Archive for the ‘RNA Biology’ Category

First single-course ‘curative’ CRISPR Shot by Intellia rivals Alnylam, Ionis and Pfizer

Reporter: Aviva Lev-Ari, PhD, RN


Intellia to kick-start first single-course ‘curative’ CRISPR shot, as it hopes to beat rivals Alnylam, Ionis and Pfizer

It’s been a good year for Intellia: One of its founders, Jennifer Doudna, Ph.D., nabbed the Nobel Prize in Chemistry for her CRISPR research.

Now, the biotech she helped build is putting that to work, saying it now plans the world’s first clinical trial for a single-course therapy that “potentially halts and reverses” a condition known as hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN).

This genetic disorder occurs when a person is born with a specific DNA mutation in the TTR gene, which causes the liver to produce a protein called transthyretin (TTR) in a misfolded form and build up in the body.

hATTR can manifest as polyneuropathy (hATTR-PN), which can lead to nerve damage, or cardiomyopathy (hATTR-CM), which involves heart muscle disease that can lead to heart failure.

This disorder has seen a lot of interest in recent years, with an RNAi approach from Alnylam seeing an approval for Onpattro a few years back, specifically for hATTR in adults with damage to peripheral nerves.

Ionis Pharmaceuticals and its rival RNAi drug Tegsedi also saw an approval in 2018 for a similar indication.

They both battle with Pfizer’s older med tafamidis, which has been approved in Europe for years in polyneuropathy, and the fight could spread to the U.S. soon.

The drug, now marketed as Vyndaqel and Vyndamax, snatched up an FDA nod last May to treat both hereditary and wild-type ATTR patients with a heart condition called cardiomyopathy.

While coming into an increasingly crowed R&D area, Intellia is looking for a next-gen approach, and has been given the go-ahead by regulators ion the U.K, to start a phase 1 this year.

The idea is for Intellia’s candidate NTLA-2001, which is also partnered with Regeneron, to go beyond its rivals and be the first curative treatment for ATTR.

By applying the company’s in vivo liver knockout technology, NTLA-2001 allows for the possibility of lifelong transthyretin (TTR) protein reduction after a single course of treatment. If this works, this could in essence cure patients of the their disease.

The 38-patient is set to start by year’s end.

“Starting our global NTLA-2001 Phase 1 trial for ATTR patients is a major milestone in Intellia’s mission to develop medicines to cure severe and life-threatening diseases,” said Intellia’s president and chief John Leonard, M.D.

“Our trial is the first step toward demonstrating that our therapeutic approach could have a permanent effect, potentially halting and reversing all forms of ATTR. Once we have established safety and the optimal dose, our goal is to expand this study and rapidly move to pivotal studies, in which we aim to enroll both polyneuropathy and cardiomyopathy patients.”



Other related articles published in this Open Access Online Scientific Journal include the following:


Familial transthyretin amyloid polyneuropathy

Curator: Larry H. Bernstein, MD, FCAP



Stabilizers that prevent transthyretin-mediated cardiomyocyte amyloidotic toxicity

Reporter and curator: Larry H. Bernstein, MD, FCAP



Transthyretin amyloid cardiomyopathy (ATTR-CM): U.S. FDA APPROVES VYNDAQEL® AND VYNDAMAX™ for this Rare and Fatal Disease

Reporter: Aviva Lev-Ari, PhD, RN



Alnylam Announces First-Ever FDA Approval of an RNAi Therapeutic, ONPATTRO™ (patisiran) for the Treatment of the Polyneuropathy of Hereditary Transthyretin-Mediated Amyloidosis in Adults

Reporter: Aviva Lev-Ari, PhD, RN




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Dysregulation of ncRNAs in association with Neurodegenerative Disorders

Curator: Amandeep Kaur

Research over the years has added evidences to the hypothesis of “RNA world” which explains the evolution of DNA and protein from a simple RNA molecule. Our understanding of RNA biology has dramatically changed over the last 50 years and rendered the scientists with the conclusion that apart from coding for protein synthesis, RNA also plays an important role in regulation of gene expression.

Figure: Overall Taxonomy of ncRNAs
Figure: Overall Taxonomy of ncRNAs

The universe of non-coding RNAs (ncRNAs) is transcending the margins of preconception and altered the traditional thought that the coding RNAs or messenger RNAs (mRNAs) are more prevalent in our cells. Research on the potential use of ncRNAs in therapeutic relevance increased greatly after the discovery of RNA interference (RNAi) and provided important insights into our further understanding of etiology of complex disorders.

Figure: Atomic Structure of Non-coding RNA

Latest research on neurodegenerative disorders has shown the perturbed expression of ncRNAs which provides the functional association between neurodegeneration and ncRNAs dysfunction. Due to the diversity of functions and abundance of ncRNAs, they are classified into Housekeeping RNAs and Regulatory ncRNAs.

The best known classes of ncRNAs are the microRNAs (miRNAs) which are extensively studied and are of research focus. miRNAs are present in both intronic and exonic regions of matured RNA (mRNA) and are crucial for development of CNS. The reduction of Dicer-1, a miRNA biogenesis-related protein affects neural development and the elimination of Dicer in specifically dopaminergic neurons causes progressive degeneration of these neuronal cells in striatum of mice.

A new class of regulatory ncRNAs, tRNAs-derived fragments (tRFs) is superabundantly present in brain cells. tRFs are considered as risk factors in conditions of neural degeneration because of accumulation with aging. tRFs have heterogenous functions with regulation of gene expression at multiple layers including regulation of mRNA processing and translation, inducing the activity of silencing of target genes, controlling cell growth and differentiation processes.

The existence of long non-coding RNAs (lncRNAs) was comfirmed by the ENCODE project. Numerous studies reported that approximately 40% of lncRNAs are involved in gene expression, imprinting and pluripotency regulation in the CNS. lncRNA H19 is of paramount significance in neural viability and contribute in epilepsy condition by activating glial cells. Other lncRNAs are highly bountiful in neurons including Evf2 and MALAT1 which play important function in regulating neural differentiation and synapse formation and development of dendritic cells respectively.

Recently, a review article in Nature mentioned about the complex mechanisms of ncRNAs contributing to neurodegenerative conditions. The ncRNA-mediated mechanisms of regulation are as follows:

  • Epigenetic regulation: Various lncRNAs such as BDNF-AS, TUG1, MEG3, NEAT1 and TUNA are differentially expressed in brain tissue and act as epigenetic regulators.
  • RNAi: RNA interference includes post-transcriptional repression by small-interfering RNAs (siRNAs) and binding of miRNAs to target genes. In a wide spectrum of neurodegenerative diseases such as Alzheimer’s disease, Parkinson disease, Huntington’s disease, Amyotrophic lateral sclerosis, Fragile X syndrome, Frontotemporal dementia, and Spinocerebellar ataxia, have shown perturbed expression of miRNA.
  • Alternative splicing: Variation in splicing of transcripts of ncRNAs has shown adverse affects in neuropathology of degenerative diseases.
  • mRNA stability: The stability of mRNA may be affected by RNA-RNA duplex formation which leads to the degradation of sense mRNA or blocking the access to proteins involved in RNA turnover and modify the progression of neurodegenerative disorders.
  • Translational regulation: Numerous ncRNAs including BC200 directly control the translational process of transcripts of mRNAs and effect human brain of Alzheimer’s disease.
  • Molecular decoys: Non-coding RNAs (ncRNAs) dilute the expression of other RNAs by molecular trapping, also known as competing endogenous RNAs (ceRNAs) which hinder the normal functioning of RNAs. The ceRNAs proportion must be equivalent to the number of target miRNAs that can be sequestered by each ncRNAs in order to induce consequential de-repression of the target molecules.
Table: ncRNAs and related processes involved in neurodegenerative disorders

The unknown functions of numerous annotated ncRNAs may explain the underlying complexity in neurodegenerative disorders. The profiling of ncRNAs of patients suffering from neurodevelopmental and neurodegenerative conditions are required to outline the changes in ncRNAs and their role in specific regions of brain and cells. Analysis of Large-scale gene expression and functional studies of ncRNAs may contribute to our understanding of these diseases and their remarkable connections. Therefore, targeting ncRNAs may provide effective therapeutic perspective for the treatment of neurodegenerative diseases.

