2.0?

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biopearl123
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Joined: Fri Jul 20, 2018 5:13 pm

2.0?

Post by biopearl123 » Tue Aug 31, 2021 2:53 am


rinconj
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Joined: Tue Jul 24, 2018 5:05 pm

Re: 2.0?

Post by rinconj » Sat Sep 04, 2021 4:53 pm

The authors are all affiliated with Oxford university and have nothing to do with Geron? How strong are Geron's patents?
If some other company developed a better telomerase inhibitors than Imetelstat, do they have to pay Geron?

LWS
Posts: 581
Joined: Thu Jul 14, 2016 2:00 am

Re: 2.0?

Post by LWS » Sat Sep 04, 2021 6:59 pm

Geron has concentrated on blood cancers, where they have had considerable successes. There were early attempts with some solid tumors that did not succeed. I believe that was in part due to the delivery system that this article addresses. IMET 2.0 will likely be about delivery systems, as well as alterative telomerase control.

biopearl123
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Joined: Fri Jul 20, 2018 5:13 pm

Re: 2.0?

Post by biopearl123 » Sat Sep 04, 2021 11:21 pm

Rinconj, you will notice that most of the preclinical work that pertains to the telomere is often done at institutions not directly associated with Geron. They may receive support but since this is such an active area of research, it s logical that many academic centers would be interested.

cheng_ho
Posts: 202
Joined: Sun Apr 03, 2016 11:27 pm

Re: 2.0?

Post by cheng_ho » Mon Sep 13, 2021 5:05 pm

rinconj, Geron was forced by the Janssen deal to shut down its lab... they don't have one.

Now, repackaging the old imet into a less obsolete form for oilgo delivery is easy... but then it would have to start approval all over.

There ARE many other companies using telomerase inhibitors, many combo trials use azacitidine from the 1990s. CNST and ARGX, e.g.

And MAIA Biotechnology has a trial of Dr. Shay's favorite telomerase inhibitor, 6-thio-dG, in combo with a Regeneron antibody in Australia:

https://www.businesswire.com/news/home/ ... 005869/en/

huntingonthebluffs
Posts: 246
Joined: Wed Feb 24, 2016 12:00 am

Re: 2.0?

Post by huntingonthebluffs » Sat Sep 25, 2021 7:28 pm

Interesting post as always biopearl123! Given the title “Oligonucleotide-Functionalized Gold Nanoparticles for Synchronous Telomerase Inhibition, Radiosensitization, and Delivery of Theranostic Radionuclides” gives us neophytes pause as usual.

But after having sloshed around in this article and related for a while it seems “we” have been involved in this type of research for a long time, certainly over a decade. The knowledge and capabilities have and continue to expand significantly. Given the level of sophistication of the human cell structure is staggering, the effort/approaches studied to deliver existing and new novel drugs to target areas are equally as staggering. Most of the detail is out of my reach, so I mostly try to stay with the abstracts, introductions and conclusions/recommendations.

The study, is in part, about linking a radio active component such as indium-111 (a radioactive chemical) to a cell-targeting molecule. And “One of the most promising therapeutic approaches is the use of anti-hTR oligonucleotides that bind the RNA template and thus act as catalytic inhibitors of telomerase.” Of which I believe Imetelstat qualifies and is the farthest down the road towards approval. This study also in part notes that linking a radionuclide would then make Imetelstat a tumor seeking missile. This missile softens up the tumors defenses and the radiation or chemo riding along in the package can accelerate the destruction of the cancerous tumor cells. Separately, radiation and chemo could also accompany the treatment regimen when/if deemed appropriate. Of course, regardless of how promising it still must go through the regulators requirement for multiple CTs.

