Archive for the ‘Gene Therapy Clinics’ Category

New ‘hit-and-run’ gene editing tool temporarily rewrites genetics to treat cancer and HIV – GeekWire

Gene Therapy Clinics | Posted by admin
Sep 02 2017

Nanoparticles (orange) deliver temporary gene therapy to immune cells (blue) to give them disease-fighting tools. (Fred Hutch Illustration / Kimberly Carney)

CAR T immunotherapies are all the rage in the medical community, reprogramming a patients immune system to fight cancer. For some patients, theyve produced near-miraculous recoveries, and they could be a huge breakthrough in cancer treatment.

The business community is taking note as well: Kite Pharma, a biotech company developing these therapies, announced a deal to be acquired for $11.9 billion on Monday, sending stock prices of Seattle immunotherapy developer Juno Therapeuticsskyrocketing.

But there are still giant pitfalls to using the therapies on a large scale because they are incredibly complex and expensive to produce. Researchers from Seattles Fred Hutchinson Cancer Research Center are taking the problem head-on with new hit-and-run gene editing technology.

In a study published Wednesday in the journal Nature Communications, researchers led by Dr.Matthias Stephan reported they have developed a nanoparticle delivery system that can temporarily alter cells so they are able to fight cancer and other diseases.

The best part? The treatment is a powder that just needs to be mixed with water to activate and even better, it could be an essential breakthrough in making cutting-edge medical technology affordable for patients.

Stephan told GeekWire in a previous piece on the technology that his goal is to make immunotherapy so easy to access that it replaces chemotherapy as the front-line treatment for cancer.

What I envision is like the Walgreens flu shot scenario, or you go to your doctor and you get hepatitis B shot, he said at the time. You go there every Friday, and thats it.

We realized in order to outcompete chemotherapy, we have to design something that is at least as affordable and can be manufactured at large scale by one biotech company and shipped out to local infusion centers, Stephan said. At the moment, CAR T cell therapies must be made individually for each patient in specialized labs.

Heres how the new tech works: The nanoparticles designed by Stephan and his team act like shipping containers for bundles of mRNA, the molecules that tell cells how to build disease-fighting proteins. The nanoparticles also have molecules attached to the outside to help them find the right kind of cells, like a shipping label on a package.

When the mRNA is delivered to the cell, it prompts the cell to grow disease-fighting features, like the chimeric antigen receptor in CAR T cells that help them identify and kill cancer.Researchers said the technology could potentially be used to develop treatments for HIV, diabetes and other immune-related diseases.

In the short run, the tech could help researchers discover new treatments and therapies in the lab. It could one day be used in hospitals and clinics around the world, but will first need to undergo extensive clinical trials to ensure the tech is effective and safe to use in humans.

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New 'hit-and-run' gene editing tool temporarily rewrites genetics to treat cancer and HIV - GeekWire

How one California county is fighting high-priced surgeries – Los Angeles Times

Gene Therapy Clinics | Posted by admin
Sep 02 2017

Retiree Leslie Robinson-Stone and her husband enjoyed a weeklong, all-expenses-paid trip to a luxury resort all thanks to the county she worked for.

The couple also received more than a thousand dollars in spending money and a personal concierge, who attended to their every need. For Santa Barbara County, it was money well spent: Sending Robinson-Stone 250 miles away for knee replacement surgery near San Diego saved the government $30,000.

The only difference between our two hospitals is one is expensive and the other is exorbitant, said Andreas Pyper, assistant director of human resources for Santa Barbara County, referring to the local options.

After years of hospital industry consolidation, frustration with sky-high hospital bills and a lack of local competition is common to many employers and consumers across the country. Fed up with wildly different price tags for routine operations, some private employers are steering patients they insure to top-performing providers who offer bargain prices. Santa Barbara County, with about 4,000 employees, is among a handful of public entities to join them.

The county has saved nearly 50% on four surgery cases since starting its out-of-town program last year, officials said. The program is voluntary for covered employees.

