Archive for the ‘Molecular Genetics & Pharmaceutical’ Category

Bacterial multidrug resistance problem solved by a broad-spectrum synthetic antibiotic

Posted in Advanced Drug Manufacturing Technology, Antibiotic resistance, Bacterial Resistance, Biochemical pathways, Cell Biology, Cell Biology, Signaling & Cell Circuits, Disease Biology, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Drug Carrier Design, Drug Delivery Platform Technology, Drug Development Process, Drug Discovery Chemistry, Drug Toxicity, Infectious Disease & New Antibiotic Targets, Microbiology, Molecular Genetics & Pharmaceutical, New Drug Approval, Pharmaceutical Drug Discovery, Population Health Management, Genetics & Pharmaceutical, Prescription Drugs Costs, Small Molecules in Development of Therapeutic Drugs, tagged Antibiotic resistance, antibiotics, antimicrobial resistance, bacteria, drug resistance, synthetic on March 1, 2023| Leave a Comment »

Bacterial multidrug resistance problem solved by a broad-spectrum synthetic antibiotic

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

There is an increasing demand for new antibiotics that effectively treat patients with refractory bacteremia, do not evoke bacterial resistance, and can be readily modified to address current and anticipated patient needs. Recently scientists described a promising compound of COE (conjugated oligo electrolytes) family, COE2-2hexyl, that exhibited broad-spectrum antibacterial activity. COE2-2hexyl effectively-treated mice infected with bacteria derived from sepsis patients with refractory bacteremia, including a CRE K. pneumoniae strain resistant to nearly all clinical antibiotics tested. Notably, this lead compound did not evoke drug resistance in several pathogens tested. COE2-2hexyl has specific effects on multiple membrane-associated functions (e.g., septation, motility, ATP synthesis, respiration, membrane permeability to small molecules) that may act together to abrogate bacterial cell viability and the evolution of drug-resistance. Impeding these bacterial properties may occur through alteration of vital protein–protein or protein-lipid membrane interfaces – a mechanism of action distinct from many membrane disrupting antimicrobials or detergents that destabilize membranes to induce bacterial cell lysis. The diversity and ease of COE design and chemical synthesis have the potential to establish a new standard for drug design and personalized antibiotic treatment.

Recent studies have shown that small molecules can preferentially target bacterial membranes due to significant differences in lipid composition, presence of a cell wall, and the absence of cholesterol. The inner membranes of Gram-negative bacteria are generally more negatively charged at their surface because they contain more anionic lipids such as cardiolipin and phosphatidylglycerol within their outer leaflet compared to mammalian membranes. In contrast, membranes of mammalian cells are largely composed of more-neutral phospholipids, sphingomyelins, as well as cholesterol, which affords membrane rigidity and ability to withstand mechanical stresses; and may stabilize the membrane against structural damage to membrane-disrupting agents such as COEs. Consistent with these studies, COE2-2hexyl was well tolerated in mice, suggesting that COEs are not intrinsically toxic in vivo, which is often a primary concern with membrane-targeting antibiotics. The COE refinement workflow potentially accelerates lead compound optimization by more rapid screening of novel compounds for the iterative directed-design process. It also reduces the time and cost of subsequent biophysical characterization, medicinal chemistry and bioassays, ultimately facilitating the discovery of novel compounds with improved pharmacological properties.

Additionally, COEs provide an approach to gain new insights into microbial physiology, including membrane structure/function and mechanism of drug action/resistance, while also generating a suite of tools that enable the modulation of bacterial and mammalian membranes for scientific or manufacturing uses. Notably, further COE safety and efficacy studies are required to be conducted on a larger scale to ensure adequate understanding of the clinical benefits and risks to assure clinical efficacy and toxicity before COEs can be added to the therapeutic armamentarium. Despite these limitations, the ease of molecular design, synthesis and modular nature of COEs offer many advantages over conventional antimicrobials, making synthesis simple, scalable and affordable. It enables the construction of a spectrum of compounds with the potential for development as a new versatile therapy for the emergence and rapid global spread of pathogens that are resistant to all, or nearly all, existing antimicrobial medicines.

References:

https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(23)00026-9/fulltext#%20

https://pubmed.ncbi.nlm.nih.gov/36801104/

https://www.sciencedaily.com/releases/2023/02/230216161214.htm

https://www.nature.com/articles/s41586-021-04045-6

https://www.nature.com/articles/d43747-020-00804-y

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Sperm epigenetic clock and pregnancy outcomes

Posted in Biological Engineering, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Biomedical Measurement Science, Cell Biology, Cell Biology, Signaling & Cell Circuits, Cell Processing System in Cell Therapy Process Development, Epigenetics and Environmental Factors, Genomic Endocrinology, Human aging, Methylation, MicroEngineering Cell-Tissue & Systems, Molecular Genetics & Pharmaceutical, Population Health Management, Genetics & Pharmaceutical, Preimplantation Genetic Diagnosis and Reproductive Genomics, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, Reproductive Biology & Bio Instrumentation, tagged DNA methylation, Epigenetics, infertility, pregnancy, sperm on May 14, 2022| 1 Comment »

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

Infertility has been primarily treated as a female predicament but around one-half of infertility cases can be tracked to male factors. Clinically, male infertility is typically determined using measures of semen quality recommended by World Health Organization (WHO). A major limitation, however, is that standard semen analyses are relatively poor predictors of reproductive capacity and success. Despite major advances in understanding the molecular and cellular functions in sperm over the last several decades, semen analyses remain the primary method to assess male fecundity and fertility.

Chronological age is a significant determinant of human fecundity and fertility. The disease burden of infertility is likely to continue to rise as parental age at the time of conception has been steadily increasing. While the emphasis has been on the effects of advanced maternal age on adverse reproductive and offspring health, new evidence suggests that, irrespective of maternal age, higher male age contributes to longer time-to-conception, poor pregnancy outcomes and adverse health of the offspring in later life. The effect of chronological age on the genomic landscape of DNA methylation is profound and likely occurs through the accumulation of maintenance errors of DNA methylation over the lifespan, which have been originally described as epigenetic drift.

In recent years, the strong relation between age and DNA methylation profiles has enabled the development of statistical models to estimate biological age in most somatic tissue via different epigenetic ‘clock’ metrics, such as DNA methylation age and epigenetic age acceleration, which describe the degree to which predicted biological age deviates from chronological age. In turn, these epigenetic clock metrics have emerged as novel biomarkers of a host of phenotypes such as allergy and asthma in children, early menopause, increased incidence of cancer types and cardiovascular-related diseases, frailty and cognitive decline in adults. They also display good predictive ability for cancer, cardiovascular and all-cause mortality.

Epigenetic clock metrics are powerful tools to better understand the aging process in somatic tissue as well as their associations with adverse disease outcomes and mortality. Only a few studies have constructed epigenetic clocks specific to male germ cells and only one study reported that smokers trended toward an increased epigenetic age compared to non-smokers. These results indicate that sperm epigenetic clocks hold promise as a novel biomarker for reproductive health and/or environmental exposures. However, the relation between sperm epigenetic clocks and reproductive outcomes has not been examined.