I think this excerpt shows promise and can speed the cycle up somewhat but still…. “several studies have shown that the use of oligonucleotide template inhibitors causes cancer cell sensitization to radiotherapy and chemotherapy as a result of telomere length-dependent and telomere length-independent mechanisms.(14−20) To exploit this radiosensitizing effect, an oligonucleotide hTR inhibitor was conjugated to indium-111 (111In) for concomitant telomerase inhibition and targeted radionuclide therapy (TRT).(21)111In emits Auger electrons that cause dense ionizations over a short range (nm to μm), thus allowing for irradiation of individual cells and sparing of non-targeted tissue.(22,23) This 111In-labeled hTR-targeted oligonucleotide construct causes sequence- and telomerase-dependent DNA damage and cell-killing effects in cancer cells.(21) However, the use of oligonucleotides as anticancer agents is hampered by poor cellular uptake and unfavorable pharmacokinetics. There is therefore an impetus in the field of DNA therapeutics to devise new oligonucleotide delivery methods that can overcome this barrier to the clinic.(24)”

The bottom-line for me was in these excerpts:
“Nanosized drug carriers provide a platform for target-specific delivery.(25) In particular, gold nanoparticles (AuNPs) exploit unique physicochemical properties that can augment intra-cellular uptake of oligonucleotides.”

“In-labeled anti-hTR oligonucleotide- and Tat-functionalized AuNP constructs have a telomerase-dependent cell-killing effect, thereby providing a new avenue for the treatment of telomerase-positive cancers. Fyi, Tat stands for "Trans-Activator of Transcription" and Transcription is the process of copying a segment of DNA into RNA.
And, for example, gold nano particles (AnNP) could be loaded up and tuned to whatever components the target tumor was most sensitive to and would most effectively disarm and kill the tumor cells along with Imetelstat or whatever oligonucleotide template inhibitors are used. Also, the uptake of oligonucleotides was markedly improved by linking them to AuNPs"

“o assess the cellular uptake of AuNP constructs, a 24 h internalization assay was performed in telomerase-positive MDA-MB-435 cells, and the uptake was measured and calculated as a percentage of the total amount of the added radioactivity (Figure 2A). The uptake of oligonucleotides was markedly improved by linking them to AuNPs.”

If interested I also found this excerpt helpful:

https://pubmed.ncbi.nlm.nih.gov/24059327/

“Radionuclide therapy (RNT) based on the concept of delivering cytotoxic levels of radiation to disease sites is one of the rapidly growing fields of nuclear medicine. Unlike conventional external beam therapy, RNT targets diseases at the cellular level rather than on a gross anatomical level. This concept is a blend of a tracer moiety that mediates a site specific accumulation followed by induction of cytotoxicity with the short-range biological effectiveness of particulate radiations. Knowledge of the biochemical reactions taking place at cellular levels has stimulated the development of sophisticated molecular carriers, catalyzing a shift towards using more specific targeting radiolabelled agents. There is also improved understanding of factors of importance for choice of appropriate radionuclides based on availability, the types of emissions, linear energy transfer (LET), and physical half-life. This article discusses the applications of radionuclide therapy for treatment of cancer as well as other diseases. The primary objective of this review is to provide an overview on the role of radionuclide therapy in the treatment of different diseases such as polycythaemia, thyroid malignancies, metastatic bone pain, radiation synovectomy, hepatocellular carcinoma (HCC), neuroendocrine tumors (NETs), non-Hodgkin's lymphoma (NHL) and others. In addition, recent developments on the systematic approach in designing treatment regimens as well as recent progress, challenges and future perspectives are discussed. An examination of the progress of radionuclide therapy indicates that although a rapid stride has been made for treating hematological tumors, the development for treating solid tumors has, so far, been limited. However, the emergence of novel tumor-specific targeting agents coupled with successful characterization of new target structures would be expected to pave the way for future treatment for such tumors.”

While I am hopeful, I have to wonder how valuable radionuclide therapy is as a component of the delivery vehicle for Imetelstat when treating hematological cancers. Certainly it would speed up the delivery of multiple cytotoxic components to the cancerous cells so that the action of killing the cells is faster but doesn’t that present the danger of increasing cytopenias beyond the tolerable or even recoverable level? I suppose there are antidotes for that as well as dose specific aspects but seems they have to be extremely careful here with sick old people to not completely tip the cart over (again using my extremely technical terminology). Again we are probably talking years of research in the making and years left to see the light of day via the CT cycle. Certainly it is important to be thinking and planning on the future enhancements and approaches, I don’t think Dr. Scarlett will lose his laser focus on getting Imetelstat flawlessly through the Phase 3s and commercialized but I’m sure he has the plans and roadmap beyond Imetelstat 1.0 well in hand.

All in all, this has been a very interesting line of thought that us Geronites will want to keep an eye on and pay close attention to any details from the November Investor Conference that can further explain Geron’s future plans.

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