Novel Efficient Cell-Penetrating, Peptide-Mediated Strategy for Enhancing Telomerase Inhibitor Oligonucleotides

[Fishermangents]

(thanks to hiprock)

Novel Efficient Cell-Penetrating, Peptide-Mediated Strategy for Enhancing Telomerase Inhibitor Oligonucleotides.
A. Muñoz-Alarcón, J. Eriksson (Department of Neurochemistry, Stockholm University , Stockholm, Sweden)
Ü. Langel (Laboratory of Molecular Biotechnology, Institute of Technology, University of Tartu , Tartu, Estonia)

Abstract
At present, there are several therapeutic approaches for targeting telomerase in tumors. One in particular, currently undergoing clinical trials, is based on synthetic lipid-modified oligonucleotide antagonists aimed at inhibiting the ribonucleoprotein subunit of human telomerase. However, while enabling efficient uptake, the lipid modifications reduce the potency of the therapeutic oligonucleotides compared to nonmodified oligonucleotides. Moreover, lipid modification may increase oligonucleotide accumulation in the liver causing undesirable hepatotoxicity. Noncovalent complexation strategies for cell-penetrating peptide (CPP)-mediated delivery present an option to circumvent the need for potency-reducing modifications, while allowing for a highly efficient uptake, and could significantly improve the efficiency of telomerase-targeting cancer therapeutics. Delivery of a nonlipidated locked nucleic acid/2'-O-methyl mixmer significantly inhibits the telomerase activity in treated HeLa cells. The inhibitory effect was further improved through addition of a CPP. Furthermore, calculated IC50-values for the oligonucleotide delivered by CPPs into HeLa cells are more than 20 times lower than telomerase inhibitor Imetelstat, currently undergoing clinical trials. These results emphasize the potential of CPP-mediated delivery of future pharmaceuticals and provide means by which to enhance an already promising therapeutic strategy for cancer treatment.

link: http://www.ncbi.nlm.nih.gov/pubmed/26479411
(also on imetelstat.info)

Any comments on what this could mean for imetelstat? Potential improvement? A competing approach? Would it fall under the Geron patents?

[scottmayhew]

Novel Efficient Cell-Penetrating, Peptide-Mediated Strategy for Enhancing Telomerase Inhibitor Oligonucleotides

Key word "strategy" ...could this strategy be used to make Imetelstat stronger?

[biopearl]

<<These results emphasize the potential of CPP-mediated delivery of future pharmaceuticals and provide means by which to enhance an already promising therapeutic strategy for cancer treatment.>>

I read this as a direct reference to enhancing imetelstat. I was surprised to read that the lipid tail reduces intracellular efficacy, I didn't know that bp

[Fishermangents]

This Muñoz-Alarcón is an expert in this area. He has some other interesting papers on this subject if you look him up.

[hiprock88]

biopearl: I read this as a direct reference to enhancing imetelstat.

I didn't read it that way. I think the author's statement is a reference to enhancing telomerase inhibition in general. In his paper, part IV, he discusses Imetelstat and the desire to test it against his inhibitor. (This paper is beautifully written and very current. It's available free online, just requires a little bit of searching.)

Janssen must be aware of this paper, and others. Seems logical they would be working feverishly on Imetelstat "2.0". I admit the more I study this drug, with my outdated knowledge of Cell Biology, the less I understand. I'm glad Dr. Scarlett licensed this technology to Janssen as it really does require cutting edge resources.

Anyone here with good understanding of Geron's patents and some insight as to how they may be used in the future?

Many thanks to all the great posts by Fisher, Bio, Scott, Phil, Irish, etc.

[Fishermangents]

Hip, can you post the link to the article? If I search it I run into membership based downloads.

Wasn't there a guy on SA who was strong into the patents? Maybe we should invite him to come over.

[hiprock88]

Fisher, If you go to diva-portal.org and search using the title of abstract you will be able to download the entire paper.

I think hoosierinvestor was one of the patent experts.

[Fishermangents]

Thanks for the link.

Hoosier is member here. Let's hope he reads this and that he can comment.

[biopearl]

Hoosier has been and insightful and highly contributory poster in the past. He undoubtedly got fed up with YMB. I hope he will share his knowledge and insights here (where they belong--thank you Fish). bp