At a Scripps Health hospital in the San Diego area, the county paid $61,600 for a spinal fusion surgery that would have cost more than twice as much locally. It avoided two other operations altogether after patients went outside the area for second opinions.

Typically, employers are seeking deals through bundled payments in which one fixed price covers tests, physician fees and hospital charges. And if complications arise, providers are on the hook financially. Medicare began experimenting with this method during the Obama administration.

Santa Barbara County is among about 400 employers on the West Coast working with Carrum Health, a South San Francisco, Calif., start-up that negotiates bundled prices and chooses surgeons based on data on complications and readmissions.

Not all surgeons are equal. We dont want to give Scripps a blank check. That defeats the whole purpose, said Sachin Jain, Carrums chief executive.

Santa Barbara officials try to persuade workers and their family members to participate in its program by waiving co-pays and deductibles. The county pays about $2,700 in travel costs and still comes out way ahead.

If that doesnt speak to the inefficiencies in our healthcare system, I dont know what does, Pyper said. Its almost like buying a Toyota Corolla for $50,000 and then going to San Diego to buy the same Corolla for $16,000. How long would the more expensive Toyota dealership last?

Even as more employers and insurers embrace bundled payments, the Trump administration is applying the brakes.

In August, Medicare officials proposed canceling mandatory bundled payments for certain surgeries and scaling back the program for knee and hip replacements. Health and Human Services Secretary Tom Price, when he was still a member of Congress, accused Medicare of overstepping federal authority and interfering in the doctor-patient relationship. Hospital trade groups have voiced similar objections.

That leaves some health-policy experts dismayed.

These bundled payments put pressure on medical providers and the savings are astonishing, said Bob Kocher, a former health official in the Obama administration and now a partner in the venture capital firm Venrock.

Santa Barbara County officials said they had no choice after seeing their medical costs soar by 15% in each of the last two years. Like many local governments, it has an older workforce prone to chronic illness, blocked arteries and bum knees.

But health costs run higher than the state average in this scenic coastal county of about 450,000 people, according to data from Oakland-based Integrated Healthcare Assn. By one measure, the average health insurance premium in the individual market runs $660 a month in Santa Barbara, 27% higher than in Los Angeles.

Heidi de Marco / Kaiser Health News

Maya Barraza is Santa Barbara Countys manager for employee benefits.

Maya Barraza is Santa Barbara Countys manager for employee benefits. (Heidi de Marco / Kaiser Health News)

Still, Maya Barraza, the countys manager for employee benefits and rewards, knew the program would be a hard sell to workers. You dont want to be away from your family and whats familiar, she said.

Cottage Health, the countys largest health system, says it wants to keep patients in town for treatment and follow-up care.

Established in 1891, its grown from a single hospital to more than 500 beds across three hospitals, and annual revenue hit $746 million last year.

Valet attendants greet visitors at two entrances outside the groups white, Spanish-style hospital in the city of Santa Barbara. In the main lobby, the names of wealthy donors are splashed across one wall, including billionaire investor and Donald Trump confidant Thomas Barrack.

We are continually looking at reducing costs and improving quality, said Cottage Health spokeswoman Maria Zate. Cottage Health has some of the top surgeons in California.

Sixty miles north in Santa Maria, the states largest hospital chain, Dignity Health, offers another option: Marian Regional Medical Center.

Both Cottage and Dignity hospitals in Santa Barbara County have quality scores of fair to excellent for joint replacements, spinal procedures and coronary bypass surgeries, according to three years of Medicare data analyzed by research firm Mpirica Health.

Dignity Health didnt respond to requests for comment.

Carrum tries to help employers like Santa Barbara County find more affordable options. It has struck bundled price deals for various procedures with Scripps hospitals in the San Diego area, Stanford Health Care in the Bay Area and Swedish Medical Center in Seattle, part of the Providence Health chain.

Some companies have gone so far as to send patients overseas for cheaper care, but most employers favor a more regional approach, experts say. Workers still rely on local physicians for follow-up care.