There is a critical need for new measures of male fecundity for assessing overall reproductive success among couples in the general population. Data shows that sperm epigenetic clocks may fulfill this need as a novel biomarker that predicts pregnancy success among couples not seeking fertility treatment. Such a summary measure of sperm biological age is of clinical importance as it allows couples in the general population to realize their probability of achieving pregnancy during natural intercourse, thereby informing and expediting potential infertility treatment decisions. With the ability to customize high throughput DNA methylation arrays and capture sequencing approaches, the integration of the epigenetic clocks as part of standard clinical care can enhance our understanding of idiopathic infertility and the paternal contribution to reproductive success and offspring health.

References:

https://academic.oup.com/humrep/advance-article/doi/10.1093/humrep/deac084/6583111?login=false

https://pubmed.ncbi.nlm.nih.gov/33317634/

https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0656-7

https://pubmed.ncbi.nlm.nih.gov/19319879/

https://pubmed.ncbi.nlm.nih.gov/31901222/

https://pubmed.ncbi.nlm.nih.gov/25928123/

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Two brothers with MEPAN Syndrome: A Rare Genetic Disorder

Posted in Academic Publishing, Behavioral Genetics, Biological Networks, Biomarkers & Medical Diagnostics, Cerebrovascular and Neurodegenerative Diseases, Chemical Biology and its relations to Metabolic Disease, Clinical Diagnostics, Clinical Genomics, Disease Biology, Medical Devices R&D Investment, Metabolism, Molecular Genetics & Pharmaceutical, MRI, mtDNA, Neurodegenerative Diseases, Neurological Diseases, Oxidative phosphorylation, tagged Ataxia, dystonia, MECR gene, MEPAN Foundation, MEPAN syndrome, Metabolic processes, mtDNA, Neurological disease, NIH Undiagnosed Diseases Network, Optic atrophy, OXPHOS Deficiencies, Rare Genetic Disorder, Whole-genome or whole-exome sequencing on March 21, 2021| Leave a Comment »

Two brothers with MEPAN Syndrome: A Rare Genetic Disorder

Reporter: Amandeep Kaur

In the early 40s, a married couple named Danny and Nikki, had normal pregnancy and delivered their first child in October 2011. The couple was elated after the birth of Carson because they were uncertain about even conceiving a baby. Soon after birth, the parents started facing difficulty in feeding the newborn and had some wakeful nights, which they used to called “witching hours”. For initial six months, they were clueless that something was not correct with their infant. Shortly, they found issues in moving ability, sitting, and crawling with Carson. Their next half year went in visiting several behavioral specialists and pediatricians with no conclusion other than a suggestion that there is nothing to panic as children grow at different rates.

Later in early 2013, Caron was detected with cerebral palsy in a local regional center. The diagnosis was based on his disability to talk and delay in motor development. At the same time, Carson had his first MRI which showed no negative results. The parents convinced themselves that their child condition would be solved by therapies and thus started physical and occupational therapies. After two years, the couple gave birth to another boy child named Chase in 2013. Initially, there was nothing wrong with Chase as well. But after nine months, Chase was found to possess the same symptoms of delaying in motor development as his elder brother. It was expected that Chase may also be suffering from cerebral palsy. For around one year both boys went through enormous diagnostic tests starting from karyotyping, metabolic screen tests to diagnostic tests for Fragile X syndrome, lysosomal storage disorders, Friedreich ataxia and spinocerebellar ataxia. Gene panel tests for mitochondrial DNA and Oxidative phosphorylation (OXPHOS) deficiencies were also performed. No conclusion was drawn because each diagnostic test showed the negative results.

Over the years, the condition of boys was deteriorating as their movements became stiffer and ataxic, they were not able to crawl anymore. By the end of 2015, the boys had an MRI which showed some symmetric anomalies in their basal ganglia indicating a metabolic condition. The symptoms of Carson and Chase was not even explained by whole exome sequencing due to the absence of any positive result. The grievous journey of visits to neurologist, diagnostic tests and inconclusive results led the parents to rethink about anything happened erroneous due to them such as due to their lifestyle, insufficient intake of vitamins during pregnancy or exposure to toxic agents which left their sons in that situation.

During the diagnostic odyssey, Danny spent many restless and sleepless nights in searching PubMed for any recent cases with symptoms similar to his sons and eventually came across the NIH’s Undiagnosed Diseases Network (UDN), which gave a light of hope to the demoralized family. As soon as Danny discovered about the NIH’s Diseases Network, he gathered all the medical documents of both his sons and submitted the application. The submitted application in late 2015 got accepted a year later in December 2016 and they got their first appointment in early 2017 at the UDN site at Stanford. At Stanford, the boys had gone through whole-genome sequencing and some series of examinations which came back with inconclusive results. Finally, in February 2018, the family received some conclusive results which explained that the two boys suffer from MEPAN syndrome with pathogenic mutations in MECR gene.

MEPAN means Mitochondrial Enoyl CoA reductase Protein-Associated Neurodegeneration
MEPAN syndrome is a rare genetic neurological disorder
MEPAN syndrome is associated with symptoms of ataxia, optic atrophy and dystonia
The wild-type MECR gene encodes a mitochondrial protein which is involved in metabolic processes
The prevalence rate of MEPAN syndrome is 1 in 1 million
Currently, there are 17 patients of MEPAN syndrome worldwide

The symptoms of Carson and Chase of an early onset of motor development with no appropriate biomarkers and T-2 hyperintensity in the basal ganglia were matching with the seven known MEPAN patient at that time. The agonizing journey of five years concluded with diagnosis of rare genetic disorder.

Despite the advances in genetic testing and their low-cost, there are many families which still suffer and left undiagnostic for long years. To shorten the diagnostic journey of undiagnosed patients, the whole-exome and whole-genome sequencing can be used as a primary tool. There is need of more research to find appropriate treatments of genetic disorders and therapies to reduce the suffering of the patients and families. It is necessary to fill the gap between the researchers and clinicians to stimulate the development in diagnosis, treatment and drug development for rare genetic disorders.

The family started a foundation named “MEPAN Foundation” (https://www.mepan. org) to reach out to the world to educate people about the mutation in MECR gene. By creating awareness among the communities, clinicians, and researchers worldwide, the patients having rare genetic disorder can come closer and share their information to improve their condition and quality of life.

