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Archive for the ‘cell-based therapy’ Category


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.

 

References:

 

https://www.nih.gov/news-events/news-releases/scientists-explore-new-roles-rna

 

https://www.cell.com/consortium/exRNA

 

https://www.sciencedaily.com/releases/2016/06/160606120230.htm

 

https://www.pasteur.fr/en/multiple-roles-rnas

 

https://www.nature.com/scitable/topicpage/rna-functions-352

 

https://www.umassmed.edu/rti/biology/role-of-rna-in-biology/

 

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

 

Leigh syndrome is one of the hundreds of so-called mitochondrial diseases, which are caused by defects in the mitochondria that produce 90 percent of the body’s energy. These disorders are rare; about 1,000 to 4,000 babies in the United States are born with one every year. But they are devastating and can result in grave impairment of nearly any bodily system. They are largely untreatable, uniformly incurable and very difficult to screen.

 

Leigh syndrome is a terrible disease. It emerges shortly after birth and claims one major organ after another. Movement becomes difficult, and then impossible. A tracheotomy and feeding tube are often necessary by toddlerhood, and as the disease progresses, lungs frequently have to be suctioned manually. Most children with the condition die by the age of 5 or 6.

 

Scientists have devised a procedure called mitochondrial replacement therapy (M.R.T.) that involves transplanting the nucleus of an affected egg (mitochondrial diseases are passed down from the mother’s side) into an unaffected one whose nucleus has been removed. The procedure is sometimes called “three-parent in vitro fertilization”. Mitochondria contain a minuscule amount of DNA, any resulting embryo would have mitochondrial DNA from the donor egg and nuclear DNA from each of its parents.

 

After decades of careful study in cell and animal research M.R.T. is now finally being tested in human clinical trials by doctors in Britain (no births confirmed yet officially). In the United States, however, this procedure is effectively illegal. M.R.T. does not involve altering any genetic code. Defective mitochondria are swapped out for healthy ones.

 

Mitochondrial DNA governs only a handful of basic cellular functions. It is separate from nuclear DNA, which helps determine individual traits like physical appearance, intelligence and personality. That means M.R.T. cannot be used to produce the genetically enhanced “designer babies” and thus should be allowed in humans. But, there is no way to know how safe or effective M.R.T. is until doctors and scientists test it in humans.

 

References:

 

 

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

 

 

 

 

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Immunoediting can be a constant defense in the cancer landscape


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

 

There are many considerations in the cancer immunoediting landscape of defense and regulation in the cancer hallmark biology. The cancer hallmark biology in concert with key controls of the HLA compatibility affinity mechanisms are pivotal in architecting a unique patient-centric therapeutic application. Selection of random immune products including neoantigens, antigens, antibodies and other vital immune elements creates a high level of uncertainty and risk of undesirable immune reactions. Immunoediting is a constant process. The human innate and adaptive forces can either trigger favorable or unfavorable immunoediting features. Cancer is a multi-disease entity. There are multi-factorial initiators in a certain disease process. Namely, environmental exposures, viral and / or microbiome exposure disequilibrium, direct harm to DNA, poor immune adaptability, inherent risk and an individual’s own vibration rhythm in life.

 

When a human single cell is crippled (Deranged DNA) with mixed up molecular behavior that is the initiator of the problem. A once normal cell now transitioned into full threatening molecular time bomb. In the modeling and creation of a tumor it all begins with the singular molecular crisis and crippling of a normal human cell. At this point it is either chop suey (mixed bit responses) or a productive defensive and regulation response and posture of the immune system. Mixed bits of normal DNA, cancer-laden DNA, circulating tumor DNA, circulating normal cells, circulating tumor cells, circulating immune defense cells, circulating immune inflammatory cells forming a moiety of normal and a moiety of mess. The challenge is to scavenge the mess and amplify the normal.

