Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-04-21
2002-04-02
Cochrane Carlson, Karen (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C530S350000
Reexamination Certificate
active
06365569
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to Dirofilaria and Brugia ankyrin nucleic acid molecules, proteins encoded by such nucleic acid molecules, antibodies raised against such proteins, compounds capable of inhibiting the function of such proteins and methods to identify such inhibitors. The present invention also includes therapeutic compositions comprising such nucleic acid molecules, proteins, antibodies, and/or inhibitors, as well as their use to protect animals from diseases caused by parasitic helminths, such as heartworm disease, elephantiasis, and hydrocele.
BACKGROUND OF THE INVENTION
Parasitic helminth infections in animals, including humans, are typically treated by chemical drugs. One disadvantage with chemical drugs is that they must be administered often. For example, dogs susceptible to heartworm are typically treated monthly. Repeated administration of drugs, however, often leads to the development of resistant helminth strains that no longer respond to treatment. Furthermore, many of the chemical drugs cause harmful side effects in the animals being treated, and as larger doses become required due to the build up of resistance, the side effects become even greater. Moreover, a number of drugs only treat symptoms of a parasitic disease but are unable to prevent infection by the parasitic helminth.
An alternative method to prevent parasitic helminth infection includes administering a vaccine against a parasitic helminth. Although many investigators have tried to develop vaccines based on specific antigens, it is well understood that the ability of an antigen to stimulate antibody production does not necessarily correlate with the ability of the antigen to stimulate an immune response capable of protecting an animal from infection, particularly in the case of parasitic helminths. Although a number of prominent antigens have been identified in several parasitic helminths, including in Dirofilaria and Brugia species, there is yet to be a commercially available vaccine developed for any parasitic helminth.
As an example of the complexity of parasitic helminths, the life cycle of
D. immitis,
the helminth that causes heartworm, includes a variety of life forms, each of which presents different targets, and challenges, for immunization. In a mosquito,
D. immitis
microfilariae go through two larval stages (L1 and L2) and become mature third stage larvae (L3), which can then be transmitted back to the dog when the mosquito takes a blood meal. In a dog, the L3 molt to the fourth larval stage (L4), and subsequently to the fifth stage, or immature adults. The immature adults migrate to the heart and pulmonary arteries, where they mature to adult heartworms. Adult heartworms are quite large and preferentially inhabit the heart and pulmonary arteries of an animal. Sexually mature adults, after mating, produce microfilariae which traverse capillary beds and circulate in the vascular system of the dog. In particular, heartworm is a major problem in dogs, which typically do not develop immunity upon infection (i.e., dogs can become reinfected even after being cured by chemotherapy). In addition, heartworm infection has been reported in cats, ferrets, and humans.
As such, there remains a need to identify efficacious compositions that protect animals against diseases caused by parasitic helminths such as
D. immitis
and
B. malayi.
Such compositions would preferably also protect animals from infection by such helminths.
The mechanisms and regulatory pathways involved in
D. immitis
migration and development are not clear. From infective L3 to mature adult, the nematode has to migrate and develop, with two molts, within its definitive host. It has been shown in the free living nematode,
Caenorhabditis elegans
(
C. elegans
), that the development of the larvae is regulated by environmental signals through chemosensory neurons. Blockage of signal transmission affects the development of the nematode (Bargmann, et al., 1991,
Science,
251, 1243-1246). Many neuron-related genes have been identified in
C. elegans.
Mutations of the genes which control normal neuron function in
C. elegans
will not only affect the behavior of the nematode, but will also affect the development of the larvae and egg laying of mutated female worms. In parasitic nematodes, very little is known about mechanisms involved in the signal transmission and the developmental regulation of the parasites. However, host and tissue specificities in parasite infections suggest that parasitic nematodes might also need correct environmental signals for development.
Ankyrins are peripheral membrane proteins which have been found in erythrocyte, kidney and neuronal cells of mammals. Genes coding for three different mammalian ankyrins (ankyrin
R
, ankyrin
B
and ankyrin
G
) have been cloned Ankyrin
R
was originally identified as part of the erythrocyte membrane skeleton, and was recently also localized to the plasma membrane of a subpopulation of post mitotic neurons in rat brain (Lambert, et al., 1993,
J. Neurosci.,
13, 3725-3735). Ankyrin
B
is a developmentally regulated human brain protein which has two alternatively spliced isoforms with molecular masses of 220 kilodaltons (kD) and 440 kD (Kunimoto, et al., 1991,
J. Cell Biology,
115, 1319-1331). Ankyrin
G
is a more recently isolated human gene that encodes two neural-specific ankyrin variants (480 kD and 270 kD), which have been localized to the axonal initial segment and node of Ranvier (Kordeli, et al., 1995,
J. Biol. Chem.,
270, 2352-2359). Studies on mammalian ankyrins indicate that ankyrins bind a variety of proteins which have functions involved with the anion exchanger (Drenckhahn, et al., 1988,
Science,
230, 1287-1289), Na+/K+−ATPase, amiloride-sensitive sodium channel in kidney (Smith, et al., 1991,
Proc. Natl. Acad. Sci. U.S.A.,
88, 6971-6975), voltage dependent sodium channel of the brain and the neuromuscular junction (Srinivasan, et al., 1988,
Nature,
15 333, 177-180), and nervous system cell adhesion molecules (Davis, et al., 1994,
J. Biol. Chem.,
269,27163-27166).
Analyses of mammalian ankyrins have revealed that these large proteins are divided into three functional domains. These include an N-terminal membrane-binding domain of about 89-95 kD, a spectrin-binding domain of about 62 kD, and a C-terminal regulatory domain of about 50-55 kD. The membrane-binding domain is primarily comprised of tandem repeats of about 33 amino acids each. This domain usually has about 22-24 copies of these repeats. The repeat units appear to function in binding to membrane proteins such as anion exchangers, sodium channels, and certain adhesion molecules. The spectrin-binding domain, as the name implies, functions in binding to the spectrin-based cytoskeleton of cells positioned inside the plasma membrane. Finally, the regulatory domain, which is the most variant domain among the different ankyrins that have been studied, appears to function in as a repressor and/or an activator of the protein-binding activities of the other two domains. Some of the variability seen in this domain among different ankyrin species appears to be the result of alternative splicing of nascent transcripts. For a review of ankyrin structure and function, see, for example, Bennett, 1992,
J. Biol. Chem.,
267, 8703-8706. Bennett, ibid., is herein incorporated by reference in its entirety.
An ankyrin gene (UNC-44) has also been identified in the free living nematode,
C. elegans.
Mutation of UNC-44 affects the development and function of the nervous system (Otsuka et al., 1995,
J. Cell Biology,
129, 1081-1092). More recently, a cDNA encoding a 90-kilodalton (kD) neuronal protein, E1, which is reported to be an ankyrin-related protein, has been cloned from the filariid nematode, Onchocerca volvulus (
O. volvulus
), a human parasite. The cDNA was identified by using immuno-screening with antisera collected from putatively immune individuals from an endemic area of onchocerciasis. Localization studies by immunohistochemical assay indicated t
Blehm E. Scot
Tang Liang
Carlson Karen Cochrane
Heska Corporation
Heska Corporation
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