Reference: Danny Miller, The diagnostic odyssey: our family’s story, The American Journal of Human Genetics, Volume 108, Issue 2, 2021, Pages 217-218, ISSN 0002-9297, https://doi.org/10.1016/j.ajhg.2021.01.003 (https://www.sciencedirect.com/science/article/pii/S0002929721000033)

Sources:

https://www.variantyx.com/2020/02/26/in-silico-panel-expansion/

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=508093

https://www.mepan. org

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

Effect of mitochondrial stress on epigenetic modifiers

Larry H. Bernstein, MD, FCAP, Curator, LPBI

https://pharmaceuticalintelligence.com/2016/05/07/effect-of-mitochondrial-stress-on-epigenetic-modifiers/

The Three Parent Technique to Avoid Mitochondrial Disease in Embryo

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

https://pharmaceuticalintelligence.com/2016/10/07/the-three-parent-technique-to-avoid-mitochondrial-disease-in-embryo/

New Insights into mtDNA, mitochondrial proteins, aging, and metabolic control

Larry H. Bernstein, MD, FCAP, Curator, LPBI

https://pharmaceuticalintelligence.com/2016/04/20/new-insights-into-mtdna-mitochondrial-proteins-aging-and-metabolic-control/

Mitochondrial Isocitrate Dehydrogenase and Variants

Writer and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2015/04/02/mitochondrial-isocitrate-dehydrogenase-and-variants/

Update on mitochondrial function, respiration, and associated disorders

Larry H. Benstein, MD, FCAP, Gurator and writer

https://pharmaceuticalintelligence.com/2014/07/08/update-on-mitochondrial-function-respiration-and-associated-disorders/

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Dysregulation of ncRNAs in association with Neurodegenerative Disorders

Posted in Alzheimer's Disease, Biomarkers & Medical Diagnostics, Cerebrovascular and Neurodegenerative Diseases, Etiology, Molecular Genetics & Pharmaceutical, mRNA, mRNA Therapeutics, Neurodegenerative Diseases, Neurological Diseases, RNA Biology, RNA interference (RNAi) therapeutic, tagged Alzheimers Disease, neurodegenerative disorders, Neurological Disorders, Non-coding RNA, Parkinsons disease, RNA Biology, RNA interference (RNAi) therapeutic on January 11, 2021| Leave a Comment »

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
https://www.nature.com/articles/s42256-019-0051-2

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
https://en.wikipedia.org/wiki/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
https://www.nature.com/articles/nrn.2017.90

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

The Nobel Prize in Chemistry 2020: Emmanuelle Charpentier & Jennifer A. Doudna

Posted in Award Nominations, Cell Biology, CRISPR alternative for editing genes without cutting, CRISPR applied to Human Germ Line, CRISPR/Cas9 & Gene Editing, DNA repair, Gene Therapy & Gene Editing Development, Genetics & Innovations in Treatment, Genetics & Pharmaceutical, Genome Biology, Interviews with Key Opinion Leaders (KOLs), Molecular Genetics & Pharmaceutical, Nobel Prize WInners, Stem Cells for Regenerative Medicine, tagged CRISPR –Cas9 system for genetic engineering, CRISPR Biology • Genome Editing • Gene Drives • DNA Repair • Model and Industrial Organisms • Technology Development • Stem Cells/Cancer • Genome-Wide Screens, CRISPR-based gene editing, CRISPR-Cas9, CRISPR/Cas and base editing, gene editing, gene editing technology platform, Jennifer Doudna, nobel leureates, Nobel Prize, Nobel Prize in Chemistry, Stanford University on October 8, 2020| Leave a Comment »

The Nobel Prize in Chemistry 2020: Emmanuelle Charpentier & Jennifer A. Doudna

Reporters: Stephen J. Williams, Ph.D. and Aviva Lev-Ari, PhD, RN

The Royal Swedish Academy of Sciences has decided to award the Nobel Prize in Chemistry 2020 to

Emmanuelle Charpentier
Max Planck Unit for the Science of Pathogens, Berlin, Germany

Jennifer A. Doudna
University of California, Berkeley, USA

“for the development of a method for genome editing”

https://www.nobelprize.org/prizes/chemistry/2020/popular-information/#:~:text=Emmanuelle%20Charpentier%20and%20Jennifer%20Doudna,microorganisms%20with%20extremely%20high%20precision.

Genetic scissors: a tool for rewriting the code of life

Emmanuelle Charpentier and Jennifer A. Doudna have discovered one of gene technology’s sharpest tools: the CRISPR/Cas9 genetic scissors. Using these, researchers can change the DNA of animals, plants and microorganisms with extremely high precision. This technology has had a revolutionary impact on the life sciences, is contributing to new cancer therapies and may make the dream of curing inherited diseases come true.

Researchers need to modify genes in cells if they are to find out about life’s inner workings. This used to be time-consuming, difficult and sometimes impossible work. Using the CRISPR/Cas9 genetic scissors, it is now possible to change the code of life over the course of a few weeks.

“There is enormous power in this genetic tool, which affects us all. It has not only revolutionised basic science, but also resulted in innovative crops and will lead to ground-breaking new medical treatments,” says Claes Gustafsson, chair of the Nobel Committee for Chemistry.

As so often in science, the discovery of these genetic scissors was unexpected. During Emmanuelle Charpentier’s studies of Streptococcus pyogenes, one of the bacteria that cause the most harm to humanity, she discovered a previously unknown molecule, tracrRNA. Her work showed that tracrRNA is part of bacteria’s ancient immune system, CRISPR/Cas, that disarms viruses by cleaving their DNA.

Charpentier published her discovery in 2011. The same year, she initiated a collaboration with Jennifer Doudna, an experienced biochemist with vast knowledge of RNA. Together, they succeeded in recreating the bacteria’s genetic scissors in a test tube and simplifying the scissors’ molecular components so they were easier to use.

In an epoch-making experiment, they then reprogrammed the genetic scissors. In their natural form, the scissors recognise DNA from viruses, but Charpentier and Doudna proved that they could be controlled so that they can cut any DNA molecule at a predetermined site. Where the DNA is cut it is then easy to rewrite the code of life.

Since Charpentier and Doudna discovered the CRISPR/Cas9 genetic scissors in 2012 their use has exploded. This tool has contributed to many important discoveries in basic research, and plant researchers have been able to develop crops that withstand mould, pests and drought. In medicine, clinical trials of new cancer therapies are underway, and the dream of being able to cure inherited diseases is about to come true. These genetic scissors have taken the life sciences into a new epoch and, in many ways, are bringing the greatest benefit to humankind.

Illustrations

The illustrations are free to use for non-commercial purposes. Attribute ”© Johan Jarnestad/The Royal Swedish Academy of Sciences”

Illustration: Using the genetic scissors (pdf)
Illustration: Streptococcus’ natural immune system against viruses:CRISPR/Cas9 pdf)
Illustration: CRISPR/Cas9 genetic scissors (pdf)

Celiac Disease Breakthrough: (1) 472 genes regulated differently in organoids reflecting celiac disease than in non-celiac control organoids (2) bio-products derived from gut microorganisms can be employed to modify the epithelial response to gluten, a finding that could lead to future treatment strategies.