 

Immunoediting is a primary push-button feature that is definitely required to be hit when it comes to initiating immune defenses against cancer and an adaptation in favor of regression. As mentioned before that the tumor microenvironment is a “mixed bit” moiety, which includes elements of the immune system that can defend against circulating cancer cells and tumor growth. Personalized (Precision-Based) cancer vaccines must become the primary form of treatment in this case. Current treatment regimens in conventional therapy destroy immune defenses and regulation and create more serious complications observed in tumor progression, metastasis and survival. Commonly resistance to chemotherapeutic agents is observed. These personalized treatments will be developed in concert with cancer hallmark analytics and immunocentrics affinity and selection mapping. This mapping will demonstrate molecular pathway interface and HLA compatibility and adaptation with patientcentricity.

References:

 

https://www.linkedin.com/pulse/immunoediting-cancer-landscape-john-catanzaro/

 

https://www.cell.com/cell/fulltext/S0092-8674(16)31609-9

 

https://www.researchgate.net/publication/309432057_Circulating_tumor_cell_clusters_What_we_know_and_what_we_expect_Review

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4190561/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840207/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593672/

 

https://www.frontiersin.org/articles/10.3389/fimmu.2018.00414/full

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593672/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4190561/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4388310/

 

https://www.linkedin.com/pulse/cancer-hallmark-analytics-omics-data-pathway-studio-review-catanzaro/

 

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Gene-editing Second International Summit in Hong Kong: George Church, “Let’s be quantitative before we start being accusatory”

 

Reporter: Aviva Lev-Ari, PhD, RN

UPDATED on 11/30/2018

Gene editing takes a foreboding leap forward

He Jiankui. Photo: Zhang Wei/Chinese News Service/VCG via Getty Images

 

China is temporarily suspending the work of scientists who claimed twins were born after being genetically edited as embryos.

Why it matters: The scientific consensus is that gene editing embryos at this stage of science is “irresponsible.” But, while this particular experiment has not been verified, the fact is the technology is available to researchers, so there’s a growing call for international limitations on its use.

ICYMI: Chinese scientist He Jiankui announced earlier this week that twins were born after he used the gene-editing tool CRISPR-Cas9 to cut the CCR5 gene that’s known to play a role in HIV infection.

  • He stirred even more dismay when he mentioned the possibility of a second pregnancy.
  • China currently bans human implantation of gene-edited embryos. Its Ministry of Science and Technology is investigating the claims, per Xinhua.

There are concerns about the safety, efficacy and possible mosaicism, where a person can contain genes in both its edited and unedited forms, from cutting genes.

  • Editing embryos raises an even bigger concern: The genetic changes and all the unknowns around them can be passed down to future generations.

Between the lines: Not everyone viewed it as a complete disaster. For instance, Harvard Medical School’s George Daley suggested that it may be time to reconsider the massive amounts of research done over the past several years and look for plausible methods of moving forward.

What to watch: Scientists are cautious about predicting what the impact will be, in part because the details of this claim are thin. However, the debate is heating up and one concern is it will dampen important research.

  • Medical ethicist Jonathan Moreno from the University of Pennsylvania says the situation reminds him of other times in history where there were tremors in the science world, like the death of 18-year-old Jesse Gelsinger in 1999 from a gene therapy trial that led to years of diminished research.

The bottom line: The alarm over what could be next is real. But scientists hope the current debate will promote consensus on firm limits and promote transparency.

Go deeper:

SOURCE

From: Andrew Freedman <andrew.freedman@axios.com>

Date: Thursday, November 29, 2018 at 5:33 PM

To: Aviva Lev-Ari <AvivaLev-Ari@alum.berkeley.edu>

Subject: Axios Science: About that climate report — Gene editing takes a foreboding step — Building in harms’ way

 

 

He Jiankui spoke at the second international summit on human genome editing in Hong Kong. (Alex Hofford/EPA-EFE/Shutterstock)

CRISPR-baby scientist faces the music

The scientist who claims to have helped produce the first people born with edited genomes faced a tough crowd yesterday at a gene-editing summit in Hong Kong. He Jiankui gave a 20-minute talk about his unpublished work in animals and humans before opening a 40-minute Q&A session (watch it here). He faced difficult questions about the ethics of his work and his choice to keep it mostly under wraps until after the babies were born, and left many unanswered.

