Harvard College

The Endowment for Research in Human Biology, Inc.

Bert L Vallee

James W Fett

Wing-Ming Keung

Kotoku Kurachi

Robert Shapiro

Edward M Alderman

Wing Ming Keung

Thomas V King

Michael D Bond

Louis G Lange, Iii

Jeffrey Wade Harper

Guangyao Gao

Guo-fu Hu

Aniello Russo

The present invention provides novel antidipsotropic compounds. The invention further provides methods of inhibiting ALDH-2 using the compounds described herein. Methods for modulating alcohol consumption, alcohol dependence and/or alcohol abuse by administering the compounds of the invention to an individual are also provided. The present invention further provides a rationale for designing additional novel antidipsotropic compounds.

Compounds useful for the inhibition of ALDH

The present invention is directed to using neomycin or an analogue thereof as an therapeutic agent to treat angiogenesis-related diseases, which are characterized by excessive, undesired or inappropriate angiogenesis or proliferation of endothelial cells. The present invention is also directed to pharmaceutical compositions comprising (a) neomycin or an analogue and, optionally, (b) another anti-angiogenic agent or an anti-neoplastic agent. The present invention is further directed to a method for screening neomycin analogues having anti-angiogenic activity. A preferred embodiment of the invention relates to using neomycin to treat subjects having such diseases.

Use of neomycin for treating angiogenesis-related diseases

Methods and compounds for inhibiting aldehyde dehydrogenase are disclosed. The compounds are useful as pharmaceutical compositions in methods for therapeutically treating alcohol consumption in a human.

Method for the inhibition of ALDH-I useful in the treatment of alcohol dependence or alcohol abuse

A method for the treatment of alcohol abuse using daidzin and compounds analogous to daidzin is disclosed. Also disclosed is a method for screening compounds having antidipsotropic activity.

Methods and assays useful in the treatment of alcohol dependence or

Method for the inhibition of ALDH-I useful in the treatment of alcohol

A method of inhibiting ribonucleases is disclosed wherein a nucleotide compound having a diphosphate group contacts a ribonuclease so as to inhibit the ribonuclease from effectively catalyzing the depolymerization of ribonucleic acid. Novel compounds useful in the method are also disclosed.

Method and compounds for inhibition of ribonucleases

This invention relates to the production of antibodies to angiogenin or to fragments thereof and to methods of inhibiting angiogenesis in mammals by administering to mammals such antibodies or Fab or F(ab').sub.2 fragments thereof so as to inhibit angiogenic activity. In addition, this invention relates to pharmaceutical compositions comprising therapeutically effective amounts of antibody that are immunologically reactive with angiogenin and which can be administered to inhibit angiogenesis.

Antibodies to angiogenin: immunotherapeutic agents

Regional mutagenesis of a gene for angiogenin to produce DNA sequences encoding mutant proteins having increased angiogenic activity are disclosed. Expression vectors containing these sequences are introduced into host cells and direct the production of mutant angiogenic proteins with markedly increased angiogenic activity. Replacement of amino acids in a region at or corresponding to residues 8-22 of angiogenin, with other amino acids, in particular, with amino acids corresponding to residues 7-21 of RNase, unexpectedly yields a mutant angiogenin/RNase hybrid protein with 10-fold increased angiogenic potency in the chorioallantoic membrane assay. Other in vivo and in vitro angiogenin-related activities are altered in the mutant hybrid protein. Mutant angiogenin/RNase hybrid proteins according to the present invention are useful therapeutic compositions to promote the development of a hemovascular network in a mammal or to promote wound healing, in particular, healing of torn or traumatized fibrocartilage material.

Covalent angiogenin/RNase hybrids

An inhibitor of angiogenin and method of use of the inhibitor, wherein the inhibitor inhibits the angiogenic activity of angiogenin. The inhibitor is dispensed at a suitable concentration within a physiologically compatable medium, suitable for administration to an animal in sufficient quantity to inhibit the biological activity of naturally occurring angiogenin within the animal.

Inhibitors of angiogenin

Method for inhibiting aldehyde dehydrogenase activity using daidzin as a selective inhibitor of ALDH-I activity. Because daidzin is a potent selective, yet reversible, inhibitor of ALDH-I activity, it is useful as a pharmaceutical composition in methods for the treatment of alcohol dependence (i.e., alcoholism) or alcohol abuse, for alcohol sensitization, for extinguishing an alcohol-drinking response, for suppressing an urge for alcohol, for inducing alcohol intolerance, for preventing alcoholism in an individual with or without a susceptibility or predisposition to alcoholism or alcohol abuse, and for limiting alcohol consumption in an individual whether or not genetically predisposed.

The present invention provides fluorescence-based methods for sensitively detecting total ADH activity in human sera and selectively measuring the activity of different classes of ADH in human sera and other body fluids and tissues. The present invention also provides highly purified Class I, Class II, and Class III isozymes, and methods for their purifiation. The class of substrates consisting of various naphthaldehydes and quinoline aldehydes provide the requisite sensitivity and selectivity for measurements of the activity of ADH and individual ADH classes. These fluorescence-based methods may serve as a diagnostic aid in disease assessment, in particular, diagnosis of alcohol abuse, alcoholism, alcohol consumption, altered alcohol sensitivity or tolerance.

Methods of measuring isozymes and isozyme classes of alcohol

DNA sequences encoding a protein having angiogenic activity and mutated DNA sequences encoding a protein having decreased angiogenic activity are disclosed. Expression vectors containing these wild-type or mutated sequences are introduced into host cells and direct the production of wild-type or mutant angiogenic proteins. Proteins produced according to the invention are useful in the diagnosis of malignancies, for promoting wound healing, and for other diagnostic and therapeutic purposes. Mutant proteins produced according to the invention are useful therapeutic compositions as angiogensis inhibitors, which may retard tumor growth by inhibiting the development of a hemovascular network.

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Brookline, MA, United States of America

Bert L Vallee