Interferon-alpha mediated upregulation of aquaporin expression

Details Interferon-alpha mediated upregulation of aquaporin expression Interferon-alpha mediated upregulation of aquaporin expression

2001-09-27

2003-01-14

Mertz, Prema (Department: 1647)

Drug, bio-affecting and body treating compositions

Lymphokine

Interferon

C424S085400, C424S085100, C514S008100, C514S851000, C514S826000

Reexamination Certificate

active

06506377

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a method for relieving xerotic symptoms (abnormal dryness) by up regulating aquaporin production in cells. More particularly, the present invention is directed to a method. for enhancing expression of aquaporin proteins in aquaporin producing cells of a warm-blooded vertebrate by contacting said cells with an effective amount of interferon-alpha (IFN-&agr;).
BACKGROUND/SUMMARY OF THE INVENTION
Aquaporin proteins are members of the MIP (Major Intrinsic Protein) family. Such proteins occur in many different organisms, such as yeasts, plants, bacteria, insects, and mammals, including humans. The member proteins of the MIP family comprise approximately 250-290 amino acid units and the sequences differ mainly at their N and C termini. All MIPs are found in vivo as intrinsic membrane proteins (i.e, they sequester with the membrane fraction in centrifugations of cell suspensions, etc.). Current studies indicate that MIPs, including aquaporins, are membrane-bound channel proteins.
Aquaporins are large and highly conserved membrane proteins that function as highly selective water channels. After being formed within the cell, aquaporin lodges in the plasma membrane, with six transmembrane regions looping through the membrane bilayer and forming the protein channel through which water passes freely.
Aquaporins move water using a passive process driven by the osmotic gradient across the cell membrane. To date, six mammalian aquaporins, numbered 0-5, have been identified. For example, Aquaporin 5 (AQ-5) is abundant in salivary and lacrimal glands, where it is thought to contribute to saliva and tear production. AQ-5 is also expressed in the adult lung, where it is believed to 6 be at least partially responsible for respiratory transpiration.
Aquaporins play a central role in water homeostasis in both plants and animals, as indicated by the localization of aquaporins to the moist surface tissues of the alveoli, the kidney tubules, the choroid plexus of the brain (where cerebrospinal fluid is produced), the ciliary epithelium of the eye (where aqueous humor is formed) and in salivary and lacrimal glands. Physiological studies further illustrate the importance of aquaporins to the maintenance of proper water homeostasis. For example, Xu et al. demonstrated that Aquaporin 2 is upregulated in kidney collecting tubules during congestive heart failure, thereby exacerbating the disease by causing increased water retention.
J. Clin. Invest.,
99(7): 1500-5(1997). Due to their important role in water regulation of biological systems, aquaporins are believed to be potential targets for therapeutic intervention in disease states involving symptoms of improper water homeostasis.
The present invention is based in part on the discovery that interferon upregulates expression of aquaporin proteins, and further that administration of interferon in vivo for contact with relevant cell populations is beneficial in treating disease states wherein water homeostasis is compromised.
“Interferon” is a term generically describing a group of vertebrate glycoproteins and proteins which are known to have antiviral, antiproliferative and immunomodulatory activity. In the early years of interferon research, an international committee was assembled to devise a system for orderly nomenclature of interferons and defined “interferon” as follows: “To qualify as an interferon a factor must be a protein which exerts virus non-specific, antiviral activity at least in homologous cells through cellular metabolic process involving synthesis of both RNA and protein.”
Journal of Interferon Research,
1, pp. vi (1980). “Interferon” as used herein in describing the present invention shall be deemed to have that definition and shall contemplate such proteins, including glycoproteins, regardless of their source or method of preparation or isolation.
Interferons have generally been named in terms of the species of animal cells producing the substance, the type of cell involved (e.g., leukocyte/lymphoblastoid or fibroblast) and, occasionally, the type of inducing material responsible for interferon production. The designations alpha (&agr;), beta(&bgr;) and gamma(&ggr;) have been used to correspond to the previous designations of leukocyte, fibroblast, and immune interferons, respectively. Alpha and beta interferons are usually acid-stable and correspond to what have been called Type I interferons; gamma interferons are usually acid-labile and correspond to what have been called Type II interferons. More recently, interferon tau has been described as an interferon-alpha related Type I interferon produced by bovine and ovine trophoblasts.
Interferon of human and murine origin is quantified in the art in terms of International Units (IU). Interferons of other than human or murine origin can be used in accordance with this invention. In that presently accepted practices may not extend the use of “International Units” to quantify non-human and non-murine interferons, it shall be understood that administration of amounts of non-human
on-murine interferons having the same efficacy as the quantities (IU's) of human interferon specified in this description are within the scope of the present invention.
In accordance with this invention, interferon-alpha is administered to a patient suffering from a disease state characterized generally by conditions of dryness of mucosal tissue. For the purpose of the present invention, appropriate IFN-&agr; treatment dosages range from about 0.1 IU/lb to about 100 IU/lb of patient body weight, more typically about 0.5 to about 10 IU/lb of patient body weight. Thus, unit dosage forms for human use typically comprise about 5 IU to about 2500 IU of interferon-&agr;, more typically about 10 IU to about 300 IU of interferon-&agr;, in combination with a pharmaceutically acceptable carrier therefor. Dosage forms for treatment in accordance with this invention can be in solid, liquid, aerosol, ointment or cream formulation and are typically administered from one to four times daily until the xerotic condition being treated is alleviated. Chronic administration may be required for sustained benefit. Generally speaking, the dosage forms are administered in a disease state-dependent manner, including particularly administration topically, bucally/sublingually, by oral ingestion or by inhalation.


REFERENCES:
patent: 5863530 (1999-01-01), Gillies et al.
Li et al. The Journal of Immunology. vol. 157, No. 8, pp. 3216-3219. Oct. 1996.*
Ferraccioli et al. Clinical Exp. Rhheumatology (Italy). vol. 14 No. 4, pp. 367-371, (1996).*
“Localization and expression of AQP5 in cornea, serous salivary glands, and pulmonary epithelial cells,” H. Funaki, et al., The American Physiological Society, 0363-6143/98, C1151-C1157 (1998).
“Aquaporins in complex tissues. I. Development patterns in respiratory and glandular tissues of rat,” L. King et al., The American Physiological Society, 0363-6143/97, C1541-C1548 (1997).
“Aquaporins in complex tissues. II. Subcellular distribution in respiratory and glansnular tissues of rat,” L. King et al., The American Physiological Society, 0363-6143/97, C1549-C1561 (1997).
“Genetics of airway responsiveness in the inbred mouse,” G. De Sanctis, et al., PubMed Abstract, PMID 9176291.

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