RNA interference approach for prevention and treatment of STDs ?

In my earlier blog “Diverse use of Nucleic acids”, did mention that 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. Lots of research is being done in each specified fields and in fact there are already few drugs in “antisense category” and this time something really interesting has been reported by a Post Doc., Dr. Kim Woodrow in the field of RNA interference category. The following lines briefly summerise, what actually RNAis..

RNA interference (RNAi) is a system within living cells that helps to control which genes are active and how active they are. Two types of small RNA molecules – microRNA (miRNA) and small interfering RNA (siRNA) – are central to RNA interference. RNAs are the direct products of genes, and these small RNAs can bind to specific other RNAs and either increase or decrease their activity, for example by preventing a messenger RNA from producing a protein. RNA interference has an important role in defending cells against parasitic genes, viruses and transposons – but also in directing development as well as gene expression in general

The RNAi pathway is found in many eukaryotes including animals and is initiated by the enzyme Dicer, which cleaves long double-stranded RNA (dsRNA) molecules into short fragments of ~20 nucleotides. One of the two strands of each fragment, known as the guide strand, is then incorporated into the RNA-induced silencing complex (RISC). The most well-studied outcome is post-transcriptional gene silencing, which occurs when the guide strand base pairs with a complementary sequence of a messenger RNA molecule and induces cleavage by Argonaute, the catalytic component of the RISC complex. This process is known to spread systemically throughout the organism despite initially limited molar concentrations of siRNA. The importance of the siRNA lies in the fact that “RNAi is selective on gene expression” and hence can be used in the similar fashion like the antisense drugs (already a few drugs by ISIS, Serono and others). I did work on a few oligonucleotides (phosparothiamidates), while working in Innovasynth Technologies Limited Khopoli and know how difficult is to get the precursors of the antisense drugs. In 2006, Andrew Fire and Craig C. Mello shared the Nobel Prize in Physiology or Medicine for their work on RNA interference in the nematode worm C. elegans.

Gene interference therapy is moving rapidly from basic research to application. The PLGA packaging these researchers chose is already approved as safe and non-toxic by the FDA, speeding the path to clinical trials for infectious agents such as HPV and HIV.

Congrats Dr.Kim and co workers for this achievement. The significance of this research is the fact that “a safe and effective administration of potential antiviral drugs - small interfering RNA (siRNA) molecules using densely-loaded nanoparticles made of a biodegradable polymer known as PLGA. The researchers created a stable "time release" vehicle for delivery of siRNAs to sensitive mucosal tissue like that of the female reproductive system.

Ref : http://www.nature.com/nmat/journal/vaop/ncurrent/abs/nmat2444.html

Can Antisense drugs revolutionize the drug discovery ?

Antisense therapy, is an important technology for drug discovery and development. It is broadly used by the pharmaceutical industry as a tool for functional genomics and as highly specific drugs for a wide range of diseases (Anticancer, anti-inflammatory, cardiovascular and neurodegenerative diseases) The most interesting factor of antisense drugs is “specificity” in contrast to the traditional drugs (which binds to the proteins and charge interactions so often ending with undesirable side effects). With the combined efforts of human genome programme and bioinformatics, we may soon have a lesser number of targets, I think this interesting field may revolutionize the drug discovery. But the real concern is, there are a few players as of now. In my opinion, something like High Throughput Screening (HTS), with co-ordination of educational and private institutes may help to have more drug contenders (as for as my knowledge goes, Southern Research Institute, Birmingham did try for antitubercular drugs, for the drug resistant strain). Let us hope, something happen in the near future…..

Isis Initiates Phase 1 Study in Patients With Cancer With the First Generation 2.5 Antisense Drug, ISIS-STAT3Rx

 In continuation of my update on antisense drugs...

