Presentations on Geron's Telomerase Inhibitor at AACR Special Conference

In continuation of my update on Geron's Telomerase Inhibitor..... Geron Corporation, announced several presentations at the American Association for Cancer Research (AACR) Special Conference on The Role of Telomeres and Telomerase in Cancer Research held in Fort Worth, TX between February 27th and March 1st. The conference comprised ten scientific sessions with over fifty oral presentations.

Geron scientists and collaborators presented recent data on the company's telomerase inhibitor, imetelstat sodium (GRN163L), And highlighted the drug's activity against cancer stem cells. As per the claim by the CMO & EVP, Stephen M. Kelsey,   the telomerase inhibitor is showing anti-cancer stem cell activity in a range of preclinical models. In Phase II trials of imetelstat starting this year Greron is targeting malignancies that are thought to be driven, at least in part, by cancer stem cells ....

Ref: http://www.geron.com/media/pressview.aspx?id=1213

Geron publish data on the stem cell research.....

In my earlier blog (Geron plans to advance clinical program for spinal cord injury), I did mention about the clinical program. Now Geron has come up with positive results. As per the claim by the company oligodendrocyte progenitor cells (OPCs) derived from human embryonic stem cells (hESCs), when transplanted into a rodent model of cervical spinal cord injury, reduced tissue damage within the lesion and improved recovery of locomotor function. These data provide preclinical proof-of-concept for the use of GRNOPC1, Geron's hESC-derived oligodendrocyte progenitor product, in patients with cervical spinal cord injuries.

Oligodendrocytes have two main functions in the spinal cord; they produce the myelin that wraps around nerve fibers to enable electrical impulse conduction and they produce other molecules (neurotrophic factors) that help to maintain nerve cells. In spinal cord injury oligodendrocytes are lost, resulting in the loss of myelin and death of nerve cells that can cause paralysis below the injury. The present study, conducted in a cervical model of spinal cord injury, adds to previous work in a thoracic model, which has demonstrated that injection of hESC-derived OPCs into the site of injury improved locomotor function with evidence of remyelination of nerve fibers.

Source : http://www.geron.com/media/pressview.aspx?id=1196

Telomerase & Telomerase inhibition.......

When I read about the Nobel prize in Medicine, was really excited because the scientists who discovered the enzyme telomerase got the Nobel prize for the year 2009 and the reason for this is simple and obvious....

When I was working with my previous company (Innovasynth Technologies Limited, Khopoli), I had opportunity to learn lots of things (from Dr. Sergei Gryaznov of Geron Corporation) about the drugs with Telomerase inhibition activity. As for as my knowledge goes, there are many companies working on these class of compounds and hope in the days to come there will be many drugs from this class of compounds and antisense drugs.

About Telomerase :

Telomerase, is an enzyme that adds specific DNA sequence repeats to the 3' end of DNA strands in the telomerase regions, which are found at the ends of eukaryotic chromosomes. The telomeres contain condensed DNA material, giving stability to the chromosomes. The enzyme is a reverse transcriptase that carries its own RNA molecule. Though the existence of a compensatory shortening of telomere (telomerase) mechanism, was first predicted by Soviet biologist Alexey Olovnikov (1973), who also suggested the Telomere hypothesis of ageing and the Telomere relations to cancer. Carol Greider and Elizabeth Blackburn in 1985, discovered telomerase together with Jack Szostak. Greider and Blackburn have been awarded the Nobel Prize in Physiology or Medicine. Congrats for this remarkable achievement.