Meanwhile, prominent geneticist George Church is one of the few scientists who seem to be looking on the bright side of He’s controversial claim. “Let’s be quantitative before we start being accusatory,” Church told Science. “As long as these are normal, healthy kids it’s going to be fine for the field and the family.”

Nature | 9 min read & Science | 6 min read

Read more: Genome-edited baby claim provokes international outcry

 

SOURCE

From: Nature Briefing <briefing@nature.com>

Reply-To: Nature Briefing <briefing@nature.com>

Date: Thursday, November 29, 2018 at 12:18 PM

To: Aviva Lev-Ari <AvivaLev-Ari@alum.berkeley.edu>

Subject: CRISPR-baby scientist faces the music at gene-editing summit

 

See

SAVE

The ethical red flags of genetically edited babies

Driving the news: Chinese scientist He Jiankui announced Sunday night that a pair of twin girls had been born from embryos he modified using the gene-editing tool known as CRISPR.

  • He hasn’t provided solid proof, but if it‘s true, it would be the first time the technology has been used to engineer a human.

What they’re saying: The inventors of CRISPR technology did not seem pleased with the development — one called for a moratorium on implantation edited embryos into potential mothers.

  • “I hope we will be more cautious in the next thing we try to do, and think more carefully about when you should use technology versus when you could use technology,” said Jessica Berg, a bioethicist at Case Western Reserve University.

Between the lines: Several specific factors in He’s work sent up ethical red flags.

  • Many scientists had assumed that, when this technology was first used in humans, it would edit out mutations tied to a single gene that were certain to cause a child pain and suffering once it was born — essentially, as a last resort.
  • But He used CRISPR to, as he put it, “close a door” that HIV could have one day traveled through. That has prompted some speculation that this project was more about testing the technology than serving an acute medical need.
  • “That should make us very uneasy about the whole situation,” Berg said. “Of all the things to have started with, it does make you a little suspicious about this particular choice.”

The intrigue: There’s a lot we still don’t know about He’s work, and that’s also contributing to an attitude of skepticism.

  • How many embryos did he edit and implant before these live births?
  • How will he know it worked? As the children age, they’ll likely have their blood drawn and those samples will be exposed to HIV in a lab, but researchers aren’t going to tell them to go out and have unprotected sex or use intravenous drugs — another reason HIV seems like an odd starting place for human gene editing.
  • How did this even happen? The university where He worked said he was on leave, and Chinese officials have said he’s under investigation. But gene editing is a pretty hard thing to freelance.

The other side: He defended his work in a video message, saying, “I understand my work will be controversial but I believe families need this technology and I’m willing to take the criticism for them.”

  • “Their parents don’t want a designer baby, just a child who won’t suffer from a disease which medicine can now prevent,” He said.

Yes, but: Now that this threshold may have been crossed, attempts to create “designer babies” — within the limitations of what CRISPR can do — probably aren’t far off, some experts fear.

  • There are “likely to be places that are less regulated than others, where people are going to attempt to see what they can do,” Berg said. “I wouldn’t say everything in the world has changed now, but it’s certainly the next step.”
SOURCE

https://www.axios.com/genetic-editing-baby-china-ethics-controversy-b33f8414-8b83-445c-bad5-d8407f8841f4.html

https://pharmaceuticalintelligence.com/2018/11/26/jennifer-doudna-and-npr-science-correspondent-joe-palca-several-interviews/

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LIVE 2018 The 21st Gabay Award to LORENZ STUDER, Memorial Sloan Kettering Cancer Center, contributions in stem cell biology and patient-specific, cell-based therapy