Posted in Biochemical pathways, Cell Biology, Cell Processing System in Cell Therapy Process Development, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Gut Microbiome and Obesity, Metabolism, Metabolomics, Microbiologial genetics, Microbiology, microbiome, Molecular Genetics & Pharmaceutical, Organoids on May 13, 2019| Leave a Comment »

Celiac Disease Breakthrough: (1) 472 genes regulated differently in organoids reflecting celiac disease than in non-celiac control organoids (2) bio-products derived from gut microorganisms can be employed to modify the epithelial response to gluten, a finding that could lead to future treatment strategies.

Reporter: Aviva Lev-Ari, PhD, RN

“These results confirm our hypothesis that genes and exposure to gluten are necessary but not sufficient, since changes in both the composition and function of the gut microbiome are also needed to switch from genetic predisposition to clinical outcome, as shown by our data,” said Alessio Fasano, HMS professor of pediatrics at Mass General, director of MIBRC and co-senior author of the paper.

https://hms.harvard.edu/news/major-shift?utm_source=Silverpop&utm_medium=email&utm_term=field_news_item_3&utm_content=HMNews05132019

Image Source: iStock/wildpixel

PDF

Article | OPEN | Published: 07 May 2019

Human gut derived-organoids provide model to study gluten response and effects of microbiota-derived molecules in celiac disease

Rachel Freire,

Laura Ingano,

Gloria Serena,

Murat Cetinbas,

Anthony Anselmo,

Anna Sapone,

Ruslan I. Sadreyev,

Alessio Fasano &

Stefania Senger

Scientific Reports volume 9, Article number: 7029 (2019) | Download Citation

Abstract

Celiac disease (CD) is an immune-mediated disorder triggered by gluten exposure. The contribution of the adaptive immune response to CD pathogenesis has been extensively studied, but the absence of valid experimental models has hampered our understanding of the early steps leading to loss of gluten tolerance. Using intestinal organoids developed from duodenal biopsies from both non-celiac (NC) and celiac (CD) patients, we explored the contribution of gut epithelium to CD pathogenesis and the role of microbiota-derived molecules in modulating the epithelium’s response to gluten. When compared to NC, RNA sequencing of CD organoids revealed significantly altered expression of genes associated with gut barrier, innate immune response, and stem cell functions. Monolayers derived from CD organoids exposed to gliadin showed increased intestinal permeability and enhanced secretion of pro-inflammatory cytokines compared to NC controls. Microbiota-derived bioproducts butyrate, lactate, and polysaccharide A improved barrier function and reduced gliadin-induced cytokine secretion. We concluded that: (1) patient-derived organoids faithfully express established and newly identified molecular signatures characteristic of CD. (2) microbiota-derived bioproducts can be used to modulate the epithelial response to gluten. Finally, we validated the use of patient-derived organoids monolayers as a novel tool for the study of CD.

SOURCE

https://www.nature.com/articles/s41598-019-43426-w

Mass. General researchers develop 3D “mini-gut” model to study autoimmune response to gluten in celiac and non-celiac patient tissue

Gene expression of intestinal organoids reflects functional differences found in celiac disease

In pursuit of a novel tool for the research and treatment of celiac disease, scientists at the Mucosal Immunology and Biology Research Center (MIBRC) at Massachusetts General Hospital (MGH) have validated the use of intestinal organoids. These three-dimensional tissue cultures are miniature, simplified versions of the intestine produced in vitro. Taking tissue from duodenal biopsies of celiac and non-celiac patients, researchers created the “mini-guts” to explore how the gut epithelium and microbiota-derived molecules respond to gluten, a complex class of proteins found in wheat and other grains.

“We currently have no animal model that can recapitulate the response to gluten that we see in humans,” says Stefania Senger, PhD, co-senior author of the study published in Scientific Reports this week. “Using this human tissue model, we observed that intestinal organoids express the same molecular markers as actual epithelium in the celiac tissue, and the signature gene expression reflects the functional differences that occur when epithelia of celiac disease patients are exposed to gliadin.” Gliadin and glutenin proteins are main components of gluten.

Celiac disease is triggered when genetically predisposed individuals consume gluten. The condition affects approximately 1 percent of the U.S. population. Based on current data, the onset of celiac disease is thought to be preceded by the release of the protein zonulin, which is triggered by the activation of undigested gliadin to induce an autoimmune response. This leads to increased intestinal permeability and a disrupted barrier function. Novel evidence suggests that the microorganisms in the gastrointestinal tract may play a role in the onset of celiac disease.

Earlier studies from the MIBRC group and others have shown that human organoids “retain a gene expression that recapitulates the expression of the tissue of origin, including a diseased state,” the authors write. Through RNA sequencing, the new findings validate the organoid model as a “faithful in vitro model for celiac disease,” Senger says.
Using whole-transcriptome analysis, the researchers identified 472 genes regulated differently in organoids reflecting celiac disease than in non-celiac control organoids. These included novel genes associated with epithelial functions related to the pathogenesis of celiac disease – including gut barrier maintenance, stem cell regeneration and innate immune response. A second finding of the study shows that bioproducts derived from gut microorganisms can be employed to modify the epithelial response to gluten, a finding that could lead to future treatment strategies.

“These results confirm our hypothesis that genes and exposure to gluten are necessary but not sufficient, since changes in both the composition and function of the gut microbiome are also needed to switch from genetic predisposition to clinical outcome, as shown by our data,” says Alessio Fasano, MD, director of the Mucosal Immunology and Biology Research Center and co-senior author.

Senger adds, “We believe our observations represent a major shift in the study of celiac disease. We are confident that with adequate funding we could achieve major goals that include the development and implementation of high-throughput drug screenings to quickly identify new treatments for patients and expand the organoid repository to develop more complex models and pursue personalized treatment.”
Additional co-authors of the paper are first author Rachel Freire, PhD, along with Laura Ingano and Gloria Serena, PhD, of the MGH MIBRC; Murat Cetinbas, PhD, and Ruslan Sadreyev, PhD, MGH Department of Molecular Biology; Anthony Anselmo, PhD, formerly of MGH Molecular Biology and now with PatientsLikeMe, Cambridge, Mass.; and Anna Sapone, MD, PhD, Takeda Pharmaceuticals International. Support for the study includes National Institutes of Health grants RO1 DK104344-01A1 and 1U19 AI082655-02 and the Egan Family Foundation.

SOURCE

https://www.massgeneral.org/about/pressrelease.aspx?id=2403

Series D: e-Books on BioMedicine – Metabolomics, Immunology, Infectious Diseases

Metabolomics

VOLUME 1: Metabolic Genomics and Pharmaceutics. On Amazon.com since 7/21/2015

http://www.amazon.com/dp/B012BB0ZF0

Gluten-free Diets

Writer and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2015/03/01/gluten-free-diets/

Breakthrough Digestive Disorders Research: Conditions affecting the Gastrointestinal Tract.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/12/12/breakthrough-digestive-disorders-research-conditions-affecting-the-gastrointestinal-tract/

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

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

https://pharmaceuticalintelligence.com/2016/01/25/collagen-binding-molecular-chaperone-hsp47-role-in-intestinal-fibrosis-colonic-epithelial-cells-and-subepithelial-myofibroblasts/

Expanding area of Tolerance-inducing Autoimmune Disease Therapeutics: Key Players

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/01/17/expanding-area-of-tolerance-inducing-autoimmune-disease-therapeutics-key-players/

What is the key method to harness Inflammation to close the doors for many complex diseases?