Telomerase inhibitors :

To safeguard against cancer, adult cells keep track of how many times that they have multiplied, and once they have reached a pre-set limit — often around 80 divisions — they die. Telomerase interferes with this record keeping. So if one can find a drug or gene therapy that interferes with telomerase, it could fight the unchecked growth of cancer cells. As per the claim by lead researcher (Mark Muller), 90% all cancer cells are telomerase rich. Geron corporation, is developing modified DNA molecule (for which Innovasynth, has tie up with Geron to provide the intermediate amidites). The oligonucleotides, which target the template region, or active site, of telomerase. Geron's work has focused oligonucleotides (GRN163 and GRN163L,) and as per the claim by the company, both of them have demonstrated highly potent telomerase inhibitory activity at very low concentrations in biochemical assays, various cellular systems and animal studies. Interestingly these compounds are direct enzyme inhibitors, not antisense compounds and smaller than typical antisense compounds or other oligonucleotide drug candidates. Both compounds use a special thiophosphoramidate chemical backbone and the company is hopeful of convincing clinical trial results. All the best...

Ref : 1. http://nobelprize.org/nobel_prizes/medicine/laureates/2009/press.html
2. http://www.geron.com/products/productinformation/cancerdrug.aspx

Geron plans to advance clinical program for spinal cord injury

In my earlier blog (Euphoria over Stem Cell Therapy.....) did mentioned that, there are many companies which falsely claimed that they have got technology (stem cell treatment) to treat spinal cord injury. But an established company like Geron, has plan to advance clinical development of its human embryonic stem cell (hESC)-based product, GRNOPC1, for the treatment of spinal cord injury. The plan is expected to enable Geron to re-initiate the Phase I clinical trial of GRNOPC1 in patients with complete thoracic spinal cord injury and to support future expansion of the trial to patients with cervical injuries.

I read earlier about the preclinical studies of GRNOPC1 and the company claimed that it is developing GRNOPC1 for spinal cord injury, but is also exploring application for other neurological diseases, including multiple sclerosis, stroke and Alzheimer disease really interesting to see the results.

As I had an opportunity to talk and work (contract research) with Geron [known for its first-in-class biopharmaceuticals (especially "antisense drugs" from oligonucleotides) for the treatment of cancer and chronic degenerative diseases] company, I know its credentials and am really excited to see some interesting out come from their advance clinical program. All the best....

Ref : http://www.geron.com/media/pressview.aspx?id=1195

Geron Initiates Phase 2 Trial of GRN1005 in Brain Metastases from Breast Cancer

In continuation of my update on Paclitaxel and drug discovery....

Geron Corporation, announced the initiation of GRABM-B (GRN1005 Against Brain Metastases - Breast Cancer), a Phase 2 clinical trial to evaluate GRN1005 in patients with brain metastases arising from breast cancer. GRN1005 is the company's lead LRP-directed peptide-drug conjugate (LRP-directed PDC) that consists of the cytotoxic drug, paclitaxel, linked to a peptide (Angiopep-2) that targets the LRP receptor to cross the blood-brain barrier (BBB) and to target tumors in the brain.

The purpose of the Phase 2 study is to assess the efficacy, safety and tolerability of GRN1005 in patients with brain metastases from breast cancer. The trial is designed to include 100 patients with HER2 positive or HER2 negative metastatic breast cancer (MBC) disease, who will be assessed in two separate cohorts of 50 patients each.....

More...

Ref : http://www.geron.com/media/pressview.aspx?id=1287

Enzyme telomerase activating compound discovered....

In continuation of telomerase and its importance...

Sierra Sciences, in collaboration with TA Sciences, Geron Corporation, PhysioAge, and the Spanish National Cancer Research Center (CNIO), has announced the first compound ever discovered that activates the enzyme telomerase in the human body - a critical prerequisite for technology that could arrest or reverse the aging process in humans. This compound is a natural product derived nutraceutical known as TA-65.

TA-65, exclusively licensed to TA Sciences from Geron Corporation, is a >95% pure single chemical entity isolated from a proprietary extract of the dried root of Astragalus membranaceus and formulated into 5- to 10-mg capsules with inert excipients. Starting doses of 5–10 mg/day were considered safe on the basis of historical usage of extracts. Some subjects increased their dosage after several months on the product to 25–50 mg/day. Cumulative dose consumed during the year was recorded for each subject and used for preliminary dose–response analysis.