References https://www.nature.com/scitable/topicpage/rna-functions-352/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035743/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695195/ https://link.springer.com/article/10.1007/s13670-012-0023-4 https://www.nature.com/articles/nrn.2017.90


Other related articles were published in this Open Access Online Scientific Journal, including the following:

RNA in synthetic biology

Curator: Larry H. Bernstein, MD, FCAP


mRNA Data Survival Analysis

Curators: Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN


Recent progress in neurodegenerative diseases and gliomas

Curator: Larry H. Bernstein, MD, FCAP


Genomic Promise for Neurodegenerative Diseases, Dementias, Autism Spectrum, Schizophrenia, and Serious Depression

Reporter and writer: Larry H Bernstein, MD, FCAP


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Bioinformatic Tools for RNASeq: A Curation

Curator: Stephen J. Williams, Ph.D. 


Note:  This will be an ongoing curation as new information and tools become available.

RNASeq is a powerful tool for the analysis of the transcriptome profile and has been used to determine the transcriptional changes occurring upon stimuli such as drug treatment or detecting transcript differences between biological sample cohorts such as tumor versus normal tissue.  Unlike its genomic companion, whole genome and whole exome sequencing, which analyzes the primary sequence of the genomic DNA, RNASeq analyzes the mRNA transcripts, thereby more closely resembling the ultimate translated proteome. In addition, RNASeq and transcriptome profiling can determine if splicing variants occur as well as determining the nonexomic sequences, such as miRNA and lncRNA species, all of which have shown pertinence in the etiology of many diseases, including cancer.

However, RNASeq, like other omic technologies, generates enormous big data sets, which requires multiple types of bioinformatic tools in order to correctly analyze the sequence reads, and to visualize and interpret the output data.  This post represents a curation by the RNA-Seq blog of such tools useful for RNASeq studies and lists and reviews published literature using these curated tools.


From the RNA-Seq Blog

List of RNA-Seq bioinformatics tools

Posted by: RNA-Seq Blog in Data Analysis, Web Tools September 16, 2015 6,251 Views

from: https://en.wiki2.org/wiki/List_of_RNA-Seq_bioinformatics_tools

A review of some of the literature using some of the aforementioned curated tools are discussed below:


A.   Tools Useful for Single Cell RNA-Seq Analysis


B.  Tools for RNA-Seq Analysis of the Sliceasome


C.  Tools Useful for RNA-Seq read assembly visualization


Other articles on RNA and Transcriptomics in this Open Access Journal Include:

NIH to Award Up to $12M to Fund DNA, RNA Sequencing Research: single-cell genomics, sample preparation, transcriptomics and epigenomics, and genome-wide functional analysis.

Single-cell Genomics: Directions in Computational and Systems Biology – Contributions of Prof. Aviv Regev @Broad Institute of MIT and Harvard, Cochair, the Human Cell Atlas Organizing Committee with Sarah Teichmann of the Wellcome Trust Sanger Institute

Complex rearrangements and oncogene amplification revealed by long-read DNA and RNA sequencing of a breast cancer cell line

Single-cell RNA-seq helps in finding intra-tumoral heterogeneity in pancreatic cancer

First challenge to make use of the new NCI Cloud Pilots – Somatic Mutation Challenge – RNA: Best algorithms for detecting all of the abnormal RNA molecules in a cancer cell

Evolution of the Human Cell Genome Biology Field of Gene Expression, Gene Regulation, Gene Regulatory Networks and Application of Machine Learning Algorithms in Large-Scale Biological Data Analysis


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Single-cell RNA-seq helps in finding intra-tumoral heterogeneity in pancreatic cancer

Reporter and Curator: Dr. Sudipta Saha, Ph.D.


Pancreatic cancer is a significant cause of cancer mortality; therefore, the development of early diagnostic strategies and effective treatment is essential. Improvements in imaging technology, as well as use of biomarkers are changing the way that pancreas cancer is diagnosed and staged. Although progress in treatment for pancreas cancer has been incremental, development of combination therapies involving both chemotherapeutic and biologic agents is ongoing.


Cancer is an evolutionary disease, containing the hallmarks of an asexually reproducing unicellular organism subject to evolutionary paradigms. Pancreatic ductal adenocarcinoma (PDAC) is a particularly robust example of this phenomenon. Genomic features indicate that pancreatic cancer cells are selected for fitness advantages when encountering the geographic and resource-depleted constraints of the microenvironment. Phenotypic adaptations to these pressures help disseminated cells to survive in secondary sites, a major clinical problem for patients with this disease.


The immune system varies in cell types, states, and locations. The complex networks, interactions, and responses of immune cells produce diverse cellular ecosystems composed of multiple cell types, accompanied by genetic diversity in antigen receptors. Within this ecosystem, innate and adaptive immune cells maintain and protect tissue function, integrity, and homeostasis upon changes in functional demands and diverse insults. Characterizing this inherent complexity requires studies at single-cell resolution. Recent advances such as massively parallel single-cell RNA sequencing and sophisticated computational methods are catalyzing a revolution in our understanding of immunology.


PDAC is the most common type of pancreatic cancer featured with high intra-tumoral heterogeneity and poor prognosis. In the present study to comprehensively delineate the PDAC intra-tumoral heterogeneity and the underlying mechanism for PDAC progression, single-cell RNA-seq (scRNA-seq) was employed to acquire the transcriptomic atlas of 57,530 individual pancreatic cells from primary PDAC tumors and control pancreases. The diverse malignant and stromal cell types, including two ductal subtypes with abnormal and malignant gene expression profiles respectively, were identified in PDAC.


The researchers found that the heterogenous malignant subtype was composed of several subpopulations with differential proliferative and migratory potentials. Cell trajectory analysis revealed that components of multiple tumor-related pathways and transcription factors (TFs) were differentially expressed along PDAC progression. Furthermore, it was found a subset of ductal cells with unique proliferative features were associated with an inactivation state in tumor-infiltrating T cells, providing novel markers for the prediction of antitumor immune response. Together, the findings provided a valuable resource for deciphering the intra-tumoral heterogeneity in PDAC and uncover a connection between tumor intrinsic transcriptional state and T cell activation, suggesting potential biomarkers for anticancer treatment such as targeted therapy and immunotherapy.
















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scPopCorn: A New Computational Method for Subpopulation Detection and their Comparative Analysis Across Single-Cell Experiments

Reporter and Curator: Dr. Sudipta Saha, Ph.D.


