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Methods for treatment of conditions associated with lactosylceramide
| Details |
Inventors: Chatterjee, Subroto;
Assignee: Johns Hopkins University (Baltimore, MD)
Primary Examiner: Higel; Floyd D.
Assistant Examiner: Sackey; Ebenezer
Attorney, Agent or Firm: Corless; Peter F., Schray; Kerri Pollard, Buchanan; Robert L.
The present invention includes methods for treatment and prophylaxis of diseases, post-surgical disorders and bacterial infections associated with lactosylceramide. The methods generally provide for administration for a mammal, particularly a human, of a therapeutically effective amount of a compound that inhibits UDPGal:GlcCer.beta.1->4 galactosylceramide (GalT-2). In vitro and in vivo assays for detecting compounds with therapeutic capacity to modulate GalT-2 are also provided. |
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DETAILED DESCRIPTION We have now discovered therapies to treat or prevent various diseases, post-surgical disorders and bacterial infections modulated by lactosylceramide (LacCer).
In particular, we have discovered therapies that include altering activity of UDP-galactose, GlcCer, .
beta.
1->4 galactosyl-transferase (GalT-2).
More specifically, the invention provides methods for treatment of proliferative disorders such as vasculopathies, e.
g.
atherosclerosis and restenosis; pathologies involving neovascularization; tumor or cyst development, e.
g.
, polycystic kidney disease and post-surgical keloid formation; inflammatory diseases involving a proinflammatory cytokine such as TNF-.
alpha.
or interleukin-6; and lipid storage diseases such as Gaucher's disease.
Therapies of the invention are particularly effective for the treatment and prevention of undesired vascular restenoses.
In one protocol of the invention, a near absence of intimal proliferation was observed at the site of balloon angioplasty in the test subject (rabbit), whereas a control subject exhibited significant intimal proliferation.
See the results set forth in the examples which follow.
LacCer-modulated diseases that can be treated in accordance with the invention also include lipid storage diseases (i.
e.
glycospingolipodoses) such as Gaucher's disease, cholesterol storage disease and the like.
Additional disorders that can be treated in accordance with the invention include bacterial infections, particularly those infections involving production of a toxin, such as an exotoxin that can specifically bind LaCer, e.
g.
Neisseria gonorrhoeae.
See Paruchuri, D.
K.
et al.
(1990) Proc.
Natl.
Acad.
Sci.
(USA), 87:333-337.
Therapeutic methods of the invention in general comprise administering to a subject, particularly a mammal such as a primate, especially a human, a therapeutically effective amount of a compound that can inhibit GalT-2 activity.
Preferably, an administered compound inhibits cell proliferation by at least about 15% or 25% in a standard in vitro cell proliferation assay
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