For some hospitals, there are advantages in offering deep discounts: They get patients they otherwise would never see and are paid in full right after the patient is discharged, avoiding the onerous billing and collections process.

They also have the financial capacity to offer such sharply reduced prices.

Michael Bark, assistant vice president of payer relations at Scripps Health, said most hospitals significantly mark up their commercial rates for orthopedic procedures and cardiac surgeries to compensate for lower government reimbursements.

There are immense profit margins built into those cases, Bark said.

Robinson-Stone, a former county sheriffs deputy and a computer support specialist, was initially wary of traveling for her surgery. But the 62-year-old had ongoing pain that kept her from biking, walking her dogs and tending to her fruit trees. Medication and cortisone shots didnt work, and she had no ties to local surgeons. So she signed up online and was given a choice of six orthopedic surgeons at Scripps Green Hospital in La Jolla.

In June 2016, she and her husband, Frank Stone, checked in at the Estancia La Jolla Hotel and Spa.

Robinson-Stone met the surgeon on a Wednesday, had the operation the next day and returned to her hotel room by Saturday. She continued physical therapy at the hotel and returned to the hospital a few days later to have the staples removed.

She was back on her bike within two months and eventually lost about 20 pounds.

I just celebrated one year from surgery, she said, and Im a happy camper.

Chad Terhune is a senior correspondent for Kaiser Health News, an editorially independent publication of the Kaiser Family Foundation. Heidi DeMarco contributed to this story.

ALSO

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FDA cracks down on clinics selling unproven stem cell 'therapies'

Gilead is buying Kite Pharma, a cancer-fighting Santa Monica biotech firm, for $11.9 billion

Knocking on doors, climbing through fences: How L.A. County's health investigators are out trying to stop syphilis

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How one California county is fighting high-priced surgeries - Los Angeles Times

Australian Market Declines – Markets Insider

Gene Therapy Clinics | Posted by admin
Aug 29 2017

(RTTNews) - The Australian stock market is declining on Monday after the banking regulator's announcement of the launch of an independent inquiry into Commonwealth Bank dragged down banking stocks. In addition, weakness in base metal prices weighed on mining stocks.

In late-morning trades, the benchmark S&P/ASX 200 Index is declining 39.80 points or 0.69 percent to 5,704.10, off a low of 5,700.50. The broader All Ordinaries Index is down 36.70 points or 0.63 percent to 5,766.70.

The big four banks - ANZ Banking, Westpac, Commonwealth Bank and National Australia Bank - are lower in a range of 1.1 percent to 1.7 percent.

The Australian Prudential Regulation Authority or APRA said it will launch an inquiry to look at governance, culture and accountability practices at Commonwealth Bank after recent allegations that it violated laws.

In the mining space, Rio Tinto is declining more than 1 percent and Fortescue Metals is losing almost 2 percent, while BHP Billiton is up 0.2 percent.

Gold miners are advancing after gold prices gained on Friday. Newcrest Mining is edging up less than 0.1 percent and Evolution Mining is adding almost 1 percent.

Oil stocks are also higher after crude oil prices rose on Friday. Santos is rising more than 2 percent, Oil Search is adding 0.3 percent and Woodside Petroleum is up 0.2 percent.

Australian Pharmaceutical Industries, the operator of Priceline pharmacies, has withdrawn from the potential acquisition of Laser Clinics Australia saying the sale price was too high. Shares of API are adding 0.2 percent.

Amaysim Australia reported a 6.5 percent decline in net profit for the full year, while its underlying earnings rose 22.9 percent. The mobile service provider's shares are gaining almost 6 percent.

CSL has agreed to acquire U.S. biotechnology company Calimmune, which is developing a stem cell gene therapy to treat rate conditions such as sickle cell disease, for an up-front payment of $91 million. Shares of CSL are adding 0.3 percent.

