Polynucleotide compositions for intramuscular administration

Synthetic resins or natural rubbers -- part of the class 520 ser – Synthetic resins – At least one aryl ring which is part of a fused or bridged...

Reexamination Certificate

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C524S612000, C525S09200D, C525S09200D, C424S426000, C536S023700, C536S024100, C536S024310, C536S024500

Reexamination Certificate

active

06359054

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to block copolymer compositions and methods for intramuscular administration of polynucleotides.
BACKGROUND OF THE INVENTION
The unique features of smooth, skeletal, and cardiac muscles, have presented numerous challenges for the development and administration of effective polynucleotide compositions for intramuscular administration. Direct injection of purified plasmids (“naked DNA”) in isotonic saline into muscle was found to result in DNA uptake and gene expression in smooth, skeletal, and cardiac muscles of various species. Rolland A.,
Critical Reviews in Therapeutic Drug Carrier Systems,
Begell House, 143 (1998). It is believed that the unique cytoarchitectural features of muscle tissue are responsible for the uptake of polynucleotides because skeletal and cardiac muscle cells appear to be better suited to take-up and express injected foreign DNA vectors relative to other types of tissues. Dowty & Wolff,
Gene Therapeutics: Methods and Applications of Direct Gene Transfer,
Birkhäuser, Boston, p.182 (1994). The relatively low expression levels attained by this method, however, have limited its applications. See Aihara and Miyazaki,
Nature Biotechnology,
16:867 (1998). Additionally, traditional gene delivery systems such as polycations, cationic liposomes, and lipids that are commonly proposed to boost gene expression in other tissues usually result in inhibition of gene expression in skeletal and cardiac muscles. Dowty & Wolff,
Gene Therapeutics: Methods and Applications of Direct Gene Transfer,
Birkhäuser, Boston, p. 82 (1994).
Anionic polymers such as dextran sulfate and salmon DNA can decrease gene expression in the muscle. Rolland A.,
Critical Reviews in Therapeutic Drug Carrier Systems,
Begell House, 1998, p. 143. Various noncondensive interactive polymers have been used with a limited success to modify gene expression in striated muscle. Nonionic polymers such as poly(vinyl pyrrolidone) poly(vinyl alcohol) interact with plasmids through hydrogen bonding. Rolland A.,
Critical Reviews in Therapeutic Drug Carrier Systems,
Begell House, 1998, p. 143. These polymers may facilitate the uptake of polynucleotides in muscle cells and cause up to 10-fold enhancement of gene expression. However, to achieve a significant increase in gene expression, high concentrations of polymers (about 5% and more) need to be administered. Mumper et al.,
Pharmacol. Res.,
13, 701-709 (1996); March et al.,
Human Gene Therapy,
6(1), 41-53 (1995). This high concentration of poly(vinyl pyrrolidone) poly(vinyl alcohol) needed to improve gene expression can be associated with toxicity, inflammation, and other adverse effects in muscle tissues. Block copolymers have been used to improve gene expression in muscle or to modify the physiology of the muscle for subsequent therapeutic applications. See U.S. Pat. Nos. 5,552,309; 5,470,568; 5,605,687; and 5,824,322. For example, block copolymers can be used in a gel-like form (more than 1% of block copolymers) to formulate virus particles used to perform gene transfer in the vasculature. In the same range of block copolymers concentration (1-10%), it is possible with block copolymer to modify the permeability of damaged muscle tissue (radiation and electrical injury, and frost bite). In addition DNA molecules can be incorporated into cells following membrane permeabilization with block copolymers. For these applications, block copolymers were used at concentrations giving gel-like structures and viscous delivery systems. These systems are unlikely to enable diffusion of the DNA injected into the muscle, however, thus limiting infusion of the DNA into the myofibers.
There is thus a need for compositions and methods increasing efficacy of polynucleotides expression upon administration in the muscle.
Beside the need to improve gene expression in muscle other tissues in the body would benefit from a gene transfer in a situation when there is a genetic disorder, and/or an abnormal over-expression of a gene, and/or absence of a normal gene. Several polynucleotides such as RNA, DNA, viruses, ribozymes can be used for gene therapy purposes. However, many problems, like the ones described below, have been encountered for successful gene therapies.
The use of antisense polynucleotides to treat genetic diseases, cell mutations (including cancer causing or enhancing mutations) and viral infections has gained widespread attention. This treatment tool is believed to operate, in one aspect, by binding to “sense” strands of mRNA encoding a protein believed to be involved in causing the disease site sought to be treated, thereby stopping or inhibiting the translation of the mRNA into the unwanted protein. In another aspect, genomic DNA is targeted for binding by the antisense polynucleotide (forming a triple helix), for instance, to inhibit transcription. See Helene,
Anti
-
Cancer Drug Design,
6:569 (1991). Once the sequence of the mRNA sought to be bound is known, an antisense molecule can be designed that binds the sense strand by the Watson-Crick base-pairing rules, forming a duplex structure analogous to the DNA double helix.
Gene Regulation: Biology of Antisense RNA and DNA
, Erikson and lxzant, eds., Raven Press, New York, 1991; Helene,
Anti
-
Cancer Drug Design,
6:569 (1991); Crooke,
Anti
-
Cancer Drug Design,
6:609 (1991). A serious barrier to fully exploiting this technology is the problem of efficiently introducing into cells a sufficient number of antisense molecules to effectively interfere with the translation of the targeted mRNA or the function of DNA.
SUMMARY OF THE INVENTION
The invention relates to compositions of polynucleotides, such as RNA, DNA or their derivatives, and block copolymers. These compositions are useful for gene therapy purposes, including gene replacement or excision therapy, and gene addition therapy, vaccination, as well as therapeutic situations in which it is desirable to express or down-regulat a polypeptide in the body or in vitro.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the terms below have the following meaning:
DEFI-
NITIONS
Backbone:
Used in graft copolymer nomenclature to describe the chain
onto which the graft is formed.
Block
A combination of two or more chains of constitutionally or
copolymer:
configurationally different features.
Branched
A combination of two or more chains linked to each other,
polymer:
in which the end of at least one chain is bonded at some
point along the other chain.
Chain:
A polymer molecule formed by covalent linking of
monomeric units.
Con-
Organization of atoms along the polymer chain, which can
figuration:
be interconverted only by the breakage and reformation of
primary chemical bonds.
Con-
Arrangements of atoms and substituents of the polymer
formation:
chain brought about by rotations about single bonds.
Copolymer:
A polymer that is derived from more than one species of
monomer.
Cross-link:
A structure bonding two or more polymer chains together.
Dendrimer:
A regularly branched polymer in which branches start from
one or more centers.
Dispersion:
Particulate matter distributed throughout a continuous
medium.
Graft
A combination of two or more chains of con-stitutionally or
copolymer:
configurationally different features, one of which serves as
a backbone main chain, and at least one of which is bonded
at some points along the backbone and constitutes a side
chain.
Homo-
Polymer that is derived from one species of monomer.
polymer:
A covalent chemical bond between two atoms, including
Link:
bond between two monomeric units, or between two
polymer chains.
Polymer
An intimate combination of two or more polymer chains of
blend:
constitutionally or configurationally different features,
which are not bonded to each other.
Polymer
A portion of polymer molecule in which the monomeric
fragment (or
units have at least one constitutional or configurational
Polymer
feature absent from adjacent portions.
segment):
Poly-
A natural or synthetic nucleic acid sequence.
nucleotide:
Repeating
Monomeric unit linked into a polymer chai

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