Isis Pharmaceuticals, Inc.  announced the initiation of a Phase 1 study of ISIS-STAT3Rx, a Generation 2.5 antisense drug designed to treat cancer.  ISIS-STAT3Rx specifically reduces the production of signal transducer and activator of transcription 3 (STAT3). Because STAT3 is over expressed in numerous types of cancers, ISIS-STAT3Rx has the potential to be broadly useful for both solid and liquid tumors.  The ISIS-STAT3Rx development plan is initially focused on key cancers where there is a high unmet medical need and a strong link to STAT3, such as hepatocellular carcinoma (HCC) and ovarian cancer.  Advancements in Isis' technology platform have resulted in the improved potency of Generation 2.5 antisense drugs creating opportunities for drugs like ISIS-STAT3Rx to be effective in the more difficult to treat types of cancer. 

 

"The role of STAT3 as a key factor critical for tumor cell growth and survival of cancer cells has made STAT3 widely viewed as an important target of interest," said David S. Hong, M.D., Assistant Professor, Department of Investigational Cancer Therapeutics at the University of Texas MD Anderson Cancer Center.  "STAT3 is a well understood transcription factor involved in multiple survival mechanisms that intersect with the growth, metastasis and invasiveness of cancer. The ability to selectively inhibit STAT3 could allow us to effectively treat some of the most difficult to treat cancers."

 
Isis Initiates Phase 1 Study in Patients With Cancer With the First Generation 2.5 Antisense Drug, ISIS-STAT3Rx

Ref : http://ir.isispharm.com/phoenix.zhtml?c=222170&p=irol-newsArticle&ID=1691711&highlight=

NDA of Cladribine as a drug for Multiple Sclerosis !

When I was working with Innovasynth Technologies, Khopoli, I worked in the field of "antisense drugs" and as the company has tie up with many MNCs (working with these class of compounds) I had many times interacted with Serono, Pharmaceuticals (US) for some of the intermediates (oligonucleotides). When I read this article, I am happy there are many drugs still to be established as antisense drugs and more over this NDA (new drug application) is something to cherish.

We know that 2-chlorodeoxyadenosine, Cladribine (Leustatin) is drug used to treat hairy cell leukemia (leukemic reticuloendotheliosis).

As a purine analog, it is a synthetic anticancer agent that also suppresses the immune system. Chemically, it mimics the nucleoside adenosine and thus inhibits the enzyme adenosine deaminase, which interferes with the cell's ability to process DNA. It is easily destroyed by normal cells except for blood cells, with the result that it produces relatively few side effects and results in very little non-target cell loss.

Though it has been used to treat leukemic reticuloendotheliosis, other activities like B cell leukemias and lymphomas, such as mantle cell lymphoma are still to be established. Now EMD Serono has applied for this NDA with FDA. As per the claim by the company, Cladribine Tablets has the potential to be the first orally administered disease-modifying therapy available for people living with relapsing MS, as all disease-modifying therapies currently approved for the treatment of MS are parenteral therapies. Hope FDA will approve the drug and will help many patients with relapsing forms of multiple scleorosis will have a relief in the days to come..

Ref : http://www.emdserono.com/cmg.emdserono_us/en/images/Cladribine%20Tablets%20FDA%20Submission%20FINAL%20US%20FINAL_tcm115_44365.pdf

New approach to kill specific bacteria could be alternative to antibiotics

A new approach to killing C. difficile that silences key bacterial genes while sparing other bacteria may provide a new way to treat the most common hospital-acquired bacterial infection in the United States, according to researchers.

While conventional antibiotics treat bacterial infections, they can also cause a condition in the colon called C. difficile infection, due to the drug killing both good and bad bacteria in the gut.

In a lab, researchers created three new antibiotics that kill C. difficile by preventing the expression of bacterial genes that are important for its survival. This approach -- called antisense therapy -- allows the drug to kill only C. difficile, unlike many antibiotics that kill multiple forms of bacteria.

"We were able to show that these drugs can zero in on and kill C. difficile bacteria while leaving other bacteria alone," said Arun Sharma, associate professor of pharmacology, Penn State College of Medicine. "We're still working to refine these drugs and make them even better, with the eventual goal of testing them clinically."