Author and Curator: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/03/21/what-is-the-key-method-to-harness-inflammation-to-close-the-doors-for-many-complex-diseases/

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Use of 3D Bioprinting for Development of Toxicity Prediction Models

Posted in 3D Plotting Scaffolds, 3D Printing for Medical Application, Bio-MEMS, BioBanking, Bioengineering & reverse engineering design, BioInks, Biological Engineering, Biological Networks, BioPrinting in Regenerative Medicine, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Cell Level, Disease Biology, Drug Development using MultiOrgan Chip, Drug Development/Formulation using 3D Printing, Drug Toxicity, MEMS, MicroEngineering Cell-Tissue & Systems, Organoids, Pharmaceutical Analytics, Pharmaceutical Discovery, Pharmaceutical Drug Discovery, Pharmacologic toxicities, Tissue Engineering and Regenerative Medicine, Tissue Microenvironment, Translational Research, tagged 3-D printed liver tissue, 3D bioprinting, 3D tissue, Amnion Foundation, bioprinting, Brigham & Women's Hospital, drug induced liver injury, ECM, Harvard Medical School, hepatoxicity, Liver Tissue Engineeering, National Institutes of Health (NIH) ’s Common Fund, organova, Tissue engineering, toxicology on April 27, 2019| Leave a Comment »

Use of 3D Bioprinting for Development of Toxicity Prediction Models

Curator: Stephen J. Williams, PhD

SOT FDA Colloquium on 3D Bioprinted Tissue Models: Tuesday, April 9, 2019

The Society of Toxicology (SOT) and the U.S. Food and Drug Administration (FDA) will hold a workshop on “Alternative Methods for Predictive Safety Testing: 3D Bioprinted Tissue Models” on Tuesday, April 9, at the FDA Center for Food Safety and Applied Nutrition in College Park, Maryland. This workshop is the latest in the series, “SOT FDA Colloquia on Emerging Toxicological Science: Challenges in Food and Ingredient Safety.”

Human 3D bioprinted tissues represent a valuable in vitro approach for chemical, personal care product, cosmetic, and preclinical toxicity/safety testing. Bioprinting of skin, liver, and kidney is already appearing in toxicity testing applications for chemical exposures and disease modeling. The use of 3D bioprinted tissues and organs may provide future alternative approaches for testing that may more closely resemble and simulate intact human tissues to more accurately predict human responses to chemical and drug exposures.

A synopsis of the schedule and related works from the speakers is given below:

8:40 AM–9:20 AM	Overview and Challenges of Bioprinting Sharon Presnell, Amnion Foundation, Winston-Salem, NC
9:20 AM–10:00 AM	Putting 3D Bioprinting to the Use of Tissue Model Fabrication Y. Shrike Zhang, Brigham and Women’s Hospital, Harvard Medical School and Harvard-MIT Division of Health Sciences and Technology, Boston, MA
10:00 AM–10:20 AM	Break
10:20 AM–11:00 AM	Uses of Bioprinted Liver Tissue in Drug Development Jean-Louis Klein, GlaxoSmithKline, Collegeville, PA
11:00 AM–11:40 AM	Biofabrication of 3D Tissue Models for Disease Modeling and Chemical Screening Marc Ferrer, National Center for Advancing Translational Sciences, NIH, Rockville, MD

Sharon Presnell, Ph.D. President, Amnion Foundation

Dr. Sharon Presnell was most recently the Chief Scientific Officer at Organovo, Inc., and the President of their wholly-owned subsidiary, Samsara Sciences. She received a Ph.D. in Cell & Molecular Pathology from the Medical College of Virginia and completed her undergraduate degree in biology at NC State. In addition to her most recent roles, Presnell has served as the director of cell biology R&D at Becton Dickinson’s corporate research center in RTP, and as the SVP of R&D at Tengion. Her roles have always involved the commercial and clinical translation of basic research and early development in the cell biology space. She serves on the board of the Coulter Foundation at the University of Virginia and is a member of the College of Life Sciences Foundation Board at NC State. In January 2019, Dr. Presnell will begin a new role as President of the Amnion Foundation, a non-profit organization in Winston-Salem.

A few of her relevant publications:

Bioprinted liver provides early insight into the role of Kupffer cells in TGF-β1 and methotrexate-induced fibrogenesis

Integrating Kupffer cells into a 3D bioprinted model of human liver recapitulates fibrotic responses of certain toxicants in a time and context dependent manner. This work establishes that the presence of Kupffer cells or macrophages are important mediators in fibrotic responses to certain hepatotoxins and both should be incorporated into bioprinted human liver models for toxicology testing.

Bioprinted 3D Primary Liver Tissues Allow Assessment of Organ-Level Response to Clinical Drug Induced Toxicity In Vitro

Abstract: Modeling clinically relevant tissue responses using cell models poses a significant challenge for drug development, in particular for drug induced liver injury (DILI). This is mainly because existing liver models lack longevity and tissue-level complexity which limits their utility in predictive toxicology. In this study, we established and characterized novel bioprinted human liver tissue mimetics comprised of patient-derived hepatocytes and non-parenchymal cells in a defined architecture. Scaffold-free assembly of different cell types in an in vivo-relevant architecture allowed for histologic analysis that revealed distinct intercellular hepatocyte junctions, CD31+ endothelial networks, and desmin positive, smooth muscle actin negative quiescent stellates. Unlike what was seen in 2D hepatocyte cultures, the tissues maintained levels of ATP, Albumin as well as expression and drug-induced enzyme activity of Cytochrome P450s over 4 weeks in culture. To assess the ability of the 3D liver cultures to model tissue-level DILI, dose responses of Trovafloxacin, a drug whose hepatotoxic potential could not be assessed by standard pre-clinical models, were compared to the structurally related non-toxic drug Levofloxacin. Trovafloxacin induced significant, dose-dependent toxicity at clinically relevant doses (≤ 4uM). Interestingly, Trovafloxacin toxicity was observed without lipopolysaccharide stimulation and in the absence of resident macrophages in contrast to earlier reports. Together, these results demonstrate that 3D bioprinted liver tissues can both effectively model DILI and distinguish between highly related compounds with differential profile. Thus, the combination of patient-derived primary cells with bioprinting technology here for the first time demonstrates superior performance in terms of mimicking human drug response in a known target organ at the tissue level.