Present day technological advances have facilitated unprecedented opportunities for studying biological systems at single-cell level resolution. For example, single-cell RNA sequencing (scRNA-seq) enables the measurement of transcriptomic information of thousands of individual cells in one experiment. Analyses of such data provide information that was not accessible using bulk sequencing, which can only assess average properties of cell populations. Single-cell measurements, however, can capture the heterogeneity of a population of cells. In particular, single-cell studies allow for the identification of novel cell types, states, and dynamics.


One of the most prominent uses of the scRNA-seq technology is the identification of subpopulations of cells present in a sample and comparing such subpopulations across samples. Such information is crucial for understanding the heterogeneity of cells in a sample and for comparative analysis of samples from different conditions, tissues, and species. A frequently used approach is to cluster every dataset separately, inspect marker genes for each cluster, and compare these clusters in an attempt to determine which cell types were shared between samples. This approach, however, relies on the existence of predefined or clearly identifiable marker genes and their consistent measurement across subpopulations.


Although the aligned data can then be clustered to reveal subpopulations and their correspondence, solving the subpopulation-mapping problem by performing global alignment first and clustering second overlooks the original information about subpopulations existing in each experiment. In contrast, an approach addressing this problem directly might represent a more suitable solution. So, keeping this in mind the researchers developed a computational method, single-cell subpopulations comparison (scPopCorn), that allows for comparative analysis of two or more single-cell populations.


The performance of scPopCorn was tested in three distinct settings. First, its potential was demonstrated in identifying and aligning subpopulations from single-cell data from human and mouse pancreatic single-cell data. Next, scPopCorn was applied to the task of aligning biological replicates of mouse kidney single-cell data. scPopCorn achieved the best performance over the previously published tools. Finally, it was applied to compare populations of cells from cancer and healthy brain tissues, revealing the relation of neoplastic cells to neural cells and astrocytes. Consequently, as a result of this integrative approach, scPopCorn provides a powerful tool for comparative analysis of single-cell populations.


This scPopCorn is basically a computational method for the identification of subpopulations of cells present within individual single-cell experiments and mapping of these subpopulations across these experiments. Different from other approaches, scPopCorn performs the tasks of population identification and mapping simultaneously by optimizing a function that combines both objectives. When applied to complex biological data, scPopCorn outperforms previous methods. However, it should be kept in mind that scPopCorn assumes the input single-cell data to consist of separable subpopulations and it is not designed to perform a comparative analysis of single cell trajectories datasets that do not fulfill this constraint.


Several innovations developed in this work contributed to the performance of scPopCorn. First, unifying the above-mentioned tasks into a single problem statement allowed for integrating the signal from different experiments while identifying subpopulations within each experiment. Such an incorporation aids the reduction of biological and experimental noise. The researchers believe that the ideas introduced in scPopCorn not only enabled the design of a highly accurate identification of subpopulations and mapping approach, but can also provide a stepping stone for other tools to interrogate the relationships between single cell experiments.















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Reporter and Curator: Dr. Sudipta Saha, Ph.D.


RNA plays various roles in determining how the information in our genes drives cell behavior. One of its roles is to carry information encoded by our genes from the cell nucleus to the rest of the cell where it can be acted on by other cell components. Rresearchers have now defined how RNA also participates in transmitting information outside cells, known as extracellular RNA or exRNA. This new role of RNA in cell-to-cell communication has led to new discoveries of potential disease biomarkers and therapeutic targets. Cells using RNA to talk to each other is a significant shift in the general thought process about RNA biology.


Researchers explored basic exRNA biology, including how exRNA molecules and their transport packages (or carriers) were made, how they were expelled by producer cells and taken up by target cells, and what the exRNA molecules did when they got to their destination. They encountered surprising complexity both in the types of carriers that transport exRNA molecules between cells and in the different types of exRNA molecules associated with the carriers. The researchers had to be exceptionally creative in developing molecular and data-centric tools to begin making sense of the complexity, and found that the type of carrier affected how exRNA messages were sent and received.


As couriers of information between cells, exRNA molecules and their carriers give researchers an opportunity to intercept exRNA messages to see if they are associated with disease. If scientists could change or engineer designer exRNA messages, it may be a new way to treat disease. The researchers identified potential exRNA biomarkers for nearly 30 diseases including cardiovascular disease, diseases of the brain and central nervous system, pregnancy complications, glaucoma, diabetes, autoimmune diseases and multiple types of cancer.


As for example some researchers found that exRNA in urine showed promise as a biomarker of muscular dystrophy where current studies rely on markers obtained through painful muscle biopsies. Some other researchers laid the groundwork for exRNA as therapeutics with preliminary studies demonstrating how researchers might load exRNA molecules into suitable carriers and target carriers to intended recipient cells, and determining whether engineered carriers could have adverse side effects. Scientists engineered carriers with designer RNA messages to target lab-grown breast cancer cells displaying a certain protein on their surface. In an animal model of breast cancer with the cell surface protein, the researchers showed a reduction in tumor growth after engineered carriers deposited their RNA cargo.


Other than the above research work the scientists also created a catalog of exRNA molecules found in human biofluids like plasma, saliva and urine. They analyzed over 50,000 samples from over 2000 donors, generating exRNA profiles for 13 biofluids. This included over 1000 exRNA profiles from healthy volunteers. The researchers found that exRNA profiles varied greatly among healthy individuals depending on characteristics like age and environmental factors like exercise. This means that exRNA profiles can give important and detailed information about health and disease, but careful comparisons need to be made with exRNA data generated from people with similar characteristics.


Next the researchers will develop tools to efficiently and reproducibly isolate, identify and analyze different carrier types and their exRNA cargos and allow analysis of one carrier and its cargo at a time. These tools will be shared with the research community to fill gaps in knowledge generated till now and to continue to move this field forward.
















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Alnylam Announces First-Ever FDA Approval of an RNAi Therapeutic, ONPATTRO™ (patisiran) for the Treatment of the Polyneuropathy of Hereditary Transthyretin-Mediated Amyloidosis in Adults

Reporter: Aviva Lev-Ari, PhD, RN

Aug 10,2018

− First and Only FDA-approved Treatment Available in the United States for this Indication –

− ONPATTRO Shown to Improve Polyneuropathy Relative to Placebo, with Reversal of Neuropathy Impairment Compared to Baseline in Majority of Patients –

− Improvement in Specified Measures of Quality of Life and Disease Burden Demonstrated Across Diverse, Global Patient Population –

− Alnylam to Host Conference Call Today at 3:00 p.m. ET. −

CAMBRIDGE, Mass.–(BUSINESS WIRE)–Aug. 10, 2018– Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, announced today that the United States Food and Drug Administration (FDA) approved ONPATTRO™ (patisiran) lipid complex injection, a first-of-its-kind RNA interference (RNAi) therapeutic, for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults. ONPATTRO is the first and only FDA-approved treatment for this indication. hATTR amyloidosis is a rare, inherited, rapidly progressive and life-threatening disease with a constellation of manifestations. In addition to polyneuropathy, hATTR amyloidosis can lead to other significant disabilities including decreased ambulation with the loss of the ability to walk unaided, a reduced quality of life, and a decline in cardiac functioning. In the largest controlled study of hATTR amyloidosis, ONPATTRO was shown to improve polyneuropathy – with reversal of neuropathy impairment in a majority of patients – and to improve a composite quality of life measure, reduce autonomic symptoms, and improve activities of daily living.

