Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues
Reexamination Certificate
1998-05-27
2001-05-22
Houtteman, Scott W. (Department: 1656)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
C530S387900
Reexamination Certificate
active
06235879
ABSTRACT:
BACKGROUND OF THE INVENTION
This application relates to a family of apoptosis modulators that interact with the Huntington's Disease gene product, and to methods and compositions relating thereto.
“Interacting proteins” are proteins which associate in vivo to form specific complexes. Non-covalent bonds, including hydrogen bonds, hydrophobic interactions and other molecular associations form between the proteins when two protein surfaces are matched or have affinity for each other. This affinity or match is required for the recognition of the two proteins, and the formation of an interaction. Protein-protein interactions are involved in the assembly of enzyme subunits; in antigen-antibody reactions; in forming the supramolecular structures of ribosomes, filaments, and viruses; in transport; and in the interaction of receptors on a cell with growth factors and hormones.
Huntington's disease is an adult onset disorder characterized by selective neuronal loss in discrete regions of the brain and spinal chord that lead to progressive movement disorder, personality change and intellectual decline. From onset, which generally occurs around age 40, the disease progresses with worsening symptoms, ending in death approximately 18 years after onset.
The biochemical cause of Huntington's disease is unclear. While the biochemical cause of Huntington's disease has remained elusive, a mutation in a gene within chromosome 4p16.3 subband has been identified and linked to the disease. This gene, referred to as the Huntington's Disease or HD gene, contains two repeat regions, a CAG repeat region and a CCG repeat region. Testing of Huntington's disease patients has shown that the CAG region is highly polymorphic, and that the number of CAG repeat units in the CAG repeat region is a very reliable indicator of having inherited the gene for Huntington's disease. Thus, in control individuals and in most individuals suffering from neuropsychiatric disorders other than Huntington's disease, the number of CAG repeats is between 9 and 35, while in individuals suffering from Huntington's disease the number of CAG repeats is expanded and is 36 or greater.
To date, no differences have been observed at either the total RNA, mRNA or protein levels between normal and HD-affected individuals. Thus, the function of the HD protein and its role in the pathogenesis of Huntington's Disease remain to be elucidated.
SUMMARY OF THE INVENTION
We have now identified a protein designated as HIP1, that interact differently with the gene product of a normal (16 CAG repeat) and an expanded (>44 CAG repeat) HD gene. The HIP1 protein originally isolated from a yeast two-hybrid screen is encoded by a 1.2 kb cDNA (Seq. ID. No. 1), devoid of stop codons, that is expressed as a 400 amino acid polypeptide (Seq. ID. No. 2). Subsequent study has elucidated additional sequence for HIP1 such that a 1090 amino acid protein is now known. (Seq. ID No. 5). Expression of the HIP1 protein was found to be enriched in the brain.
Analysis of the sequence of the HIP1 protein indicated that it includes a death effector domain (DED), suggesting an apoptotic function. Thus, it appears that a normal function of huntingtin may be to bind HIP1 and related apoptosis modulators, reducing its effectiveness in stimulating cell death. Since expanded huntingtin performs this function less well, there is an increase in HIP1-modulated cell death in individuals with an expanded repeat in the HD gene. Furthermore, additional members of the same family of proteins have been identified which also contain a DED. Thus, the present invention provides a new class of apoptotic modulators which are referred to as HIP-apoptosis modulating proteins.
This understanding of the likely role of huntingtin and HIP1 or related proteins in the pathology of Huntington's Disease offers several possibilities for therapy. First, because the function of huntingtin apparently depends at least in part on the ability to interact with HIP-apoptosis modulating proteins, added expression (e.g., via gene therapy) of normal (non-expanded) huntingtin or of the HIP-binding region of huntingtin should provide a therapeutic benefit. Other DED-interacting peptides could also be used to mask and reduce the interaction of HIP-apoptosis modulating proteins with the death signaling complex. Alternatively, a mutant form of HIP-protein from which the DED has been deleted might be introduced, for example using gene therapy techniques. Because HIP-apoptosis modulating proteins have been shown to self-associate, a protein with a deleted DED may compete with endogenous HIP-protein in the formation of these associations, thereby reducing the amount of apoptotically-active HIP-protein.
REFERENCES:
Wanker et al., HIP-I: A Huntingtin Interacting Protein Isolated by the Yeast Two-hybrid System. Human Molecular Genetics, Mar. 1997, vol. 6, No. 3, pp. 487-495, see entire document.
Chopra Vikramjit S.
Goldberg Paul
Hackam Abigail
Hayden Michael R.
Kalchman Michael
Houtteman Scott W.
Oppedahl & Larson LLP
University of British Columbia
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