David Stewart, an associate professor of surgery at the University of Arizona who along with Sharma is a co-principal investigator on this study, said the drug works in a completely different manner than the antibiotics currently used.

"These drugs are organism specific, meaning that they target only one kind of bacteria, kind of like smart antibiotics," Stewart said. "They're precise. And that's especially important with C. difficile infections because this bacteria is uniquely, selectively advantaged to exploit ecological disturbances in the human gut."

While C. difficile is normally present in the gut, other "good" bacteria are also present, and all these bacteria contribute to a person's microbiome. When a person's microbiome is healthy and balanced, it keeps bad bacteria like C. difficile under control.

But if a patient takes an antibiotic for another condition, the antibiotic kills many different types of bacteria, including the good ones keeping C. difficile under control. This allows C. difficile to thrive, causing an infection that can result in severe gastrointestinal symptoms. Since antibiotics can contribute to C. difficile infections, the researchers said a new, alternative treatment for these infections is desirable.

"Ideally, a treatment for C. difficile would have no effect on other bacteria," Stewart said.

The researchers, who recently published their findings in the Journal of Antibiotics, said that while most antibiotics lack organismal specificity -- the ability to target just one type of organism -- antisense treatments show great potential for being able to target only specific bacteria.

"Our antisense antibiotics contain genetic material which is complementary to bacterial genetic material, so we designed our genetic material to target specific genes in C. difficile," Stewart said. "And when our genetic material binds to the bacterial genetic material, it prevents the expression of bacterial genes. And that can cause C. difficile to die."

The drug tested in the study consisted of two components: the antisense compound that targeted the genetic material in C. difficile -- referred to as an antisense oligonucleotide (ASO) -- and a carrier compound that transported the ASO into the bacteria, referred to by the research team as a CAB. The researchers tested three versions of the drug, each with a different version of CAB.

The researchers tested each compound to see how much of the drug was required to kill C. difficile bacteria, whether it was toxic or not to human colon cells, and whether it also harmed other bacteria normally found in the gut -- like E. coli.

"Ultimately, we wanted these compounds to deliver the drug into the C. difficile bacteria without hurting other bacteria or the patient," Sharma said. "After testing these three, we found that one carrier in particular -- CYDE-21 -- was the best at delivering an effective dose of the drug into the bacteria."

 

In the future, the researchers said they will conduct further studies to continue to refine the carriers to increase their capacity and minimize their effect on other bacteria and human cells.

"In this study, as a first effort, the carrier is pretty good, and we'd like to do even better," Stewart said. "It has minimal antibacterial activity, minimal toxicity and it's an effective carrier of our cargo. So what we're working on now is modifying our carriers for future testing in preparation for animal studies."

Ref : https://www.nature.com/articles/s41429-018-0056-9

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

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)

Antisense Pharma presents data from trabedersen Phase I/II cancer study at ASCO 2012

In continuation of my update on antisense drugs

Trabedersen, is an antisense compound that specifically inhibits expression of transforming growth factor beta 2 (TGF-β2) – a protein which is overexpressed in advanced tumors and which triggers key cancer pathomechanisms, i.e. suppression of antitumor immune response and metastasis. 

Antisense Pharma presents data from trabedersen Phase I/II cancer study at ASCO 2012: The biopharmaceutical company Antisense Pharma today presents trabedersen complete data from its clinical Phase I/II study in patients with advanced pancreatic cancer, malignant melanoma or colorectal cancer at the international cancer congress ASCO 2012 in Chicago, USA.

New drug shows promise against Huntington's disease

A drug that would be the first to target the cause of Huntington's disease (HD) is effective and safe when tested in mice and monkeys, according to data released today that will be presented at the American Academy of Neurology's 68th Annual Meeting in Vancouver, Canada, April 15 to 21, 2016. A study to test the drug in humans has begun.