REAL TIME Reporter: Aviva Lev-Ari, PhD, RN

AWARD LECTURE

Tue., Oct. 9, 2018
4:00 PM
Shapiro Campus Center Theater
Brandeis University

CURRENT WINNER

lorenzstuder.jpgLORENZ STUDER

MACARTHUR FELLOWS PROGRAM

Lorenz Studer

Stem Cell Biologist | Class of 2015

Pioneering a new method for large-scale generation of dopaminergic neurons that could provide one of the first treatments for Parkinson’s disease and prove the broader feasibility of stem cell–based therapies for other neurological disorders.

https://www.macfound.org/fellows/947/

118 publications on PubMed

https://www.ncbi.nlm.nih.gov/pubmed/?term=LORENZ+STUDER

 

PRESIDING

Dagmar Ringe Professor of Biochemistry, Chemistry and Rosenstiel Basic Medical Sciences Research Center

WELCOME

Lisa Lynch Provost and Maurice B. Hexter Professor of Social and Economic Policy Brandeis University

 

RESPONSE Lorenz Studer, MD Director, Center for Stem Cell Biology Memorial Sloan Kettering Cancer Center Member, Developmental Biology Program Memorial Sloan Kettering Cancer Center

Fully defined protocol for all ectodermal lineage

  • Nervous system: Forebrain, Midbrain, Spinal cord:
  • CNS lineage to PNS Lineage
  • Excitatory cortical neurons
  • cortical interneurons Astrocytes
  • microglia
  • Age-reset disease – late-onset during reprogramming – Is age reversible?
  • Loss of age-related markers
  • iPSC-derived cells yield stage cell upon differentiation
  • In vitro differentiation techniques: 2D Directed Differentiation 3D- Organoids
  • Graded MORPHOGEN SIGNALING
  • DOXYCYLINE: ISHH-ORGANIZER – 5 discrete forebrain regions
  • Building Human brain cells in 2D and in 3D
  • Organized cells –>>>  directed organoids –>> Organized Organoids
  • Parkinson, 1817 – Essay on Shaky Palsy (Niagrostaterial pathway)
  • Genetics and related dysfunction: affecting PD
  • Charckot, 1889
  • PD – new approach following drugs and deep brain stimulation failure in advanced disease: Fetal tissue transplant trials: Fetal Grafting
  • graft-induced dyskinesia
  • Long term, 15 years positive effects
  • Stem-cell-based regenerative therapy could transform PD therapy
  • 1995  Fetal DA neuron grafting for PD in Switzerland
  • 1998 – midbrain stem cell derived DA neuron
  • 200-2003 – Stem cell in brain implantation in WashDC
  • 2011 – Behavioral assays that are restored in mice
  • Optogenetics: manipulating – Light on the brain – control animal’s neurons
  • MOA of Graft function
  • Dopamine neurons – Stratium area of the human brain
  • From bench to bedside – WNT boost enhances EN1 expression
  • Neuron melanin induction
  • Manufacturing and QA testing: GMP – Off the shelf Allogenic Product
  • 1,000 human dose equivalents
  • cryopreserve
  • MSK-DA01 is highly enriched for mDA neuron precursors without detectable hESC Contaminants
  • FDA feedback and final steps to IND – PRE-IND MEETING: 2014, 2016
  • GLP STUDIES:
  • TUMORIGENICITY, BIODISTRIBUTION AND TOXISITY
  • HISTOLOGY OF FINAL PRODUCT
  • CLINICAL TRIAL DESIGN – STEM-PD – MSK and Weill Cornell Medicine
  • HLA expression is absent in edited iPSC with expression of HLA-E to block NK clearance
  • FUTURE: CRISPR
  • ATLaS-PD – assessing the longitudinal Symptoms/signs to moderate of severe stage
  • Development of a new PD therapy from Pluripotent Stem Cells
  • BlueRock Therapeutics – MSK-PD – Start up – $240Million funding
  • Stem cell based dopamine therapy for PD
  • Immunosuppression for 12 months
  • defined levodopa response > 45% improvement
  • Conclusions
  • Cell banks for clinical trials
  • NY state Stem cell science consortia

http://www.brandeis.edu/rosenstiel/images/pdfs/gabbay21program.pdf

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