Researchers discovered that TA-65 was associated with a statistically significant "age-reversal" effect in the immune system, in that it led to declines in the percentage of senescent cytotoxic T cells and natural killer cells after six to twelve months of use. In addition, further analysis with automated high-throughput confocal microscopy (HT-qFISH) revealed a decline in the percentage of white blood cells with critically short telomeres after twelve to eighteen months of use.

Telomere shortening is thought to be the "clock of aging" contained within the human body. It has been repeatedly demonstrated that a human cell that does not undergo telomere shortening will divide indefinitely and is, by all available measurements, immortal.

Researchers reports that TA-65 can cause telomerase, an enzyme that lengthens telomeres, to become active in human cells.  Telomerase activation by TA-65 was shown to lengthen the shortest telomeres in humans, potentially extending human lifespan and healthspan. Telomerase activation is thought to be a keystone of future regenerative medicine and a necessary condition for clinical immortality. Although TA-65 is probably too weak to completely arrest the aging process, it is the first telomerase activator recognized as safe for human use.

"We are on the cusp of curing aging," said William Andrews, Ph.D., co-author of this study and President and CEO of Sierra Sciences, LLC. "TA-65 is going to go down in history as the first supplement you can take that doesn't merely extend your life a few years by improving your health, but actually affects the underlying mechanisms of aging. Better telomerase inducers will be developed in the coming years, but TA-65 is the first of a whole new family of telomerase-activating therapies that could eventually keep us young and healthy forever."

Telomerase activation has potential medical applications beyond extending human lifespan.  Epidemiological studies have shown that short telomeres in humans are a risk factor for diseases including, among others, atherosclerosis, diabetes, Alzheimer's, and cancer. The present study also reports encouraging news on the effect of TA-65 on the body's immune system. Infectious diseases lead to telomere shortening in the immune system, as immune cells divide to fight infections. Telomerase activation should prevent this telomere shortening and allow the body's immune system to fight a chronic infection indefinitely.

The present study on TA-65 lends support to this hypothesis. In individuals infected with CMV, a virus which prematurely ages the immune system and significantly reduces life expectancy, TA-65 caused an apparent "age reversal" of approximately 5 to 20 years based on one biomarker of immune aging. For the same reason, telomerase activation is a potential treatment for AIDS.

"We tend to see HIV turning into AIDS when the cells of the immune system develop critically short telomeres," said Andrews...

HIV can essentially cause the immune system to die of old age while the majority of the body is still young and therefore the researchers are hopeful that a telomerase activator could theoretically prevent an HIV-positive individual from ever developing AIDS....

Ref : http://www.liebertonline.com/doi/abs/10.1089/rej.2010.1085

SPC3649 ( LNA- locked nucleic acid) - a new hope for hepatitis C.....

When  I was working with Innovasynth Technologies, Khopoli, I had an opportunity to do literature survey about  Lock Nucleic Acids (LNAs) and Peptide Nucleic Acids (PNAs) (we were supposed to work on the preparation of  some of the LNAs & PNAs for US based companies). In my opinion though these class of compounds (including oligonucleotides) are  still emerging,  I think in the days to come there will be more and more drugs from oligonucleotides, Locked Nucleic Acids (LNAs) and Peptide Nucleic Acids, (PNAs) class of compounds.

LNAs : A locked nucleic acid (LNA) (see the right side general structure), is a modified RNA nucleotide. Ribose moiety of an LNA nucleotide is modified with an extra bridge

connecting the 2' oxygen and 4' carbon. The bridge "locks" the ribose  in the 3'-endo (North) conformation, which is often found in the A-form of DNA or RNA. LNA nucleotides can be mixed with DNA or RNA bases in the oligonucleotide whenever desired. This locking  significantly increases the thermal stability (mp) of oligonucleotide.