ONPATTRO was reviewed by the FDA under Priority Review and had previously been granted Breakthrough Therapy and Orphan Drug Designations. On July 27, patisiran received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) for the treatment of hereditary transthyretin-mediated amyloidosis in adults with stage 1 or stage 2 polyneuropathy under accelerated assessment by the European Medicines Agency. The recommended Summary of Product Characteristics (SmPC) for the European Union (EU) includes data on secondary and exploratory endpoints. Expected in September, the European Commission will review the CHMP recommendation to make a final decision on marketing authorization, applicable to all 28 EU member states, plus Iceland, Liechtenstein and Norway. Regulatory filings in other markets, including Japan, are planned beginning in mid-2018.

This press release features multimedia. View the full release here: https://www.businesswire.com/news/home/20180810005398/en/



Alnylam protects its Intellectual Property (IP) with fundamental, chemistry, delivery, and target patents and patent applications covering the development and commercialization of RNAi therapeutics as well as that afforded by the various trademark, copyright, and trade secret laws.

Alnylam’s patent estate includes a large number of issued patents and pending patent applications in the world’s major pharmaceutical markets—United States, European Union, and Japan, along with other countries throughout the world. This broad portfolio covers, for example, oligonucleotides, including synthetic RNA molecules, both modified and unmodified, optimized for a variety of delivery modalities, such as lipid- and conjugate-based systems, their synthesis and use, including use as therapeutics, diagnostics, and research reagents. We believe these patents and pending applications place Alnylam in the strongest possible position to not only build our company over the long term and accelerate our efforts to bring life-saving drugs to patients in need, but to enable other companies for advancement of RNAi therapeutics with licenses to our IP estate and associated know-how. This belief has been validated by the progress of Alnylam to date with multiple programs in pre-clinical and clinical development and with well over 30 distinct agreements entered into with leading pharmaceutical, biotechnology, and research reagent companies.

Alnylam has an extensive array of registered trademarks in the United States, European Union, Japan and other countries throughout the world as well as various copyrighted works. In addition to patent protection, Alnylam further safeguards its IP through the use of trade secret protection afforded by the relevant state and federal trade secret laws.



Post       : Patisiran

URL        : http://newdrugapprovals.org/2018/08/13/patisiran/

Posted     : August 13, 2018 at 9:51 am


Tags       : 50FKX8CB2Y, 6024128, ALN-18328, ALN-TTR02, Alnylam


GENZ-438027, Onpattro, Orphan Drug Designation, patisiran, Priority

review, SAR-438037

Categories : 0rphan drug status, Breakthrough Therapy Designation,

FAST TRACK FDA, FDA 2018, Priority review




Sense strand:




Anti-sense strand:



RNA, (A-U-G-G-A-A-Um-A-C-U-C-U-U-G-G-U-Um-A-C-dT-dT), complex with RNA

(G-Um-A-A-Cm-Cm-A-A-G-A-G-Um-A-Um-Um-Cm-Cm-A-Um-dT-dT) (1:1),

ALN-18328, 6024128  , ALN-TTR02  , GENZ-438027  , SAR-438037  ,

50FKX8CB2Y (UNII code)

for RNA, (A-U-G-G-A-A-Um-A-C-U-C-U-U-G-G-U-Um-A-C-dT-dT), complex

with RNA(G-Um-A-A-Cm-Cm-A-A-G-A-G-Um-A-Um-Um-Cm-Cm-A-Um-dT-dT) (1:1)

Nucleic Acid Sequence

Sequence Length: 42, 21, 2112 a 7 c 7 g 4 t 12 umultistranded (2);


CAS 1420706-45-1

Treatment of Amyloidosis,



Lipid-nanoparticle-encapsulated double-stranded siRNA targeting a 3

untranslated region of mutant and wild-type transthyretin mRNA

Patisiran (trade name Onpattro®) is a medication for the treatment of

polyneuropathy ( https://en.wikipedia.org/wiki/Polyneuropathy )  in

people with hereditary transthyretin-mediated amyloidosis (



) . It is the first small interfering RNA (

https://en.wikipedia.org/wiki/Small_interfering_RNA ) -based drug

approved by the FDA ( https://en.wikipedia.org/wiki/FDA ) . Through

this mechanism, it is a gene silencing (

https://en.wikipedia.org/wiki/Gene_silencing )  drug that interferes

with the production of an abnormal form of transthyretin (

https://en.wikipedia.org/wiki/Transthyretin ) .



( https://en.wikipedia.org/wiki/File:Patisiran.png )

Chemical structure of Patisiran.

During its development, patisiran was granted orphan drug status (

https://en.wikipedia.org/wiki/Orphan_drug_status ) , fast track

designation ( https://en.wikipedia.org/wiki/Fast_track_designation ) ,

priority review ( https://en.wikipedia.org/wiki/Priority_review )  and

breakthrough therapy designation (

https://en.wikipedia.org/wiki/Breakthrough_therapy_designation )  due

to its novel mechanism and the rarity of the condition it is designed

to treat.[1] ( https://en.wikipedia.org/wiki/Patisiran#cite_note-1 )

[2] ( https://en.wikipedia.org/wiki/Patisiran#cite_note-2 )  It was

approved by the FDA in August 2018 and is expected to cost around

$345,000 to $450,000 per year.[3] (

https://en.wikipedia.org/wiki/Patisiran#cite_note-3 )

Patisiran was granted orphan drug designation in the U.S. and Japan

for the treatment of familial amyloid polyneuropathy. Fast track

designation was also granted in the U.S. for this indication. In the

E.U., orphan drug designation was assigned to the compound for the

treatment of transthyretin-mediated amyloidosis (initially for the

treatment of familial amyloid polyneuropathy)

Hereditary transthyretin-mediated amyloidosis (



)  is a fatal rare disease (

https://en.wikipedia.org/wiki/Rare_disease )  that is estimated to

affect 50,000 people worldwide. Patisiran is the first drug approved

by the FDA to treat this condition.[4] (

https://en.wikipedia.org/wiki/Patisiran#cite_note-4 )

Patisiran is a second-generation siRNA therapy targeting mutant

transthyretin (TTR) developed by Alnylam for the treatment of familial

amyloid polyneuropathy. The product is delivered by means of Arbutus

Biopharma’s (formerly Tekmira Pharmaceuticals) lipid nanoparticle



“A lot of peo­ple think it’s win­ter out there for RNAi. But I think

it’s spring­time.” — Al­ny­lam CEO John Maraganore, NYT, Feb­ru­ary 7,


Patisiran — designed to silence messenger RNA and block the production

of TTR protein before it is made — is number 6 on Clarivate’s list of

blockbusters (



)  set to launch this year, with a 2022 sales forecast of $1.22

billion. Some of the peak sales estimates range significantly higher

as analysts crunch the numbers on a disease that afflicts only about

30,000 people worldwide.