A great interview with Dr. Presnell and the 3D Models 2017 Symposium is located here:

Please click here for Web based and PDF version of interview

Some highlights of the interview include

Exciting advances in field showing we can model complex tissue-level disease-state phenotypes that develop in response to chronic long term injury or exposure
Sees the field developing a means to converge both the biology and physiology of tissues, namely modeling the connectivity between tissues such as fluid flow
Future work will need to be dedicated to develop comprehensive analytics for 3D tissue analysis. As she states “we are very conditioned to get information in a simple way from biochemical readouts in two dimension, monocellular systems” however how we address the complexity of various cellular responses in a 3D multicellular environment will be pertinent.
Additional challenges include the scalability of such systems and making such system accessible in a larger way

Shrike Zhang, Brigham and Women’s Hospital, Harvard Medical School and Harvard-MIT Division of Health Sciences and Technology

Dr. Zhang currently holds an Assistant Professor position at Harvard Medical School and is an Associate Bioengineer at Brigham and Women’s Hospital. His research interests include organ-on-a-chip, 3D bioprinting, biomaterials, regenerative engineering, biomedical imaging, biosensing, nanomedicine, and developmental biology. His scientific contributions have been recognized by >40 international, national, and regional awards. He has been invited to deliver >70 lectures worldwide, and has served as reviewer for >400 manuscripts for >30 journals. He is serving as Editor-in-Chief for Microphysiological Systems, and Associate Editor for Bio-Design and Manufacturing. He is also on Editorial Board of Bioprinting, Heliyon, BMC Materials, and Essays in Biochemistry, and on Advisory Panel of Nanotechnology.

Some relevant references from Dr. Zhang

Multi-tissue interactions in an integrated three-tissue organ-on-a-chip platform.

Skardal A, Murphy SV, Devarasetty M, Mead I, Kang HW, Seol YJ, Shrike Zhang Y, Shin SR, Zhao L, Aleman J, Hall AR, Shupe TD, Kleensang A, Dokmeci MR, Jin Lee S, Jackson JD, Yoo JJ, Hartung T, Khademhosseini A, Soker S, Bishop CE, Atala A.

Sci Rep. 2017 Aug 18;7(1):8837. doi: 10.1038/s41598-017-08879-x.

Reconstruction of Large-scale Defects with a Novel Hybrid Scaffold Made from Poly(L-lactic acid)/Nanohydroxyapatite/Alendronate-loaded Chitosan Microsphere: in vitro and in vivo Studies.

Wu H, Lei P, Liu G, Shrike Zhang Y, Yang J, Zhang L, Xie J, Niu W, Liu H, Ruan J, Hu Y, Zhang C.

Sci Rep. 2017 Mar 23;7(1):359. doi: 10.1038/s41598-017-00506-z.

A liver-on-a-chip platform with bioprinted hepatic spheroids.

Bhise NS, Manoharan V, Massa S, Tamayol A, Ghaderi M, Miscuglio M, Lang Q, Shrike Zhang Y, Shin SR, Calzone G, Annabi N, Shupe TD, Bishop CE, Atala A, Dokmeci MR, Khademhosseini A.

Biofabrication. 2016 Jan 12;8(1):014101. doi: 10.1088/1758-5090/8/1/014101.

Marc Ferrer, National Center for Advancing Translational Sciences, NIH

Marc Ferrer is a team leader in the NCATS Chemical Genomics Center, which was part of the National Human Genome Research Institute when Ferrer began working there in 2010. He has extensive experience in drug discovery, both in the pharmaceutical industry and academic research. Before joining NIH, he was director of assay development and screening at Merck Research Laboratories. For 10 years at Merck, Ferrer led the development of assays for high-throughput screening of small molecules and small interfering RNA (siRNA) to support programs for lead and target identification across all disease areas.

At NCATS, Ferrer leads the implementation of probe development programs, discovery of drug combinations and development of innovative assay paradigms for more effective drug discovery. He advises collaborators on strategies for discovering small molecule therapeutics, including assays for screening and lead identification and optimization. Ferrer has experience implementing high-throughput screens for a broad range of disease areas with a wide array of assay technologies. He has led and managed highly productive teams by setting clear research strategies and goals and by establishing effective collaborations between scientists from diverse disciplines within industry, academia and technology providers.

Ferrer has a Ph.D. in biological chemistry from the University of Minnesota, Twin Cities, and completed postdoctoral training at Harvard University’s Department of Molecular and Cellular Biology. He received a B.Sc. degree in organic chemistry from the University of Barcelona in Spain.

Some relevant references for Dr. Ferrer

Fully 3D Bioprinted Skin Equivalent Constructs with Validated Morphology and Barrier Function.

Derr K, Zou J, Luo K, Song MJ, Sittampalam GS, Zhou C, Michael S, Ferrer M, Derr P.

Tissue Eng Part C Methods. 2019 Apr 22. doi: 10.1089/ten.TEC.2018.0318. [Epub ahead of print]

Determination of the Elasticity Modulus of 3D-Printed Octet-Truss Structures for Use in Porous Prosthesis Implants.

Bagheri A, Buj-Corral I, Ferrer M, Pastor MM, Roure F.

Materials (Basel). 2018 Nov 29;11(12). pii: E2420. doi: 10.3390/ma11122420.

Mutation Profiles in Glioblastoma 3D Oncospheres Modulate Drug Efficacy.

Wilson KM, Mathews-Griner LA, Williamson T, Guha R, Chen L, Shinn P, McKnight C, Michael S, Klumpp-Thomas C, Binder ZA, Ferrer M, Gallia GL, Thomas CJ, Riggins GJ.

SLAS Technol. 2019 Feb;24(1):28-40. doi: 10.1177/2472630318803749. Epub 2018 Oct 5.

A high-throughput imaging and nuclear segmentation analysis protocol for cleared 3D culture models.

Boutin ME, Voss TC, Titus SA, Cruz-Gutierrez K, Michael S, Ferrer M.

Sci Rep. 2018 Jul 24;8(1):11135. doi: 10.1038/s41598-018-29169-0.

A High-Throughput Screening Model of the Tumor Microenvironment for Ovarian Cancer Cell Growth.

Lal-Nag M, McGee L, Guha R, Lengyel E, Kenny HA, Ferrer M.

SLAS Discov. 2017 Jun;22(5):494-506. doi: 10.1177/2472555216687082. Epub 2017 Jan 31.

Exploring Drug Dosing Regimens In Vitro Using Real-Time 3D Spheroid Tumor Growth Assays.

Lal-Nag M, McGee L, Titus SA, Brimacombe K, Michael S, Sittampalam G, Ferrer M.

SLAS Discov. 2017 Jun;22(5):537-546. doi: 10.1177/2472555217698818. Epub 2017 Mar 15.

RNAi High-Throughput Screening of Single- and Multi-Cell-Type Tumor Spheroids: A Comprehensive Analysis in Two and Three Dimensions.

Fu J, Fernandez D, Ferrer M, Titus SA, Buehler E, Lal-Nag MA.

SLAS Discov. 2017 Jun;22(5):525-536. doi: 10.1177/2472555217696796. Epub 2017 Mar 9.