Huntington's disease is a rare, hereditary disease that causes uncontrolled movements, loss of intellectual abilities, emotional problems and eventually death. The disease is passed from parent to child through a mutation in the huntingtin gene. The mutation results in the production of a disease-causing huntingtin protein. Each child has a 50/50 chance of inheriting the gene mutation. Everyone who inherits the mutated gene will eventually develop the disease.

The new drug, called IONIS-HTTRx, is an antisense drug that acts as a "gene silencer" to inhibit the production of huntingtin protein in people with Huntington's disease.

"It is very exciting to have the possibility of a treatment that could alter the course of this devastating disease," said clinical study principal investigator Blair R. Leavitt, MD, of the University of British Columbia in Vancouver. "Right now we only have treatments that work on the symptoms of the disease." Leavitt notes the drug is still years away from being used in human clinical practice.

Earlier studies in mouse models of Huntington's disease showed that treatment with antisense drugs delays disease progression and results in sustained reversal of the disease phenotype. In YAC128 mice, a transgenic model of HD, motor deficits improved within one month of initiating antisense treatment and were restored to normal at two months after treatment termination. Motor skills of antisense-treated BACHD mice, another transgenic model of HD, improved eight weeks after initiation of treatment and persisted for at least nine months after treatment termination. In monkeys, dose-dependent reductions in HTT mRNA and Htt protein throughout the central nervous system were observed after intrathecal administration of an antisense drug. Reduction of cortical huntingtin levels by 50 percent was readily achieved in monkeys and correlated with 15 to 20 percent reduction in the caudate. In further tests in rodents and monkeys, IONIS-HTTRx was found to be well-tolerated without any dose-limiting side effects.

New drug shows promise against Huntington's disease

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

Ebola, Marburg Virus Treatments Safe in Phase 1 Studies

In continuation of my update on antisense drugs and RNAi

AVI BioPharma Inc. announced positive safety results from the first five cohorts of Phase 1 single ascending dose trials of AVI-6002 and AVI-6003, AVI's lead drug candidates being evaluated for the treatment of the Ebola virus and Marburg virus.

Data were evaluated by an independent Data and Safety Monitoring Board (DSMB), which issued recommendations for both studies to progress as planned to the next highest dosing level after no safety concerns were identified. The Phase 1 single ascending dose trials are designed to characterize the safety, tolerability, and pharmacokinetics of each therapeutic candidate in healthy adult volunteers.

"We are very encouraged that these two drugs, which use our advanced PMOplus chemistry, have demonstrated a favorable safety profile through five cohorts in our dose-escalation studies,”says Chris Garabedian, president and chief executive officer of AVI BioPharma...

Ref : http://phx.corporate-ir.net/phoenix.zhtml?c=64231&p=RssLanding&cat=news&id=1619940

To date, 25 healthy human subjects (five per group) have been enrolled into five sequential dose groups in each of the two studies. Within each group, four subjects received the indicated dose of the therapeutic and one subject received placebo. For each group, safety, clinical laboratory and renal biomarker results through five days after treatment were reviewed by a DSMB. Subjects enrolled in the sixth group for the drug studies will receive 9.0 mg/kg of the therapeutic or placebo. Final, un-blinded safety and pharmacokinetic results for all subjects will be available upon completion of the trial.

Both candidates employ AVI's patented PMOplus technology that selectively introduces positive charges to its phosphorodiamidate morpholino oligomer (PMO) backbone to improve interaction between the drug and its target.

FDA Approves Vyondys 53 (golodirsen) Injection for the Treatment of Duchenne Muscular Dystrophy (DMD) in Patients Amenable to Skipping Exon 53

In continuation of my update on oligonucleotide.

