New data on novel gene-silencing oligonucleotide technology...

Idera announced new data on its novel gene-silencing oligonucleotide (GSO) technology at the Cell Symposium on Regulatory RNAs in Chicago, IL. In preclinical studies, systemic delivery of GSOs targeted to ApoB or PCSK9 mRNA caused a reduction in the level of the targeted mRNA and associated protein and resulted in a decrease in serum total cholesterol and LDL-cholesterol concentration. ApoB and PCSK9 are two validated targets associated with cardiovascular diseases.

In this study, Idera created 19mer GSOs for apolipoprotein B (ApoB) and proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA and evaluated their in vivo activity in mice following subcutaneous administration. The data demonstrate that treatment with each GSO led to a significant reduction in the concentration of the target associated mRNAs and protein. The effects were specific, with no significant effects being observed on ABCA1, ABCG1 or LXR mRNA levels. In addition, treatment with GSOs for either ApoB or PCSK9 resulted in a decrease in total serum cholesterol and LDL-cholesterol. 

More...

Japanese patent for Archexin (a novel anti-cancer drug)....

Rexahn Pharmaceuticals, Inc., a clinical stage pharmaceutical company commercializing potential best in class oncology and CNS therapeutics, announced that the Japanese Patent Office has issued a patent for its novel anti-cancer compound, Archexin. As per the claim by the company,  Archexin is a first in class, potent inhibitor of Akt protein kinase in the treatment of cancer. 

The AKT pathway is an important therapeutic target for cancer drug discovery as it functions as a main point for transducing extracellular and intracellular oncogenic signals. Moreover, alternations of the AKT pathway have been found in a wide range of cancers. Akt regulates signal processes of cell proliferation and survival, angiogenesis, and drug resistance in cancer. Archexin is being developed to treat solid tumors and has FDA Orphan drug designation for RCC, pancreatic, stomach, glioblastoma, and ovarian cancers. Archexin is in Phase II clinical development for pancreatic cancer as lead indication.

Archexin(R) was fromerly named as RX-0201, is  an oligonucleotide compound that  inhibits the expression of human Akt-1. I am really happy for this approval because, in my opinion this will boost the new field of drugs (ologonucleotides/antisense). I have covered some developments in this field, those interested can read earlier articles...

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

First live targeting of tumors with RNA-based technology

Researchers at Duke University Medical Center have devised a way they might deliver the right therapy directly to tumors using special molecules, called aptamers, (Aptamers are oligonucleotides or peptide molecules that bind to a specific target molecule) which specifically bind to living tumor tissue.......

More....First live targeting of tumors with RNA-based technology

Positive results from mipomersen- a new hope for FH sufferers...

About Familial hypercholesterolemia :

Familial hypercholesterolemia (also spelled familial hypercholesterolaemia) is a genetic disorder characterized by high cholesterol levels, specifically very high low-density lipoprotein (LDL, "bad cholesterol") levels, in the blood and early cardiovascular disease. Many patients have mutations in the LDLR gene that encodes the LDL receptor protein, which normally removes LDL from the circulation, or apolipoprotein B (ApoB), which is the part of LDL that binds with the receptor; mutations in other genes are rare. Patients who have one abnormal copy (are heterozygous) of the LDLR gene may have premature cardiovascular disease at the age of 30 to 40. Having two abnormal copies (being homozygous) may cause severe cardiovascular disease in childhood. Heterozygous FH is a common genetic disorder, occurring in 1:500 people in most countries; homozygous FH is much rarer, occurring in 1 in a million births.

Heterozygous (FH) is normally treated with statins, bile acid sequestrants or other hypolipidemic agents that lower cholesterol levels. New cases are generally offered genetic counseling. Homozygous FH often does not respond to medical therapy and may require other treatments, including LDL apheresis (removal of LDL in a method similar to dialysis) and occasionally liver transplantation.

Recently, Genzyme Corp. and Isis Pharmaceuticals Inc have come up with some intresting results from the drug mipomersen [mipomersen - is an antisense oligonucleotide, with phosphorothioate linkage at 5'- postion and 2'-O-methoxymethyl moety] ( phase 3). As per the claim by the companies, the study met its primary endpoint in an intent-to-treat analysis, with a 25 percent reduction in LDL-cholesterol after 26 weeks of treatment, vs. 3 percent for placebo (p<0.001)>.

The trial met all of its secondary and tertiary endpoints, suggesting that mipomersen may offer potential benefits to patients beyond LDL-C reduction. Patients treated with mipomersen experienced a 27 percent reduction in apolipoprotein B vs. 3 percent for placebo; a 21 percent reduction in total cholesterol vs. 2 percent for placebo; and a 25 percent reduction in non-HDL cholesterol vs. 3 percent for placebo (all p<0.001).>Mipomersen patients’ HDL-C levels increased 15 percent (p=0.035 vs. placebo), which combined with the LDL-C reductions observed, resulted in improved LDL/HDL ratios, a ratio considered an important measure of cardiovascular risk. Mipomersen patients’ LDL/HDL ratios decreased by 34% (p<0.001>Mipomersen a representative of Isis’ leadership in the field of RNA targeted therapeutics will bring a sigh of relief to the sufferers of FH, in the days to come.

I had an opportunity to work with ISIS (as contract R & D, Innovasynth Technologies Limited, Khopoli) and really excited to see the results..

Ref : http://ir.isispharm.com/phoenix.zhtml?c=222170&p=irol-newsArticle&ID=1356364&highlight=

Antisense Therapeutics completes repeat-dosing toxicology studies for ATL1103

Antisense Therapeutics completes repeat-dosing toxicology studies for ATL1103

One can see the products under development...(by the same co)..

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)