WO 2016033326


Transthyretin (TTR) is a tetrameric protein produced primarily in the


Mutations in the TTR gene destabilize the protein tetramer, leading to

misfolding of monomers and aggregation into TTR amyloid fibrils

(ATTR). Tissue deposition results in systemic ATTR amyloidosis

(Coutinho et al, Forty years of experience with type I amyloid

neuropathy. Review of 483 cases. In: Glenner et al, Amyloid and

Amyloidosis, Amsterdam: Excerpta Media, 1980 pg. 88-93; Hou et al.,

Transthyretin and familial amyloidotic polyneuropathy. Recent progress

in understanding the molecular mechanism of

neurodegeneration. FEBS J 2007, 274: 1637-1650; Westermark et al,

Fibril in senile systemic amyloidosis is derived from normal

transthyretin. Proc Natl Acad Sci USA 1990, 87: 2843-2845). Over 100

reported TTR mutations exhibit a spectrum of disease symptoms.

[0004] TTR amyloidosis manifests in various forms. When the peripheral

nervous system is affected more prominently, the disease is termed

familial amyloidotic

polyneuropathy (FAP). When the heart is primarily involved but the

nervous system is not, the disease is called familial amyloidotic

cardiomyopathy (FAC). A third major type of TTR amyloidosis is called

leptomeningeal/CNS (Central Nervous System) amyloidosis.

[0005] The most common mutations associated with familial amyloid

polyneuropathy (FAP) and ATTR-associated cardiomyopathy, respectively, are Val30Met

(Coelho et al, Tafamidis for transthyretin familial amyloid

polyneuropathy: a randomized, controlled trial. Neurology 2012, 79:

785-792) and Vall22Ile (Connors et al, Cardiac amyloidosis in African

Americans: comparison of clinical and laboratory features of

transthyretin VI 221 amyloidosis and immunoglobulin light chain

amyloidosis. Am Heart J 2009, 158: 607-614). [0006] Current treatment

options for FAP focus on stabilizing or decreasing the amount of

circulating amyloidogenic protein. Orthotopic liver transplantation

reduces mutant TTR levels (Holmgren et al, Biochemical effect of liver

transplantation in two Swedish patients with familial amyloidotic

polyneuropathy (FAP-met30). Clin Genet 1991, 40: 242-246), with

improved survival reported in patients with early-stage FAP, although

deposition of wild-type TTR may continue (Yazaki et al, Progressive

wild-type transthyretin deposition after liver transplantation

preferentially occurs into myocardium in FAP patients. Am J Transplant

2007, 7:235-242; Adams et al, Rapid progression of familial amyloid

polyneuropathy: a multinational natural history study Neurology 2015

Aug 25; 85(8) 675-82; Yamashita et al, Long-term survival after liver

transplantation in patients with familial amyloid polyneuropathy.

Neurology 2012, 78: 637-643; Okamoto et al., Liver

transplantation for familial amyloidotic polyneuropathy: impact on

Swedish patients’ survival. Liver Transpl 2009, 15: 1229-1235; Stangou

et al, Progressive cardiac amyloidosis following liver transplantation

for familial amyloid polyneuropathy: implications for amyloid

fibrillogenesis. Transplantation 1998, 66:229-233; Fosby et al, Liver

transplantation in the Nordic countries – An intention to treat and

post-transplant analysis from The Nordic Liver Transplant Registry

1982-2013. Scand J Gastroenterol. 2015 Jun; 50(6):797-808.

Transplantation, in press).

[0007] Tafamidis and diflunisal stabilize circulating TTR tetramers,

which can slow the rate of disease progression (Berk et al,

Repurposing diflunisal for familial amyloid polyneuropathy: a

randomized clinical trial. JAMA 2013, 310: 2658-2667; Coelho et al.,

2012; Coelho et al, Long-term effects of tafamidis for the treatment

of transthyretin familial amyloid polyneuropathy. J Neurol 2013, 260:

2802-2814; Lozeron et al, Effect on disability and safety of Tafamidis

in late onset of Met30 transthyretin familial amyloid polyneuropathy.

Eur J Neurol 2013, 20: 1539-1545). However, symptoms continue to

worsen on treatment in a large proportion of patients, highlighting

the need for new, disease-modifying treatment options for FAP.

[0008] Description of dsRNA targeting TTR can be found in, for example,

International patent application no. PCT/US2009/061381 (WO2010/048228) and

International patent application no. PCT/US2010/05531 1 (WO201



[0009] Described herein are methods for reducing or arresting an increase

in a Neuropathy Impairment Score (NIS) or a modified NIS (mNIS+7) in a

human subject by administering an effective amount of a transthyretin

(TTR)-inhibiting composition, wherein the effective amount reduces a

concentration of TTR protein in serum of the human subject to below 50

μg/ml or by at least 80%. Also described herein are methods for

adjusting a dosage of a TTR- inhibiting composition for treatment of

increasing NIS or Familial Amyloidotic Polyneuropathy (FAP) by

administering the TTR- inhibiting composition to a subject having the

increasing NIS or FAP, and determining a level of TTR protein in the

subject having the increasing NIS or FAP. In some embodiments, the

amount of the TTR- inhibiting composition subsequently administered to

the subject is increased if the level of TTR protein is greater than

50 μg/ml, and the amount of the TTR- inhibiting composition

subsequently administered to the subject is decreased if the level of

TTR protein is below 50 μg/ml. Also described herein are formulated

versions of a TTR inhibiting siRNA.




WO 2016203402


Annals of Medicine (Abingdon, United Kingdom) (2015), 47(8), 625-638.

Pharmaceutical Research (2017), 34(7), 1339-1363

Annual Review of Pharmacology and Toxicology (2017), 57, 81-105




Alnylam Announces First-Ever FDA Approval of an RNAi Therapeutic,

ONPATTRO™ (patisiran) for the Treatment of the Polyneuropathy of

Hereditary Transthyretin-Mediated Amyloidosis in Adults

Aug 10,2018

− First and Only FDA-approved Treatment Available in the United States

for this Indication –

− ONPATTRO Shown to Improve Polyneuropathy Relative to Placebo, with

Reversal of Neuropathy Impairment Compared to Baseline in Majority of

Patients –

− Improvement in Specified Measures of Quality of Life and Disease

Burden Demonstrated Across Diverse, Global Patient Population –



https://endpts.com/gung-ho-alnylam-lands-historic-fda-ok-on-patisir an-revving-up-the-first-global-rollout-for-an-rnai-breakthrough/

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Medical Scientific Discoveries for the 21st Century & Interviews with Scientific Leaders at https://www.amazon.com/dp/B078313281 – electronic Table of Contents 

Author, Curator and Editor: Larry H Bernstein, MD, FCAP

Available on Kindle Store @ Amazon.com since 12/9/2017

List of Contributors & Contributors’ Biographies

Volume Author, Curator and Editor

Larry H Bernstein, MD, FCAP

Preface, all Introductions, all Summaries and Epilogue

Part One:

1.4, 1.5, 1.6, 2.1.1, 2.1.2, 2.1.3, 2.1.4, 2.2.1, 2.2.2, 2.2.3, 2.3, 2.4, 2.4.1, 2.4.2, 2.5, 2.6.1, 2.6.2, 2.6.3, 2.6.4, 2.7, 2.8, 2.9, 2.10, 3.1, 3.2, 3.3, 3.4, 4.1, 4.2, 4.3

Part Two:

