocyte DNA synthesis and cytokinesis. In some embodi
ments, periostin, fragments or variants thereof, is delivered
locally.
In another aspect, the invention discloses a method of
inducing division of post mitotic cells, comprising adminis
results in compensatory responses that are inadequate to
restore function. Unreplaced loss of cardiomyocytes leads to
tering an integrin activator or a pharmaceutically acceptable
derivative thereof to a subject in an amount effective to stimu
heart failure, a signi?cant health problem worldwide.
Current therapies are also limited in their effectiveness. In
mitotic cells can be cardiomyocytes, and preferably mamma
55
late de-differentiation of post-mitotic cells. The integrin acti
order to suf?ciently repair cardiac injury, it is necessary to
vator activates at least one of the integrin subunits selected
provide a source of new cardiomyocytes. Proliferation of
from the group comprising (xV, [31, and [33, and [35 integrin
differentiated endogenous cardiomyocytes can enhance the
subunits. The integrin activator can be periostin or fragments
regenerative capacity of mammalian hearts.
thereof. In some embodiments, activation of integrin causes
ERK1/2 and/ or Akt phosphorylation. In some embodiments,
Accordingly, there is a need in the art for methods of
60
the integrin activator or a pharmaceutically acceptable deriva
tive thereof can be delivered locally to the target cells or target
area. Local and/ or targeted delivery can be administered
increasing and/or promoting proliferation of adult mamma
lian cardiomyocytes.
SUMMARY OF THE INVENTION
65
The present invention provides compositions and methods
for increasing proliferation, increasing cell cycle activity,
using a slow controlled release delivery system, such as, for
example, a biodegradable matrix. The invention can be used
with a long-term, short-term and/or controlled release deliv
ery systems.