LNA nucleotides are used to increase the sensitivity and specificity of expression in DNA microarrays, FISH probes, real-time PCR probes and other molecular biology techniques based on oligonucleotides. For the in situ detection of miRNA the use of LNA is currently the only efficient method. A triplet of LNA nucleotides surrounding a single-base mismatch site maximizes LNA probe specificity unless the probe contains the  G-T mismatch. We have already seen some antisense drugs (oligonucleotides from Geron & Isis) and some are into clinical trials.

Now its interesting to see that Santaris Pharma   is currently advancing LNA based compounds within infectious diseases, metabolic disorders, oncology, inflammatory and rare genetic disorders.

Santaris Pharama, has developed a LNA,  SPC3649 - which captures a small RNA molecule in the liver, called microRNA122, that is required for HCV replication.

As per the claim by the company, SPC3649 works by altering the environment in the host liver cell to inhibit viral replication rather than inhibiting the virus itself. This subtle difference (in comparison  with other therapies) may have significant implications, as it may reduce the risk of the virus becoming resistant to therapy – a major concern with current therapies.

As per the claim by Dr. Robert Lanford,  (who has collaboration with Santaris Pharma), that in a preclinical study  SPC3649 successfully inhibited miR-122, a liver-expressed microRNA important for Hepatitis C viral replication. By inhibiting miR-122, SPC3649 dramatically reduced Hepatitis C virus in the liver and in the bloodstream in chimpanzees chronically infected with the Hepatitis C virus. Four HCV chronically infected chimpanzees were treated weekly with 5 or 1 mg/kg of SPC3649 for 12 weeks followed by a treatment free period of 17 weeks. The two animals that received the 5 mg/kg dose had a significant decline in viral levels in the blood and liver of approximately 2.5 orders of magnitude or approximately 350 fold. Hope the new therapy could potentially replace interferon (interferon and ribavirin is  approved by FDA for hepatitis C and this treatment is very toxic, requires 48 weeks with 50% success) in future cocktails, since it provides a high barrier to resistance. This antiviral could be used alone to treat disease progression and there are indications that it can convert interferon non-responders to responders, so that non-responders to the current therapy could be treated with the combination of this drug with interferon.   More....

Those interested  can see the video demo with the link

Diverse use of Nucleic acids.....

There is much interest in the medical uses of nucleic acids. For example, antisense, ribozymes, aptamer and RNA interference (RNAi) technologies are all being developed for potential therapeutic applications. The design of nucleic acids, particularly oligonucleotides, for in vivo delivery requires consideration of various factors including binding strength, target specificity, serum stability, resistance to nucleases and cellular uptake. A number of approaches have been proposed in order to produce oligonucleotides that have characteristics suitable for in vivo use, such as modified backbone chemistry, formulation in delivery vehicles and conjugation to various other moieties. Therapeutic oligonucleotides with characteristics suitable for systemic delivery would be particularly beneficial.

There are many oligonucleotides with modified chemical backbones, like peptide nucleic acids (PNAs), locked nucleic acids (LNAs), methylphosphonates, phosphoramidates and thiophosphoramidates. Each of these types of oligonucleotides has reported advantages and disadvantages. For example, peptide nucleic acids (PNAs) display good nuclease resistance and binding strength, but have reduced cellular uptake in test cultures; phosphorothioates display good nuclease resistance and solubility, but are typically synthesized as P-chiral mixtures and display several sequence- non-specific biological effects; methylphosphonates display good nuclease resistance and cellular uptake, but are also typically synthesized as P-chiral mixtures and have reduced duplex stability.