Ten Network has been acquired by U.S. media giant CBS Corp. Shares of Ten Network are in a trading halt since June 13 after it was placed into voluntary administration.

In the currency market, the Australian dollar rose against the U.S. dollar, which weakened after the Jackson Hole speeches by global central bankers. In early trades, the local unit was trading at US$0.7925, up from US$0.7904 on Friday.

On Wall Street, stocks closed mixed on Friday after seeing early strength that partly reflected optimism about tax reform following comments from President Donald Trump's chief economic adviser Gary Cohn.

The Nasdaq edged down 5.68 points or 0.1 percent to 6,265.64, while the Dow inched up 30.27 points or 0.1 percent to 21,813.67 and the S&P 500 ticked up 4.08 points or 0.2 percent to 2,443.05.

The major European markets moved modestly lower on Friday. While the French CAC 40 Index slipped by 0.2 percent, the U.K.'s FTSE 100 and the German DAX Index both edged down by 0.1 percent.

Crude oil prices gained on Friday as the dollar fell and the U.S. petroleum industry braced for Hurricane Harvey. WTI crude rose $0.44 or 0.9 percent to close at $47.87 a barrel on the New York Mercantile Exchange.

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Australian Market Declines - Markets Insider

New Stanford drug saves child with deadly genetic disease – The Mercury News

Gene Therapy Clinics | Posted by admin
Aug 25 2017

At 7 months old, Zoe Harting got a shot at Lucile Packard Childrens Hospital Stanford that changed the course of her life.

A few months earlier, during a family Christmas vacation, Zoes parents, John and Eliza Harting of El Granada, realized something was wrong with their newborn.

Zoe was not developing at the same rate as her cousin even though the two were born just a week apart.

Her cousin was very mobile: wriggling around, pushing stuff, John Harting said. Zoe wasnt doing any of that. She was very quiet.

The Hartings got the difficult news in early 2013 that Zoe had a deadly genetic disease: spinal muscular atrophy type 1, or SMA-1. Nationwide, about 250 babies are annually diagnosed with the rare disease, or about one in 10,000.

They learned that their first child was expected to die before she turns 2.

Without effective treatment, Zoes muscles would progressively weaken, taking away her ability to walk, eat and, ultimately, breathe.

The Hartingswere told there was nothing they could do. Distraught and frustrated, they joined an SMA support group, now called Cure SMA, and found a new pediatrician.

It was a good thing we did, John Harting said, because our pediatrician happened to attend a conference where she met John Day.

Dr. Day, director of the Neuromuscular Division and Clinics at Stanford University, was about to conduct a clinical trial using nusinersen as the first drug for SMA-1.

Zoe was the first baby in the world to receive the drug.

Day emphasized to the Hartings that he didnt know if the treatment would work but they knew this was their only option.

In December 2016, the Food and Drug Administration approved Spinraza, developed by Biogen, as the first-ever sanctioned therapy for pediatric and adult patients with SMA.

Patients with SMA dont produce enough of a protein called survival motor neuron, or SMN, which helps send signals from the spinal cord to muscles. When the muscles dont get the signals, they atrophy.

Patients with SMA are missing the main gene, SMN1, that produces the protein. Patients have a second gene, SMN2, that also can produce the protein, but it only makes 5 to 10 percent of the amount needed.

The new drug works by acting like a patch to cover up the flawed portion of the SMN2 gene, which then spurs production of the protein.

What we need to do is get a person up to about 50 percent of the normal amount of protein, Day said. Its a 15-or-20 nucleic long signal that ends up being precisely paired with RNA. Thats what gives us this power. Make something incredibly focused on that flaw and it will fix that flaw but not have any other side effect.

Day said its important that families now know there is something doctors can do if they see the infants early enough.

Day said theres minimal awareness of the genetic disease largely because many patients die so young and pediatricians may not have updated information that treatment is available.

Today, a pediatrician gets a genetic test back and they might very well tell the family, Go home and love your child as long as you have them, Day said.

