[Modulation of Hsp90 function in neurodegenerative disorders: a molecular-targeted therapy against disease-causing protein.]
>>J Mol Med. 2006 Jun 2; [Epub ahead of print]
Modulation of Hsp90 function in neurodegenerative disorders: a molecular-targeted therapy against disease-causing protein.
Waza M, Adachi H, Katsuno M, Minamiyama M, Tanaka F, Doyu M, Sobue G.
Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, 466-8550, Nagoya, Japan, sobueg@med.nagoya-u.ac.jp.
Abnormal accumulation of disease-causing protein is a commonly observed characteristic in chronic neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and polyglutamine (polyQ) diseases. A therapeutic approach that could selectively eliminate would be a promising remedy for neurodegenerative disorders. Spinal and bulbar muscular atrophy (SBMA), one of the polyQ diseases, is a late-onset motor neuron disease characterized by proximal muscle atrophy, weakness, contraction fasciculations, and bulbar involvement. The pathogenic gene product is polyQ-expanded androgen receptor (AR), which belongs to the heat shock protein (Hsp) 90 client protein family. 17-Allylamino-17-demethoxygeldanamycin (17-AAG), a novel Hsp90 inhibitor, is a new derivative of geldanamycin that shares its important biological activities but shows less toxicity. 17-AAG is now in phase II clinical trials as a potential anti-cancer agent because of its ability to selectively degrade several oncoproteins. We have recently demonstrated the efficacy and safety of 17-AAG in a mouse model of SBMA. The administration of 17-AAG significantly ameliorated polyQ-mediated motor neuron degeneration by reducing the total amount of mutant AR. 17-AAG accomplished the preferential reduction of mutant AR mainly through Hsp90 chaperone complex formation and subsequent proteasome-dependent degradation. 17-AAG induced Hsp70 and Hsp40 in vivo as previously reported; however, its ability to induce HSPs was limited, suggesting that the HSP induction might support the degradation of mutant protein. The ability of 17-AAG to preferentially degrade mutant protein would be directly applicable to SBMA and other neurodegenerative diseases in which the disease-causing proteins also belong to the Hsp90 client protein family. Our proposed therapeutic approach, modulation of Hsp90 function by 17-AAG treatment, has emerged as a candidate for molecular-targeted therapies for neurodegenerative diseases. This review will consider our research findings and discuss the possibility of a clinical application of 17-AAG to SBMA and other neurodegenerative diseases.<<
From the latest 10-K:
>>Under a November 2002 license agreement with the NIH, we obtained exclusive commercial rights under patent rights relating to the geldanamycin analogs being developed under the CRADAs. Initially, our license was limited to specified medical fields of use, including the treatment of cancer, and the prevention of undesired cell growth or its deleterious effects, such as the prevention of restenosis and neurodegenerative diseases. In May 2005, we amended the license to include several additional fields of use. We have paid the NIH an up-front fee and will owe annual minimum royalties, patent fees, royalties based on net sales of licensed products, milestone payments if clinical development milestones are reached and a portion of any sublicensing revenues. Our license could terminate if we are not diligent in developing licensed products or otherwise default in performing our material obligations under the agreement and fail to cure the deficiency. We may terminate the agreement on a country-by-country basis. The agreement contains standard NIH licensing terms. Unless the agreement is earlier terminated, our license will remain in effect for the life of the licensed patents. <<
OK, so does Kosan own the commercial rights to the neurodegenerative indications of geldanamycin? It would appear so, and if so, how long have we known that? Speaking personally, I hadn't noticed potential for geldanamycin in neurodegenerative indications until seeing this paper. How long have we known about geldanamycin's potential in neuro? As far as I can tell, less than a year. Publications started coming out, mostly from this group, last fall.
Message 21699077
But I don't see any relevant patents at all for those guys, while several Kosan patents & apps speak of treating "demyelinating neuropathies," but not in the claims. They are pretty recent, too, as in a few years old at most. For example:
appft1.uspto.gov
Cheers, Tuck |