5.2, 5.3, 5.6, 6.1.2, 6.1.4, 6.2.1, 6.2.2, 6.3.2, 6.3.4, 6.3.5, 6.3.6, 6.3.8, 6.3.10, 6.4.1, 6.4.2,,,, 7.1, 7.2, 7.3, 7.4, 7.5, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 8.9.1, 8.9.3, 8.9.4, 8.9.5, 8.9.6, 8.10.1, 8.10.2, 8.10.3, 8.10.4, 9.2, 9.3, 9.5, 9.6, 9.7, 9.8, 9.9, 9.10, 9.11, 9.12, 9.13, 9.14, 9.15, 9.16, 10.2, 10.5, 10.6, 10.7, 10.8, 10.10, 10.11, 11.1, 11.2, 11.3, 11.5, 11.6, 11.7, 12.1, 12.2, 12.3, 12.4, 12.5, 12.7, 12.8, 12.9, 12.10, 12.11, 12.12, 13.1, 13.2, 13.3, 13.6, 13.12, 13.13, 14.1, 14.2

Guest Authors:

Pnina Abir-Am, PhD Part Two: 6.1.1

Stephen J Williams, PhDPart Two: 6.2.6,, 10.4, 10.9, 13.4

Aviva Lev-Ari, PhD, RN:

Part One:

1.1, 1.2, 1.3, 1.4, 1.5, 1.7, 2.2.1, 2.3

Part Two:

5.1, 5.4, 5.5, 5.7, 5.8, 5.9, 5.10, 5.11, 6.1.3, 6.2.3, 6.2.4, 6.2.5, 6.3.1, 6.3.3, 6.3.7, 6.3.9, 6.4.3,,,,, 6.5.4, 6.5.5, 6,5,6, 8.9.2, 8.10.2, 9.1, 9.4, 10.1, 10.3, 11.4, 12.6, 13.5, 13.7, 13.8, 13.9, 13.10, 13.11

Adam Sonnenberg, BSC, MSc(c)Part Two: 13.9


electronic Table of Contents


Physician as Authors, Writers in Medicine and Educator in Public Health


Chapter 1: Physicians as Authors


1.1  The Young Surgeon and The Retired Pathologist: On Science, Medicine and HealthCare Policy – Best writers Among the WRITERS

1.2 Atul Gawande: Physician and Writer

1.3 Editorial & Publication of Articles in e-Books by  Leaders in Pharmaceutical Business Intelligence:  Contributions of Larry H Bernstein, MD, FCAP

1.4 Abraham Verghese, MD, Physician and Notable Author

1.5 Eric Topol, M.D.

1.6 Gregory House, MD

1.7 Peter Mueller, MD  Professor of Radiology @MGH & HMS – 2015 Synergy’s Honorary Award Recipient


Chapter 2: Professional Recognition


2.1 Proceedings

2.1.1 Research Presentations

2.1.2 Proceedings of the NYAS

2.1.3 Cold Spring Harbor Conference Meetings

2.1.4 Young Scientist Seminars

2.2 Meet Great Minds

2.2.1 Meet the Laureates

2.2.2 Richard Feynman, Genius and Laureate

2.2.3 Fractals and Heat Energy

2.3 MacArthur Foundation Awards

2.4 Women’s Contributions went beyond Rosie the Riveter

2.4.1 Secret Maoist Chinese Operation Conquered Malaria

2.4.2 Antiparasite Drug Developers Win Nobel

2.5 Impact Factors and Achievement

2.6   RAPsodisiac Medicine

2.6.1 Outstanding-achievements-in-radiology-or-radiotherapy

2.6.2 Outstanding-achievement-in-anesthesiology

2.6.3 Outstanding-achievement-in-pathology

2.6.4 Topics in Pathology – Special Issues from Medscape Pathology

2.7 How to win the Nobel Prize

2.8 Conversations about Medicine

2.9 Current Advances in Medical Technology

2.10 Atul Butte, MD, PhD


Chapter 3:  Medical and Allied Health Sciences Education


3.1 National Outstanding Medical Student Award Winners

3.2 Outstanding Awards in Medical Education

3.3 Promoting Excellence in Physicians and Nurses

3.4 Excellence in mentoring


Chapter 4: Science Teaching in Math and Technology (STEM)


4.1 Science Teaching in Math and Technology

4.2 Television as a Medium for Science Education

4.2.1 Science Discovery TV

4.3 From Turing to Watson



Medical Scientific Discoveries Interviews with Scientific Leaders

Chapter 5: Cardiovascular System


5.1 Physiologist, Professor Lichtstein, Chair in Heart Studies at The Hebrew University elected Dean of the Faculty of Medicine at The Hebrew University of Jerusalem

5.2 Mitochondrial Dysfunction and Cardiac Disorders

5.3 Notable Contributions to Regenerative Cardiology

5.4 For Accomplishments in Cardiology and Cardiovascular Diseases: The Arrigo Recordati International Prize for Scientific Research

5.5 Becoming a Cardiothoracic Surgeon: An Emerging Profile in the Surgery Theater and through Scientific Publications

5.6 Diagnostics and Biomarkers: Novel Genomics Industry Trends vs Present Market Conditions and Historical Scientific Leaders Memoirs

5.7 CVD Prevention and Evaluation of Cardiovascular Imaging Modalities: Coronary Calcium Score by CT Scan Screening to justify or not the Use of Statin

5.8 2013 as A Year of Revolutionizing Medicine and Top 11 Cardiology Stories

5.9 Bridging the Gap in Medical Innovations – Elazer Edelman @ TEDMED 2013

5.10 Development of a Pancreatobiliary Chemotherapy Eluting Stent for Pancreatic Ductal Adenocarcinoma PIs: Jeffrey Clark (MGH), Robert Langer (Koch), Elazer Edelman (Harvard:MIT HST Program)

5.11 Publications on Heart Failure by Prof. William Gregory Stevenson, M.D., BWH


Chapter 6: Genomics

6.1 Genetics before the Human Genome Project

6.1.1 Why did Pauling Lose the “Race” to James Watson and Francis Crick? How Crick Describes his Discovery in a Letter to his Son

6.1.2 John Randall’s MRC Research Unit and Rosalind Franklin’s role at Kings College

6.1.3 Interview with the co-discoverer of the structure of DNA: Watson on The Double Helix and his changing view of Rosalind Franklin

6.1.4 The Initiation and Growth of Molecular Biology and Genomics, Part I

6.2 The Human Genome Project: Articles of Note  @ pharmaceuticalintelligence.com by multiple authors

6.2.1 CRACKING THE CODE OF HUMAN LIFE: The Birth of BioInformatics & Computational Genomics

6.2.2 What comes after finishing the Euchromatic Sequence of the Human Genome?

6.2.3 Human Genome Project – 10th Anniversary: Interview with Kevin Davies, PhD – The $1000 Genome

6.2.4 University of California Santa Cruz’s Genomics Institute will create a Map of Human Genetic Variations

6.2.5 Exceptional Genomes: The Process to find them

6.2.6 Multiple Lung Cancer Genomic Projects Suggest New Targets, Research Directions for Non-Small Cell Lung Cancer

6.3 The Impact of Genome Sequencing on Biology and Medicine

6.3.1 Genomics in Medicine – Establishing a Patient-Centric View of Genomic Data

6.3.2 Modification of genes by homologous recombination – Mario Capecchi, Martin Evans, Oliver Smithies

6.3.3 AAAS February 14-18, 2013, Boston: Symposia – The Science of Uncertainty in Genomic Medicine

6.3.4 The Metabolic View of Epigenetic Expression

6.3.5  Pharmacogenomics

6.3.6 Neonatal Pathophysiology

6.3.7 Genetics of Conduction Disease: Atrioventricular (AV) Conduction Disease (block): Gene Mutations – Transcription, Excitability, and Energy Homeostasis