Mode of Feeding Changes Human Breast Milk Microbiome

Posted in Allergy and Infectious Diseases, Cell Biology, Cell Biology, Signaling & Cell Circuits, Childhood malnutrition, Gut Microbiome and Obesity, Medical and Population Genetics, Microbiologial genetics, Microbiology, microbiome, Molecular Genetics & Pharmaceutical, Nutrigenomics, Nutrition, Nutrition Disorders, Population genetics, Population Health Management, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, tagged bacteria, breast feeding, breast milk, breast pump, microbiome on March 9, 2019| Leave a Comment »

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

The bacterial makeup of human milk is influenced by the mode of breastfeeding, according to a new study. Although previously considered sterile, breast milk is now known to contain a low abundance of bacteria. While the complexities of how maternal microbiota influence the infant microbiota are still unknown, this complex community of bacteria in breast milk may help to establish the infant gut microbiota. Disruptions in this process could alter the infant microbiota, causing predisposition to chronic diseases such as allergies, asthma, and obesity. While it’s unclear how the breast milk microbiome develops, there are two theories describing its origins. One theory speculates that it originates in the maternal mammary gland, while the other theory suggests that it is due to retrograde inoculation by the infant’s oral microbiome.

To address this gap in knowledge scientists carried out bacterial gene sequencing on milk samples from 393 healthy mothers three to four months after giving birth. They used this information to examine how the milk microbiota composition is affected by maternal factors, early life events, breastfeeding practices, and other milk components. Among the many factors analyzed, the mode of breastfeeding (with or without a pump) was the only consistent factor directly associated with the milk microbiota composition. Specifically, indirect breastfeeding was associated with a higher abundance of potential opportunistic pathogens, such as Stenotrophomonas and Pseudomonadaceae. By contrast, direct breastfeeding without a pump was associated with microbes typically found in the mouth, as well as higher overall bacterial richness and diversity. Taken together, the findings suggest that direct breastfeeding facilitates the acquisition of oral microbiota from infants, whereas indirect breastfeeding leads to enrichment with environmental (pump-associated) bacteria.

The researchers argued that this study supports the theory that the breast milk microbiome is due to retrograde inoculation. Their findings indicate that the act of pumping and contact with the infant oral microbiome influences the milk microbiome, though they noted more research is needed. In future studies, the researchers will further explore the composition and function of the milk microbiota. In addition to bacteria, they will profile fungi in the milk samples. They also plan to investigate how the milk microbiota influences both the gut microbiota of infants and infant development and health. Specifically, their projects will examine the association of milk microbiota with infant growth, asthma, and allergies. This work could have important implications for microbiota-based strategies for early-life prevention of chronic conditions.

References:

https://www.genomeweb.com/sequencing/human-breast-milk-microbiome-affected-mode-feeding#.XIOH0igzZPY

http://childstudy.ca/2019/02/13/breastmilk-microbiome-linked-to-method-of-feeding/

https://gizmodo.com/pumping-breast-milk-changes-its-microbiome-1832568169

https://www.sciencedaily.com/releases/2019/02/190213124445.htm

https://www.cell.com/cell-host-microbe/fulltext/S1931-3128(19)30049-6

https://www.unicef.org.uk/babyfriendly/news-and-research/baby-friendly-research/infant-health-research/epigenetics-microbiome-research/

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The second annual PureTech Health BIG (Brain-Immune-Gut) Summit 2019 – By invitation only – Selected Tweets from #BIGAxisSummit by @pharma_BI @AVIVA1950 for @pharmaceuticalintelligence.com

Posted in #BIGAxisSummit, Biochemical pathways, CANCER BIOLOGY & Innovations in Cancer Therapy, CNS-Immune Interface, Conference Coverage with Social Media, Disease Biology, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Drug Carrier Design, Drug Delivery Platform Technology, Exosomes: Natural Carriers for siRNA Delivery, Gastroenterology, Gene Regulation, Genetics & Pharmaceutical, Genome Biology, Immuno-Oncology & Genomics, Immunodiagnostics, Immunology, Immunotherapy, Infectious Disease & New Antibiotic Targets, Metabolism, Metabolomics, Microbiologial genetics, Microbiology, microbiome, Molecular Genetics & Pharmaceutical, Neuronal Circuits, Single Cell Genomics, Single-cell sequencing, Synthetic Immunology: Hacking Immune Cells, Variation in human protein-coding regions, Virology on February 1, 2019| Leave a Comment »

The second annual PureTech Health BIG (Brain-Immune-Gut) Summit 2019 – By invitation only –

Selected Tweets from #BIGAxisSummit

by @pharma_BI @AVIVA1950

for @pharmaceuticalintelligence.com

Reporter: Aviva Lev-Ari, PhD, RN

The second annual PureTech Health BIG Summit brings together an elite ensemble of leading scientific researchers, investors, and CEOs and R&D leaders from major pharmaceutical, technology, and biotech companies.

The BIG Summit is designed to stimulate ideas that will have an impact on existing pipelines and catalyze future interactions among a group of delegates that represent leaders and innovators in their fields.

Please follow the discussion on Twitter using #BIGAxisSummit

By invitation only; registration is non-transferable.

For more information, please contact PureTechHealthSummit@PureTechHealth.com

HOST COMMITTEE

Participants

BIG SUMMIT AGENDA

(Subject to Change)

PureTech Health BIG Summit 2019 Agenda_FINALv2_WEBSITE.jpg

“Almost starting to understand immunology at this thought-provoking @PureTechh #BIGAxisSummit. Great Speakers.”

-tweet by Simone Fishburn, BioCentury @SimoneFishburn

SOURCE

https://bigsummit2019.com/agenda/

Selected Tweets from #BIGAxisSummit

by @pharma_BI @AVIVA1950

for @pharmaceuticalintelligence.com

Gail S. Thornton Selections

Luke Timmerman‏ @ldtimmerman 7h7 hours ago

Back for final sessions at #BIGAxisSummit. @PureTechH Jim Harper of Sonde Health talking about how voice data — pacing, fine motor articulation, oscillation — can point the way to objective, quantitative measures for detecting and monitoring depression.

Eddie Martucci‏

@EddieMartucci 5h5 hours ago

Paul Biondi at #BIGAxisSummit : What makes big deals happen is financial, and *deep conviction* of a big future fit. Disproportionate valuation from bidders is expected.

