Massachusetts Institute of Technology

Variagenics, Inc.

University of Wales College of Medicine

The General Hospital Corporation

K.o. Technology, Inc.

David E Housman

Daniel Arie Haber

Aleksey G Kazantsev

Alan J Buckler

Katherine M Call

Elise A Rose

Jerry M Pelletier

Caryn Y Ito

Thomas M Glaser

Duncan J Shaw

Andre Darveau

J David Brook

Wendy Bruening

Elizabeth A Preisinger

Keith J Johnson

Helen G Harley

Vincent P Stanton, Jr

James F Gusella

Philippe Gros

Fred David Ledley

Ann M Graybiel

Theodore T Puck

James M Croop

Barbara Jordan

John Landers

Carol Jones

Hiroaki Kawasaki

Alain Charest

Cheryl Keys

Wendy Breuning

Aviva Varsanyi-Breiner

Anne B Young

Thomas J Hudson

Fa-Ten Kao

Martin Schalling

David J Munroe

Steven Hersch

André Darveau

The present invention is based, in part, on assays we conducted that revealed compounds that may be used to treat or prevent diseases characterized by an abnormal or undesirable association of one protein with another.

Compositions and methods for modulating interaction between polypeptides

Methods of identifying compounds that disrupt aggregation of aggregation-disposed polypeptides, such as huntingtin or beta-amyloid protein, are disclosed. Furthermore, an artificial polypeptide that contains an extended polyglutamine region and DNA that encodes the polypeptide are also disclosed.

Nucleic acids encoding a polyglutamine fusion protein

The present invention is based, in part, on the discovery of methods for identifying compounds that mediate (by promoting or inhibiting) protein-protein interaction (e.g., aggregation, dimerization, or other physiologically significant association). Compounds that mediate such interaction, which are also within the scope of the invention, can be used to treat Alzheimer's disease, disorders associated with expanded CAG repeats (such as Huntington's disease), and disorders in which polyglutamine-containing transcription factors or coactivators are undesirably active (e.g., disorders associated with homodimerization of jun or hexamerization of p53.

Methods of identifying agents that mediate polypeptide aggregation

The present invention describes the identification, isolation, sequencing and characterization of two human CalDAG-GEF, and two human cAMP-GEF genes, which are associated with the Ras pathway. Also identified are CalDAG-GEF gene homologues in mice and cAMP-GEF gene homologues in rats. Nucleic acids and proteins comprising or derived from the CalDAG-GEFs and/or cAMP-GEFs are useful in screening and diagnosing certain Ras-associated cancers, in identifying and developing therapeutics for treatment of certain Ras-associated cancers, and in producing cell lines and transgenic animals useful as models of Ras-associated cancers.

Genes integrating signal transduction pathways

The Wilms' tumor gene associated with 11p3 locus on the human chromosome, as well as a method of analyzing cells for the gene is described and characterized. The gene encodes a transcription unit approximately 50 kb in size and a mRNA of approximately 3 kb, which is expressed in predominantly in kidney and gonadal tissue. The gene is alternative spliced producing four very similar mRNA transcripts. The polypeptides encoded by the Wilms' tumor DNA includes four 'zinc fingers' and a region rich in proline and glutamine, suggesting that the polypeptide has a role in transcription regulation.

Localization and characterization of the Wilms' tumor gene

The invention encompasses methods and products related to genotyping. The method of genotyping of the invention is based on the use of single nucleotide polymorphisms (SNPs) to perform high throughput genome scans. The high throughput method can be performed by hybridizing SNP allele-specific oligonucleotides and a reduced complexity genome (RCG). The invention also relates to methods of preparing the SNP specific oligonucleotides and RCGs, methods of fingerprinting, determining allele frequency for a SNP, characterizing tumors, generating a genomic classification code for a genome, identifying previously unknown SNPs, and related compositions and kits.

Methods and products related to genotyping and DNA analysis

Methods of screening for agents that inhibit aggregation of polypeptides

The Wilms' tumor gene associated with 11p3 locus on the human chromosome, as well as a method of analyzing cells for the gene is described and characterized. The gene encodes a transcription unit approximately 50 kb in size and a mRNA of approximately 3 kb, which is expressed in predominantly in kidney and gonadal tissue. The gene is alternative spliced producing four very similar mRNA transcripts. The polypeptides encoded by the Wilms' tumor DNA includes four &ldquo;zinc fingers&rdquo; and a region rich in proline and glutamine, suggesting that the polypeptide has a role in transcription regulation.

Disclosed are methods for the treatment of proliferative disorders using compounds and/or environmental conditions which result in a difference in sensitivity of targeted and non-targeted cells. Certain of the methods involve the identification and use of allele-specific inhibitors of conditionally essential genes.

Inhibitors of alternative alleles of genes encoding products that mediate cell response to environmental changes

This invention is directed to a therapeutic strategy involving (1) identification of alternative alleles of genes coding for protein vital for cell viability or cell growth and the loss of one of those alleles in cancer cells due to loss of heterozygosity (LOH) and (2) the development of inhibitors with high specificity for the single remaining alternative allele of the vital gene retained by the cancer cell after LOH. The inhibitors of this invention are specific for one alternative allele of a gene that codes for a protein vital to cell viability or cell growth. The targeted gene has two alternative alleles in which the inhibitors of this invention blocks only one of the two alternative alleles, still present in the cancer cells. Exposure to the inhibitor inhibits or kills cancer cells which have undergone LOH. Protein is still capable of being expressed in the normal cells exposed to the inhibitor by the unblocked alternative allele. This differential effect of the inhibitor on cancer cells and normal cells accounts for the high therapeutic index of the inhibitors of this invention when used as antineoplastic agents.

Inhibitors of alternative alleles of genes as a basis for cancer

A nucleotide sequence, specifically a CTG triplet repeat, is shown to be expanded in individuals affected with myotonic dystrophy and can be identified in a sample obtained from an individual. Individuals in whom the CTG triplet repeat is present in normal copy number are likely to be minimally affected and individuals in whom the CTG triplet repeat occurs in abnormally high copy number are likely to be more severely affected.

DNA sequence encoding the myotonic dystrophy gene and uses thereof

A method by which a nucleotide sequence, specifically a CTG triplet repeat, shown to be expanded in individuals affected with myotonic dystrophy can be identified in a sample obtained from an individual. The present method can be used to identify individuals in whom the CTG triplet repeat is present in normal copy number and individuals in whom the CTG triplet repeat occurs in abnormally high copy number, as well as to further identify individuals likely to be minimally affected and individuals likely to be more severely affected.

Methods of detecting expanded nucleotide repeats in genomic DNA in a biological sample are disclosed and methods for the diagnosis of pathological and potentially pathological conditions in an individual based on the detection of the presence of expanded nucleotide repeats.

Direct detection of expanded nucleotide repeats in the human genome

Growing community of inventors

Newton, MA, United States of America

David E Housman