Surgery – Means for introducing or removing material from body for... – Treating material introduced into or removed from body...
Reexamination Certificate
2000-06-19
2004-01-06
Sykes, Angela D. (Department: 1636)
Surgery
Means for introducing or removing material from body for...
Treating material introduced into or removed from body...
C604S006160, C604S101010, C604S101030, C604S101050
Reexamination Certificate
active
06673039
ABSTRACT:
BACKGROUND OF THE INVENTION
The field of the invention is gene therapy and cardiac therapy.
It is well known that viruses naturally deliver nucleic acids to cells and have therefore been exploited as gene delivery vehicles. However, in order for a recombinant virus to delivery a nucleic acid to a cell, the virus must first have access to the cell. Circulating virus in a mammal may not have ready access to cells to which it is desired that a nucleic acid be delivered. The present invention provides a means of providing to a virus access to cells to which it is desired that a nucleic acid be delivered.
The recent cloning of full length cDNAs for gene products implicated in several muscular dystrophies (Lim et al., 1995, Nature Genetics 11: 257-265; Piccolo et al., 1995, Nature Genetics, 10: 243-245; Nigro et al., 1996, Nature Genetics 14:195-198; Bonnemann et al., 1995, Nature Genetics 11: 266-273; and Helbling-Leclerc et al., 1995, Nature Genetics 11:216-218) has been paralleled by improvement in a variety of virus-based vector systems for use in somatic gene transfer (Yang et al., 1994, Nature Genetics 7:362-369; Yeh et al. 1996, J. Virology 70: 559-565; and Wilson, 1996, New Eng. J. Med. 334:1185-1187). The universal muscle involvement and resulting respiratory insufficiency in these diseases have focussed attention on the need for systemic vector delivery in vivo to mammal tissues and organs (Boland et al., 1996, Pediatric Neurology, 14: 7-12; Stedman et al., 1991, Nature 352: 536-539; Schlenker et al., 1991, J. Appl. Physiol. 71: 1655-1662; and Smith et al., 1987, New Engl. J. Med. 316: 1197-1205). Under physiologic conditions, the continuous endothelium of the skeletal muscle microvasculature is virtually impermeable to proteins larger than albumin (Stokes radius 3.5 nanometers; Berne et al., 1992, In: Physiology, Mosby, St. Louis), and the underlying basal lamina restricts the diffusion of larger macromolecular aggregates (Majno et al., 1961, J. Biophys. Biochem. Cytol. 11:571-597).
There is an acute need to develop compositions and methods which facilitate access of large macromolecules to muscle for the purposes of delivery of compounds which are of therapeutic benefit to mammals in need of such compounds. The present invention satisfies this need.
Muscular dystrophies and other myopathies are inherited, generally progressive disorders in which non-expression or abnormal expression of a muscular gene causes weakness, hypertrophy, and/or loss of normal muscular control. Many of these disorders have been associated with chromosomal mutations, although some (e.g. mitochondrial myopathies) are instead associated with deletions in mitochondrial DNA. For example, Duchenne muscular dystrophy (DMD) has been associated with mutations in the human gene encoding dystrophin protein.
Although respiratory compromise dominates the clinical course of end-stage DMD, underlying cardiomyopathy is universally present in such DMD patients. In some muscular dystrophies, including those involving dystrophinopathy (e.g. Becker muscular dystrophy) and those involving sarcoglycanopathy (e.g. limb-girdle muscular dystrophy), heart failure severe enough to require transplantation is sometimes observed (Piccolo et al., 1994, Neuromusc. Disord. 4:143-146; Fadic et al., 1996, N. Engl. J. Med. 334:362-366). In addition, at least a dozen other gene products have been implicated in the pathogenesis of recessively inherited dilated cardiomyopathy in humans (Fadic et al., 1996, N. Engl. J. Med. 334:362-366; Piccolo et al., 1995, Nature Genet. 10:243-245; Lim et al., 1995, Nature Genet. 11:257-265; Noguchi et al., 1995, Science 270:819-822; Nigro et al., 1996, Nature Genet. 14:195-198; Nigro et al., 1997, Hum. Mol. Genet. 6:601-607; Bione et al., 1994, Nature Genet. 8:323-327; Taroni et al., 1992, Proc. Nat. Acad. Sci. U.S.A. 89:8429-8433; Witt et al., 1992, J. Neurol. 239:302-306; Ho et al., 1994, Cell 77:869-880; Reichmann et al., 1991, Eur. Heart J. 12(Suppl. D):169-170; Eishi et al., 1985, Hum. Pathol. 16:193-197; Bione et al., 1996, Nature Genet. 12:385-389; Yokoyama et al., 1987, Br. Heart J. 57:296-299; Elleder et al., 1990, Virchows Arch. A Pathol. Anat. Histopathol. 417:449-455; Nagao et al., 1991, Clin. Genet. 39:233-237; Schultheiss et al., 1996, Mol. Cell Biochem. 163-164:319-327).