Love this. We often reduce everything to mathematical analyses to champion or ridicule deals. Not that simple

PureTech Health Plc‏ @PureTechH Jan 31

Bob Langer (@MIT) asks how #lymphatics affected by #aging. Santambrogio: typically blame aging #immune cells for increased disease, but aging affects lymphatics too (less efficient trafficking shown). Rejuvenating these could affect several aging-related diseases #BigAxisSummit

PureTech Health Plc‏ @PureTechH Jan 31

Viviane Labrie (@VAInstitute) discusses why the appendix has been identified as a potential starting point for #parkinsons #BIGAxisSummit

PureTech Health Plc‏ @PureTechH Jan 31

Chris Porter (@MIPS_Australia) notes #lymphatics is major route for trafficking #immune cells that surveil gut and respond to immune & #autoimmune stimuli. This is key in #BIGAxis interactions and why lymphatics-targeted therapies could enhance #immunomodulation #BIGAxisSummit

Dr. Stephen J. Williams Selections

Dr. Irina Robu Selection

Dr. Sudipta Saha Selection

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37th Annual J.P. Morgan HEALTHCARE CONFERENCE: News at #JPM2019 for Jan. 10, 2019: Deals and Announcements

Posted in BioIT: BioInformatics, NGS, Clinical & Translational, Pharmaceutical R&D Informatics, Clinical Genomics, Cancer Informatics, BioTechnology - Venture Creation, BioTechnology - Venture Creation, Venture Capital, Conference Coverage with Social Media, Curation, Drug Development Process, FDA, FDA Regulatory Affairs, Genetics & Pharmaceutical, Molecular Genetics & Pharmaceutical, Pharmaceutical Discovery, Pharmaceutical Drug Discovery, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Informatics, Pharmaceutical R&D Investment, Precision Cancer Medicine, REAL TIME Conference Coverage Twitter's Hashtags and Handles per Presentation/session, Scientific & Biotech Conferences: Press Coverage, Transformative Technologies in Healthcare, Translational Science, Venture Capital, tagged #JPM2019, AstraZeneca, bioinvestment, Biotech Investment and Venture Growth: The Franchising of Intellectual Property as a Business Model, Biotechnology and Pharmaceuticals, Business News JP Morgan Healthcare Conference Adaptive Biotechnologies Counsyl Danaher Human Longevity JP Morgan Qiagen Thermo Fisher Scientific, Drug development, gene therapy, Global Partnering & Biotech Investment, healthcare, new drug development, ovarian cancer, pharma deals, pharmaceutical business, vaccine on January 10, 2019| Leave a Comment »

37th Annual J.P. Morgan HEALTHCARE CONFERENCE: News at #JPM2019 for Jan. 10, 2019: Deals and Announcements

Reporter: Stephen J. Williams, Ph.D.

From Biospace.com

JP Morgan Healthcare Conference Update: Sage, Mersana, Shutdown Woes and Babies

Published: Jan 10, 2019 By Alex Keown

With the J.P. Morgan Healthcare Conference winding down, companies remain busy striking deals and informing investors about pipeline advances. BioSpace snagged some of the interesting news bits to come out of the conference from Wednesday.

SAGE Therapeutics – Following a positive Phase III report that its postpartum depression treatment candidate SAGE-217 hit the mark in its late-stage clinical trial, Sage Therapeutics is eying the potential to have multiple treatment options available for patients. At the start of J.P. Morgan, Sage said that patients treated with SAGE-217 had a statistically significant improvement of 17.8 points in the Hamilton Rating Scale for Depression, compared to 13.6 for placebo. The company plans to seek approval for SAGE-2017, but before that, the FDA is expected to make a decision on Zulresso in March. Zulresso already passed muster from advisory committees in November, and if approved, would be the first drug specifically for postpartum depression. In an interview with the Business Journal, Chief Business Officer Mike Cloonan said the company believes there is room in the market for both medications, particularly since the medications address different patient populations.

Mersana Therapeutics – After a breakup with Takeda Pharmaceutical and the shelving of its lead product, Cambridge, Mass.-based Mersana is making a new path. Even though a partial clinical hold was lifted following the death of a patient the company opted to shelve development of XMT-1522. During a presentation at JPM, CEO Anna Protopapas noted that many other companies are developing therapies that target the HER2 protein, which led to the decision, according to the Boston Business Journal. Protopapas said the HER2 space is highly competitive and now the company will focus on its other asset, XMT-1536, an ADC targeting NaPi2b, an antigen highly expressed in the majority of non-squamous NSCLC and epithelial ovarian cancer. XMT-1536 is currently in Phase 1 clinical trials for NaPi2b-expressing cancers, including ovarian cancer, non-small cell lung cancer and other cancers. Data on XMT-1536 is expected in the first half of 2019.

Novavax – During a JPM presentation, Stan Erck, CEO of Novavax, pointed to the company’s RSV vaccine, which is in late-stage development. The vaccine is being developed for the mother, in order to protect an infant. The mother transfers the antibodies to the infant, which will provide the baby with protection from RSV in its first six months. Erck called the program historic. He said the Phase III program is in its fourth year and the company has vaccinated 4,636 women. He said they are tracking the women and the babies. Researchers call the mothers every week through the first six months of the baby’s life to acquire data. Erck said the company anticipates announcing trial data this quarter. If approved, Erck said the market for the vaccine could be a significant revenue driver.

“You have 3.9 million birth cohorts and we expect 80 percent to 90 percent of those mothers to be vaccinated as a pediatric vaccine and in the U.S. the market rate is somewhere between $750 million and a $1 billion and then double that for worldwide market. So it’s a large market and we will be first to market in this,” Erck said, according to a transcript of the presentation.

Denali Therapeutics – Denali forged a collaboration with Germany-based SIRION Biotech to develop gene therapies for central nervous disorders. The two companies plan to develop adeno-associated virus (AAV) vectors to enable therapeutics to cross the blood-brain barrier for clinical applications in neurodegenerative diseases including Parkinson’s, Alzheimer’s disease, ALS and certain other diseases of the CNS.

AstraZeneca – Pharma giant AstraZeneca reported that in 2019 net prices on average across the portfolio will decrease versus 2018. With a backdrop of intense public and government scrutiny over pricing, Market Access head Rick Suarez said the company is increasing its pricing transparency. Additionally, he said the company is looking at new ways to price drugs, such as value-based reimbursement agreements with payers, Pink Sheet reported.

Amarin Corporation – As the company eyes a potential label expansion approval for its cardiovascular disease treatment Vascepa, Amarin Corporation has been proactively hiring hundreds of sales reps. In the fourth quarter, the company hired 265 new sales reps, giving the company a sales team of more than 400, CEO John Thero said. Thero noted that is a label expansion is granted by the FDA, “revenues will increase at least 50 percent over what we did in the prior year, which would give us revenues of approximate $350 million in 2019.”

Government Woes – As the partial government shutdown in the United States continues into its third week, biotech leaders at JPM raised concern as the FDA’s carryover funds are dwindling. With no new funding coming in, reviews of New Drug Applications won’t be able to continue past February, Pink Sheet said. While reviews are currently ongoing, no New Drug Applications are being accepted by the FDA at this time. With the halt of NDA applications, that has also caused some companies to delay plans for an initial public offering. It’s hard to raise potential investor excitement without the regulatory support of a potential drug approval. During a panel discussion, Jonathan Leff, a partner at Deerfield Management, noted that the ongoing government shutdown is a reminder of how “overwhelmingly dependent the whole industry of biotech and drug development is on government,” Pink Sheet said.