6.3.8 3D mapping of genome in combine FISH and RNAi

6.3.9 Human Variome Project: encyclopedic catalog of sequence variants indexed to the human genome sequence

6.3.10 DNA mutagenesis and DNA repair

6.4 Scientific Leadership Recognition for Contributions to Genomics

6.4.1 Interview with Elizabeth H. Blackburn, Carol W. Greider and Jack W. Szostak (44 minutes)

6.4.2 DNA Repair Pioneers Win Nobel – Tomas Lindahl, Paul Modrich, and Aziz Sancar 2015 Nobel Prize in Chemistry for the mechanisms of DNA repair

6.4.3  Richard Lifton, MD, PhD of Yale University and Howard Hughes Medical Institute: Recipient of 2014 Breakthrough Prizes Awarded in Life Sciences for the Discovery of Genes and Biochemical Mechanisms that cause Hypertension

6.5 Contemporary Field Leaders in Genomics

6.5.1 ROBERT LANGER 2014 Breakthrough Prizes Awarded in Fundamental Physics and Life Sciences for a Total of $21 Million – MIT’s Robert Langer gets $3 Million National Medal of Science – 2006 Robert S. Langer  Confluence of Chemistry, Physics, and Biology

6.5.2 JENNIFER DOUDNA Jennifer Doudna, cosmology teams named 2015 Breakthrough Prize winners UPDATED – Medical Interpretation of the Genomics Frontier – CRISPR – Cas9: Gene Editing Technology for New Therapeutics

6.5.3 ERIC LANDER  2012 Harvey Prize in April 30: at the Technion-Israel Institute of Technology to Eric S. Lander @MIT & Eli Yablonovitch @UC, Berkeley

6.5.4 2013 Genomics: The Era Beyond the Sequencing of the Human Genome: Francis Collins, Craig Venter, Eric Lander, et al.

6.5.5 Recognitions for Contributions in Genomics by Dan David Prize Awards

6.5.6   65 Nobel Laureates meet 650 young scientists covering the fields of physiology and medicine, physics, and chemistry, 28 June – 3 July, 2015, Lindau & Mainau Island, Germany


Chapter 7: The RNAs


7.1 RNA polymerase – molecular basis for DNA transcription – Roger Kornberg, MD

7.2  One gene, one protein – Charles Yanofsky

7.3 Turning genetic information into working proteins – James E. Darnell Jr.

7.4 Small but mighty RNAs – Victor Ambros, David Baulcombe, and Gary Ruvkun, Phillip A. Sharp

7.5 Stress-response gene networks – Nina V. Fedoroff


Chapter 8: Proteomics, Protein-folding, and Cell Regulation

8.1 The Life and Work of Allan Wilson

8.2 Proteomics

8.3 More Complexity in Protein Evolution

8.4 Proteins: An evolutionary record of diversity and adaptation

8.5 Heroes in Basic Medical Research – Leroy Hood

8.6 Ubiquitin researchers win Nobel – Ciechanover, Hershko, and Rose awarded for discovery of ubiquitin-mediated proteolysis

8.7 Buffering of genetic modules involved in tricarboxylic acid cycle metabolism provides homeostatic regulation

8.8 Dynamic Protein Profiling

8.9 Protein folding

8.9.1 Protein misfolding and prions – Susan L. Lindquist, Stanley B. Prusiner

8.9.2 A Curated Census of Autophagy-Modulating Proteins and Small Molecules Candidate Targets for Cancer Therapy

8.9.3 Voluntary and Involuntary S-Insufficiency

8.9.4 Transthyretin and Lean Body Mass in Stable and Stressed State

8.9.5 The matter of stunting in the Ganges Plains

8.9.6 Proteins, Imaging and Therapeutics

8.10 Protein Folding and Vesicle Cargo

8.10.1 Heat Shock Proteins (HSP) and Molecular Chaperones

8.10.2 Collagen-binding Molecular Chaperone HSP47: Role in Intestinal Fibrosis – colonic epithelial cells and sub epithelial myofibroblasts

8.10.3 Biology, Physiology and Pathophysiology of Heat Shock Proteins

8.10.4 The Role of Exosomes in Metabolic Regulation 


Chapter 9:  Neuroscience


9.1 Nobel Prize in Physiology or Medicine 2013 for Cell Transport: James E. Rothman of Yale University; Randy W. Schekman of the University of California, Berkeley; and Dr. Thomas C. Südhof of Stanford University

9.2 Proteins that control neurotransmitter release – Richard H. Scheller

9.3 Heroes in Basic Medical Research – Robert J. Lefkowitz

9.4 MIND AND MEMORY: BIOLOGICAL AND DIGITAL – 2014 Dan David Prize Symposium

9.5 A new way of moving – Michael Sheetz, James Spudich, Ronald Vale

9.6 Role the basal ganglia

9.7 The Neurogenetics of Language – Patricia Kuhl – 2015 George A. Miller Award

9.8 The structure of our visual system

9.9 Outstanding Achievement in Schizophrenia Research

9.10 George A. Miller, a Pioneer in Cognitive Psychology, Is Dead at 92

9.11 – To understand what happens in the brain to cause mental illness

9.12 Brain and Cognition

9.13 – To reduce symptoms of mental illness and retrain the brain

9.14 Behavior

9.15 Notable Papers in Neurosciences

9.16 Pyrroloquinoline quinone (PQQ) – an unproved supplement


Chapter 10: Microbiology & Immunology


10.1 Reference Genes in the Human Gut Microbiome: The BGI Catalogue

10.2 Malnutrition in India, high newborn death rate and stunting of children age under five years

10.3 In His Own Words: Leonard Herzenberg, The Immunologist Who Revolutionized Research, Dies at 81

10.4 Heroes in Medical Research: Dr. Robert Ting, Ph.D. and Retrovirus in AIDS and Cancer

10.5 Tang Prize for 2014: Immunity and Cancer

10.6 Halstedian model of cancer progression

10.7 The History of Hematology and Related Sciences

10.8 Pathology Emergence in the 21st Century

10.9 Heroes in Medical Research: Barnett Rosenberg and the Discovery of Cisplatin

10.10  T cell-mediated immune responses & signaling pathways activated by TLRs – Bruce A. Beutler, Jules A. Hoffmann, Ralph M. Steinman

10.11 Roeder – the coactivator OCA-B, the first cell-specific coactivator, discovered by Roeder in 1992, is unique to immune system B cells


Chapter 11: Endocrine Hormones


11.1 Obesity – 2010 Douglas L. ColemanJeffrey M. Friedman

11.2 Lonely Receptors: RXR – Jensen, Chambon, and Evans – Nuclear receptors provoke RNA production in response to steroid hormones

11.3 The Fred Conrad Koch Lifetime Achievement Award—the Society’s highest honor—recognizes the lifetime achievements and exceptional contributions of an individual to the field of endocrinology