Sarepta Therapeutics, Inc. (NASDAQ:SRPT), the leader in precision genetic medicine for rare diseases, today announced that the U.S. Food and Drug Administration (FDA) has approved Vyondys 53™ (golodirsen). Vyondys 53 is an antisense oligonucleotide from Sarepta’s phosphorodiamidate morpholino oligomer (PMO) platform, indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients with a confirmed mutation amenable to exon 53 skipping. This indication is based on a statistically significant increase in dystrophin production in skeletal muscle observed in patients treated with Vyondys 53, which is reasonably likely to predict clinical benefit for those patients who are exon 53 amenable. Consistent with the accelerated approval pathway, the continued approval of Vyondys 53 may be contingent on confirmation of a clinical benefit in this post-marketing confirmatory trial.

Sarepta’s placebo-controlled, post-marketing confirmatory trial to support the Vyondys 53 accelerated approval – titled ESSENCE – is currently enrolling and expected to conclude by 2024.

Hypersensitivity reactions, including rash, pyrexia (fever), pruritis, urticaria (hives), dermatitis, and skin exfoliation have occurred in patients who were treated with Vyondys 53. Renal toxicity was observed in animal studies. Although not observed in the clinical studies with Vyondys 53, renal toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides. The most common adverse reactions that occurred in at least 20% of Vyondys 53-treated patients and more frequently than in placebo-treated patients were headache (41%), pyrexia (41%), fall (29%), abdominal pain (27%), nasopharyngitis (27%), cough (27%), vomiting (27%), and nausea (20%).

Following a New Drug Application (NDA) submission to and review by the Division of Neurology Products (the Review Division) for Vyondys 53, which the Review Division recommended for approval, the Office of Drug Evaluation 1 issued a complete response letter (CRL) in August of 2019. Thereafter, Sarepta made a formal dispute resolution request as outlined in relevant FDA Guidance. With the support of the Review Division, the matters raised in the CRL were rapidly evaluated and resolved by Dr. Peter Stein, Director of the Office of New Drugs (OND). OND granted the Company’s appeal and Sarepta re-submitted its NDA to the Review Division, which worked expeditiously to review and approve Vyondys 53.

“Today is monumental for Sarepta and, more importantly, for the DMD community,” said Doug Ingram, president and chief executive officer, Sarepta. “Vyondys 53, our second approved exon-skipping RNA therapy for DMD, may treat up to 8% of the DMD community, representing those patients who have a confirmed exon 53 amenable mutation. Along with EXONDYS 51® (eteplirsen), we now offer treatment options for approximately 20% of those with DMD in the U.S.”

Ingram continued, “In the span of four months, we commenced and completed the formal dispute resolution process culminating in the grant of our appeal, resubmitted our NDA and obtained an approval – a great benefit to DMD patients awaiting treatment. This unprecedented timing could not have been achieved without the commitment of the Review Division under the leadership of Dr. Billy Dunn, and the Office of New Drugs, which expeditiously heard and granted our appeal. Along with the DMD community, we owe our gratitude to both the Review Division and the OND for their objective, evidence-based approach to this review, for their fairness, and for the sense of urgency with which they addressed and resolved the CRL and granted this approval.”

“With the approval of Vyondys 53, up to another 8% of Duchenne families will have a therapy to treat this devastating disease,” said Pat Furlong, founding president and chief executive officer, Parent Project Muscular Dystrophy (PPMD). “For 25 years, PPMD has been working with researchers, clinicians, industry, and the Duchenne community to find treatments for all people living with Duchenne. And while we need to ensure that these approved therapies are accessible for patients, today we celebrate this approval and thank Sarepta for their continued leadership in the fight to end Duchenne.”

Vyondys 53 is priced at parity to EXONDYS 51, the price of which has not increased since its launch in 2016. Patients and physicians can access more information at www.SareptAssist.com or by calling 1-888-727-3782.

