ED11 inhibitor of Caspase 6 for the treatment of HD
Innovative Products and Technologies
Technology Offer
ED11 inhibitor of Caspase 6 for the treatment of HD
- RAMOT at Tel Aviv University Ltd.
- From Israel
- Responsive
- Innovative Products and Technologies
Summary of the technology
A novel Huntingtin based peptide inhibits caspase-6 and protects cells from Huntington’s disease related toxicity.
Aharony I, Offen D.
Neuroscience Laboratory, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University
Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disease. It is characterized by the progressive deterioration of cognitive and motor functions, with a fatal outcome after approximately 10-15 years of onset. The precise pathogenic mechanism of mutant Huntingtin is unknown. However, previous studies indicate that the pro apoptotic enzyme caspase-6 has a key role in the apoptotic events seen in HD, as it is activated early in the disease process, inducing different cellular dysfunctions. Importantly, proteolysis of mutant huntingtin at the caspase-6 site is known to be an essential process in generating toxic N-terminal fragments, which leads to neurodegeneration and appearance of disease symptoms. Therefore, inhibiting caspase-6 activity was suggested as a promising therapeutic target for reducing mutant huntingtin toxicity, and rescuing neuronal cells from degeneration.
In aim to inhibit the caspase-6 activity, we constructed a huntingtin cleavage site based peptide fused with a cell penetrating peptide. The peptide, designated ED11, significantly reduced caspase-6 activity as indicated by caspase-6 activity assay in a cell free system. Moreover, in neuronal cells ED11 inhibited caspase-6 activity, and protected the cells from glutamate toxicity, an important factor in the pathogenesis of HD. Furthermore, in PC12 cells, expressing mutant huntingtin, ED11 markedly reduced the serum deprivation induced toxicity, compared to wild-type PC12 cells.
Thus, we propose ED11 as a specific caspase-6 inhibitor which might be used as a neuroprotectant in Huntington's disease, and may aid in other neurological disorders involving caspase-6 activity.
Project ID : 10-2013-431
Details of the Technology Offer
ED11 inhibitor of Caspase 6 for the treatment of HD
Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disease. It is characterized by a progressive deterioration of cognitive and motor functions, with a fatal outcome after approximately 10-15 years of onset. The precise pathogenic mechanism of mutant Huntingtin (mHtt) is unknown. However, it was shown that caspase-6 has a key role in the apoptotic events seen in HD, as it is activated early in the disease progress, inducing cellular dysfunction. Importantly, proteolysis of mHtt at the caspase-6 cleavage site enables the generation of toxic N-terminal fragments, which leads to neurodegeneration and appearance of disease symptoms.
In aim to inhibit caspase-6 activity, we designed a peptide based on Htt caspase-6 cleavage site fused with a cell penetrating peptide. The peptide, titled ED11, significantly reduced caspase-6 activity as indicated by a purified caspase-6 activity assay. In the current project, we aim to provide an evaluation of ED11 in-vivo. Our primary objective is to test whether ED11 is able to protect BACHD mice, a Huntington’s disease mouse model, from motor, behavioral and cognitive deficits. This research will hopefully lay the foundation for clinical trials, which may eventually lead to a novel treatment for Huntington’s disease and other pathologies that involving caspase-6 activity, such as Alzheimer’s disease and stroke.