11.4 Gerald D Aurbach Award for Outstanding Translational Research

11.5 Roy O. Greep Award for Outstanding Research in Endocrinology – Martin M. Matzuk

11.6 American Physiology Society Awards

11.7 Solomon Berson and Rosalyn Yalow


Chapter 12. Stem Cells


12.1 Mature cells can be reprogrammed to become pluripotent – John Gurdon and Shinya Yamanaka

12.2 Observing the spleen colonies in mice and proving the existence of stem cells – Till and McCulloch

12.3 McEwen Award for Innovation: Irving Weissman, M.D., Stanford School of Medicine, and Hans Clevers, M.D., Ph.D., Hubrecht Institute

12.4 Developmental biology

12.5  CRISPR/Cas-mediated genome engineering – Rudolf Jaenisch

12.6 Ribozymes and RNA Machines –  Work of Jennifer A. Doudna

12.7 Ralph Brinster, ‘Father of Transgenesis’

12.8 Targeted gene modification

12.9 Stem Cells and Cancer

12.10 ALPSP Awards

12.11 Eppendorf Award for Young European Investigators

12.12 Breaking news about genomic engineering, T2DM and cancer treatments

Chapter 13: 3D Printing and Medical Application


13.1 3D Printing

13.2 What is 3D printing?

13.3 The Scientist Who Is Making 3D Printing More Human

13.4 Join These Medical 3D Printing Groups on Twitter and LinkedIn for great up to date news

13.5 Neri Oxman and her Mediated Matter group @MIT Media Lab have developed a technique for 3D-printing Molten Glass

13.6 The ‘chemputer’ that could print out any drug

13.7 3-D-Bioprinting in use to Create Cardiac Living Tissue: Print your Heart out

13.8 LPBI’s Perspective on Medical and Life Sciences Applications – 3D Printing: BioInks, BioMaterials-BioPolymer

13.9 Medical MEMS, Sensors and 3D Printing: Frontier in Process Control of BioMaterials

13.10 NIH and FDA on 3D Printing in Medical Applications: Views for On-demand Drug Printing, in-Situ direct Tissue Repair and Printed Organs for Live Implants

13.11 ‘Pop-up’ fabrication technique trumps 3D printing

13.12 Augmentation of the ONTOLOGY of the 3D Printing Research

13.13 Superresolution Microscopy


Chapter 14: Synthetic Medicinal Chemistry


14.1 Insights in Biological and Synthetic Medicinal Chemistry

14.2 Breakthrough work in cancer

Summary to Part Two

Volume Summary and Conclusions




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Knowing the genetic vulnerability of bladder cancer for therapeutic intervention

Reporter and Curator: Dr. Sudipta Saha, Ph.D.


A mutated gene called RAS gives rise to a signalling protein Ral which is involved in tumour growth in the bladder. Many researchers tried and failed to target and stop this wayward gene. Signalling proteins such as Ral usually shift between active and inactive states.


So, researchers next tried to stop Ral to get into active state. In inacvtive state Ral exposes a pocket which gets closed when active. After five years, the researchers found a small molecule dubbed BQU57 that can wedge itself into the pocket to prevent Ral from closing and becoming active. Now, BQU57 has been licensed for further development.


Researchers have a growing genetic data on bladder cancer, some of which threaten to overturn the supposed causes of bladder cancer. Genetics has also allowed bladder cancer to be reclassified from two categories into five distinct subtypes, each with different characteristics and weak spots. All these advances bode well for drug development and for improved diagnosis and prognosis.


Among the groups studying the genetics of bladder cancer are two large international teams: Uromol (named for urology and molecular biology), which is based at Aarhus University Hospital in Denmark, and The Cancer Genome Atlas (TCGA), based at institutions in Texas and Boston. Each team tackled a different type of cancer, based on the traditional classification of whether or not a tumour has grown into the muscle wall of the bladder. Uromol worked on the more common, earlier form, non-muscle-invasive bladder cancer, whereas TCGA is looking at muscle-invasive bladder cancer, which has a lower survival rate.


The Uromol team sought to identify people whose non-invasive tumours might return after treatment, becoming invasive or even metastatic. Bladder cancer has a high risk of recurrence, so people whose non-invasive cancer has been treated need to be monitored for many years, undergoing cystoscopy every few months. They looked for predictive genetic footprints in the transcriptome of the cancer, which contains all of a cell’s RNA and can tell researchers which genes are turned on or off.


They found three subgroups with distinct basal and luminal features, as proposed by other groups, each with different clinical outcomes in early-stage bladder cancer. These features sort bladder cancer into genetic categories that can help predict whether the cancer will return. The researchers also identified mutations that are linked to tumour progression. Mutations in the so-called APOBEC genes, which code for enzymes that modify RNA or DNA molecules. This effect could lead to cancer and cause it to be aggressive.


The second major research group, TCGA, led by the National Cancer Institute and the National Human Genome Research Institute, that involves thousands of researchers across USA. The project has already mapped genomic changes in 33 cancer types, including breast, skin and lung cancers. The TCGA researchers, who study muscle-invasive bladder cancer, have looked at tumours that were already identified as fast-growing and invasive.


The work by Uromol, TCGA and other labs has provided a clearer view of the genetic landscape of early- and late-stage bladder cancer. There are five subtypes for the muscle-invasive form: luminal, luminal–papillary, luminal–infiltrated, basal–squamous, and neuronal, each of which is genetically distinct and might require different therapeutic approaches.


Bladder cancer has the third-highest mutation rate of any cancer, behind only lung cancer and melanoma. The TCGA team has confirmed Uromol research showing that most bladder-cancer mutations occur in the APOBEC genes. It is not yet clear why APOBEC mutations are so common in bladder cancer, but studies of the mutations have yielded one startling implication. The APOBEC enzyme causes mutations early during the development of bladder cancer, and independent of cigarette smoke or other known exposures.


The TCGA researchers found a subset of bladder-cancer patients, those with the greatest number of APOBEC mutations, had an extremely high five-year survival rate of about 75%. Other patients with fewer APOBEC mutations fared less well which is pretty surprising.


This detailed knowledge of bladder-cancer genetics may help to pinpoint the specific vulnerabilities of cancer cells in different people. Over the past decade, Broad Institute researchers have identified more than 760 genes that cancer needs to grow and survive. Their genetic map might take another ten years to finish, but it will list every genetic vulnerability that can be exploited. The goal of cancer precision medicine is to take the patient’s tumour and decode the genetics, so the clinician can make a decision based on that information.
















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QIAGEN – International Leader in NGS and RNA Sequencing

Reporter: Aviva Lev-Ari, PhD, RN


The reader is encouraged to review all the products of QIAGEN on the company web site.

miRCURY Exosome Kits

For enrichment of exosomes and other extracellular vesicles from serum/plasma or cell/urine/CSF samples
  • Excellent recovery of exosomes and other extracellular vesicles
  • Easy and straightforward protocol that takes less than 2 hours
  • No ultracentrifugation or phenol/chloroform steps required
  • Fully compatible with the miRCURY LNA miRNA PCR System
  • Suited for a variety of applications, such as miRNA or RNA profiling

miRCURY Exosome Kits enable high-quality and scalable exosome isolation with an easy protocol that does not require special laboratory equipment. The miRCURY Exosome Serum/Plasma Kit is optimized for serum and plasma samples, while the miRCURY Exosome Cell/Urine/CSF Kit is designed for processing cell-conditioned media, urine and CSF samples. Both kits provide high exosomal recovery and seamless integration with different downstream assays.



QIAGEN – Product Profile

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