The N3'-P5'phosphoramidate internucleoside linkages are reported to display favorable binding properties, nuclease resistance, and solubility (I did work for quite some time in this field and I had opportunity to interact with Dr. Sergei Gryaznov and group). Though this field is getting wider and wider with many companies trying with some innovative ideas, the real concern in this field is that the polyanionic nature of oligonucleotides reduces the ability of the compound to cross lipid membranes, limiting the efficiency of cellular uptake.But thanks to many other groups they are trying to concentrating on this issue and hope there will be may drugs in the days to come. There are many drugs already in the market by ISIS and Geron corporation has many patents to its credit in the many patents for its novel work (Dr.Sergei, Dr.Cristzina Pongracz and many others have lot of work in this field) N3'-P5'phosphoramidate internucleoside linkages. Though there were a few players in this field of nucleic acids(5-6 years' back), now a days when ever I read any medicinal chemistry news, I do find lot many companies contributing to this field of nucleic acids. Hope there will be many drugs from this field with reduced side effects....

Imetelstat (GRN 163L) shows promising results against brain cancer glioblastoma and prostate cancer...

In continuation of my update on Telomerase inhibitors, I find this info really interesting and hence sharing here with. As mentioned in my earlier blog about imetelstat (GRN163L )  has been undergoing Phase I clinical trials designed to examine the safety, tolerability, pharmacokinetics and pharmacodynamics of the drug, alone or in combination, in solid tumors, chronic lymphoproliferative disease, multiple myeloma, lung and breast cancers and the company claims that Phase I objectives for imetelstat  (structure) have been achieved. Now  Dr. Jerry Shay, professor of cell biology of  The University of Texas Southwestern Medical Center at Dallas, claims that the same drug shows promise in fighting the brain cancer glioblastoma and prostate cancer.

Glioblastomas are the most common malignant brain tumors in adults, according to the American Cancer Society. They are difficult to treat with drugs because blood vessels in the brain have tightly constructed walls that allow only a few substances to pass through.

The researcher focused on cells called tumor-initiating cells. Some researchers believe that tumors contain a small subset of initiating cells – or cancer stem cells – that are able to initiate and drive tumors and that are often resistant to radiation therapy and chemotherapy.

In the glioblastoma study, Dr. Shay and his colleagues found that imetelstat blocked the action of telomerase in isolated tumor-initiating cells as well as the bulk of the tumor cells, eventually killing the cells. Combining imetelstat with radiation and a standard chemotherapy drug made imetelstat even more effective. When the researchers implanted human tumor-initiating cells into rodents, they found that imetelstat was able to enter brain tissue and inhibit telomerase activity.

In the prostate cancer study, the researchers isolated tumor-initiating cells from human prostate cancer cells. The cells showed significant telomerase activity. Imetelstat blocked the enzyme’s activity, and telomeres shortened greatly. As per Dr.Shay, since the drug attacks a mechanism that is active in most cancers, it might prove to be widely useful, especially when combined with other therapies.

Hope  Geron people must be really happy for these results  and conclusions.....

Ref : http://www.utsouthwestern.edu/utsw/cda/dept353744/files/570509.html

Phase III clinical study of trabedersen....

In my earlier blogs, did mention about the "antisense drugs belonging to (Geron corporation) phosphorothioate antisense oligonucleotides" . I did also mention that there are many companies working with this field (antisense). Yes now Antisense Pharma GmbH has announced that, it has received the approval by Health Canada for its pivotal Phase III clinical trial SAPPHIRE in patients with recurrent or refractory anaplastic astrocytoma. The SAPPHIRE study is a randomized, active-controlled, clinical trial designed to confirm the efficacy and safety of the investigational drug trabedersen (AP 12009 a phosphorothioate antisense oligonucleotide), observed in previous clinical studies. Trabedersen is being investigated as monotherapy compared to current standard therapy with temozolomide (alternatively BCNU (carmustine)). The results of a previous randomized, active-controlled Phase IIb study show that the novel, targeted therapy holds significant promise. Hope in the days to come, more drugs from this class of compounds...

Ref :http://www.anticancer.de/index.php?id=38.

I found this video, interesting (mode of action of trabedersen)