About Vyondys 53

Vyondys 53 is an antisense oligonucleotide indicated for the treatment of Duchenne muscular dystrophy in patients who have a confirmed mutation of the DMD gene that is amenable to exon 53 skipping. Vyondys 53 uses Sarepta’s proprietary phosphorodiamidate morpholino oligomer (PMO) chemistry and exon-skipping technology to bind to exon 53 of dystrophin pre-mRNA, resulting in exclusion, or “skipping,” of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 53 skipping. Exon skipping is intended to allow for production of an internally truncated dystrophin protein.

https://www.rxlist.com/vyondys-53-drug.htm

A Deep Insight into the World Gene Therapy Market

A new market research report related to the Biotechnologies and Genetics industry about the trends in "antisense drugs".....

Isis receives $5M milestone payment from GSK for initiating ISIS-TTRRx Phase 1 study

In continuation of my update on "antisense drugs"....
Isis receives $5M milestone payment from GSK for initiating ISIS-TTRRx Phase 1 study

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....

New journal devoted to gene therapy...

As for as my knowledge goes there was no exclusive journal totally devoted to gene therapy until last year. Yeah its really interesting to to see "The Gene Therapy Review" a journal totally devoted to gene therapy. In my opinion it is an important move and was the urgent need of the hour. Now the fields like antisense drugs & gene therapy will get its due importance and hope in the days to come, will bring together all those people to share and gain the knowledge..... Those interested can follow the blog also.....

URL : http://www.genetherapyreview.com/index.php

Blog : http://www.genetherapyreview.com/gene-therapy-blog.html

Idera's gene-silencing oligonucleotide studies published in Journal of Medicinal Chemistry

In continuation of my update on antisense drugs and nucleotides

Idera's gene-silencing oligonucleotide studies published in Journal of Medicinal Chemistry

Ref : JMC 

Regulus present advancements in microRNA platform at Oligonucleotide Therapeutics Society meeting

Recently, I did write an article regarding the future of antisense drugs for BlogNotions (wherein I did mention about the Regulus plans for mRNA platform)...


Regulus present advancements in microRNA platform at Oligonucleotide Therapeutics Society meeting

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

A new experimental drug "antagomir" (antisense oligonucleotide) as an anti- miR-21 agent..

MicroRNAs are small scraps of RNA comprising around 20 nucleotides and it is only recently that scientists have discovered their power which is they can regulate the expression (switching on and off) of a large number of human genes (they are like "master controllers"). And also these are the culprits (when microRNAs don't appear in the right place at the right time within cells) for diseases such as cancer, viral infections, inflammatory diseases and metabolic disorders. The potential to use them as targets for drugs is obvious and possibly explains why this is one of the fastest growing areas of development for new drugs and treatments.

Scientists already knew that microRNA was involved in switching genes on and off in the heart, but the underlying mechanisms and how they relate to the development of particular types of heart disease and their potential as drug targets were still relatively unknown.

Thum and colleagues discovered that miR-21 was expressed in the heart's fibroblast cells (cells that make the scaffolding of collagen or connective tissue that hold the shape of the organ) and were in greater numbers in lab mice bred to have heart failure and also in human tissue from patients who had heart failure.

In this study they showed that increasing expression of miR-21 changed the way that signals behaved in a previously unknown stress response pathway that involved the gene sprouty-1 and the MAP-kinase signaling pathway. In turn, increasing the activity of the MAP-kinase pathway led to a number of signs of heart failure, such as enhanced fibroblast survival, increased secretion of factors like fibroblast growth factor, tissue scarring (fibrosis), and cardiac dysfunction including cellular hypertrophy.

The researchers proved they could administer anti-miR-21 effectively to the heart by monitoring it with fluorescence staining. Then, in a mouse transaortic constriction model of human heart failure, they showed that anti-miR-21 silenced increased expression of miR-21 and corrected downstream changes in sprouty-1 and MAP-kinase signaling.

The interesting thing is their conclusion : Anti-miR-21, showed the most statistically significant improvement in the heart failure mouse model when given before induction of heart failure and for as long as three weeks afterward and it might be possible to target entire disease pathways with one drug. Contrats Dr. Thomas Thum.