By way of example, common human cardiac diseases have been reproduced in mice in order to exploit the ability of germline gene transfer to achieve transgene expression in all cardiac myocytes. Two studies by others suggest the potential therapeutic benefit of transgenes expressed in the heart following somatic gene transfer in the adult mammal, provided that gene transfer occurs in a large majority of, or even all, cardiac myocytes. G protein mediated signaling pathways are targeted in both studies, addressing diseases as divergent as cardiac hypertrophy and dilated cardiomyopathy.
In the first study, cDNA encoding a peptide inhibitor of beta adrenergic receptor kinase 1 (bARK1) was expressed under the control of the cardiac muscle-specific alpha myosin heavy chain promoter (Rockman et al., 1998, Proc. Natl. Acad. Sci. USA 95:7000-7005). Breeding of transgenic mice integrating this construct with mice from a recently developed cardiomyopathic line (muscle LIM protein deficient {MLP
−/−
}) led to the striking finding that the cardiomyopathy was prevented in the offspring. MLP
−/−
mice exhibit numerous abnormalities of cardiac myocyte structure and function that resemble those seen in a broad variety of human cardiomyopathies. The transgene-encoded inhibitor prevented these abnormalities through a general mechanism that is not directly coupled to normal functioning of the LIM protein This study indicates that delivery of a similar gene construct to human cardiac tissue could have significant therapeutic benefit for humans afflicted with a wide variety of cardiomyopathies, if only such a gene construct could specifically delivered to human cardiac myocytes with high efficiency.
In the second study, cDNA encoding a peptide inhibitor of binding between cardiac myocyte adrenergic receptors and a protein of the Gq subclass was expressed under the control of the cardiac muscle-specific alpha myosin heavy chain promoter (Akhter et al., 1998, Science 280:574-577). Transgenic mice integrating this construct were subjected to cardiac pressure overload by undergoing surgical transverse aortic constriction. Cardiac overexpression of this inhibitor greatly reduced the cardiac hypertrophic response to pressure overload. Several signal transduction pathways implicated in the human cardiopathological response to cardiac overload were demonstrated to be activated as a result of the surgical procedure. In the setting of strong signal activation, the reduction in cardiac hypertrophy associated with expression of the peptide inhibitor demonstrates that the inhibitor acts at a position common to multiple signal transduction cascades. This study also indicates that delivery of a similar gene construct to human cardiac tissue could have significant therapeutic benefit for humans afflicted with a wide variety of cardiomyopathies, if only such a gene construct could specifically delivered to human cardiac myocytes with high efficiency.
Other cardiac disorders (e.g. heart failure, myocardial infarction, rheumatic fever, arrhythmia, congestive heart failure, infective endocarditis, and pericarditis) are known to be associated with numerous non-congenital causes, but might nonetheless benefit from gene therapy methods if gene vectors comprising a nucleic acid encoding a beneficial gene product could be provided specifically and safely to cardiac tissue.
Unfortunately, the position of the heart within the human body has, in the past, required the use of highly invasive procedures for providing therapy directly and locally to cardiac tissue. In addition to the serious physiological complications which sometimes accompany such highly invasive procedures, these interventions may also exact a high psychological toll
Bridges Charles R.
Stedman Hansell H.
Deak Leslie R
Duane Morris LLP
Sykes Angela D.
Trustees of the University of Pennsylvania
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