By the time a family does research and come across Days comprehensive care clinic, the child might be six or nine months old with irreversible muscular atrophy.

If we see them early enough, before they see any symptoms, the child may not see any muscular impact, Day said. Its potentially that effective of a treatment if we see the patient early enough.

Day is an advocate for newborn genetic screening so SMA is identified at birth and treatment can begin before the child shows signs of the disease.

Babies are not yet being treated in utero, but such treatment is under development, Day said.

The Hartings shared their story this month as part of SMA Awareness Month, because they want families to know the importance of early detection and that there is treatment. About one in 50 parents are carriers of the recessive gene disorder.

Every four months, Zoe, who is now 4 years old, goes to Stanford for a 12 mg dose of the drug through a lumbar puncture, similar to an epidural. She gets physical therapy in between shots.

She has a weak musculature, and a simple cold can immobilize her. She cant swallow or walk by herself. But after three years of treatment, she can now sit up, interact, draw and play. SMA does not affect cognitive development and there are small signs she will continue to gain muscle strength.

Day is quick to point out that the drug isnt a magic wand that makes the disease go away. But he said Zoe, who had a fairly aggressive course of SMA at three months, has strength she didnt have before treatment and theres hope for continued improvement.

She can talk, she can move her legs and arms, she even yells at me now, Day said with a chuckle. She has personality. She can throw a beach ball around. Shes going to have a life.

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New Stanford drug saves child with deadly genetic disease - The Mercury News

Orphan Diseases Market Key Players analysis … – Digital Journal – Digital Journal

Gene Therapy Clinics | Posted by admin
Aug 25 2017

"Global Orphan Diseases Market- Global Forecast To 2022"

Global Orphan diseases Market information, by Type of Diseases (autoimmune disorders, genetic disorders, blood disorders, cancer, growth disorder, cardiovascular diseases, neurological disorders, respiratory disorders, digestive disorders, eye disorders and Others), by Type of Treatment (gene therapy, cell therapy, drug therapy and others), by End user (hospital and clinics, research laboratory and others) - Forecast to 2022

Market Synopsis of Global Orphan diseases Market:

Market Scenario:

Global orphan diseases market also known as rare disease is growing rapidly. It affects a very small percentage of the global population. Most of the orphan diseases are genetic and is remains throughout the life of the patient. There are no exact number of diseases available but approximately there are about 7000 different rare diseases and disorders throughout the globe. Global orphan diseases market is expected to grow at the average CAGR of 24.9% constantly throughout this period 2015-2022. It is also expected that this market which was US$ 121.6 billion in 2015 will grow to US$ 576.9 billion by 2022. . However due to lack of awareness, correct diagnosis, correct treatments and availability of healthcare facilities are inhibiting the growth of the global orphan diseases market.

Key Players for Global Orphan diseases Market:

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Segments:

Global orphan diseases market has been segmented

On the basis of types of diseases which includes autoimmune disorders, genetic disorders, blood disorders, cancer, growth disorder, cardiovascular diseases, neurological disorders, respiratory disorders, digestive disorders, eye disorders and others.

On the basis of treatment type it segmented into gene therapy, cell therapy, drug therapy and others.

On the basis of end user the market is segmented into hospital and clinics, research laboratory and others.

Intended Audience

Taste the market data and market information presented through more than 50 market data tables and figures spread in 110 numbers of pages of the project report. Avail the in-depth table of content TOC & market synopsis on Global Orphan Diseases Market- Global Forecast To 2022

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Table of Content

1 Report Prologue 2 Market Introduction 2.1 Definition 2.2 Scope Of The Study 2.2.1 Research Objective 2.2.2 Assumptions 2.2.3 Limitations 2.3 Market Structure 3 Research Methodology 3.1 Research Process 3.2 Primary Research 3.3 Secondary Research 3.4 Market Size Estimation 3.5 Forecast Model 4 Market Dynamics 4.1 Drivers 4.2 Restraints 4.3 Opportunities 4.4 Mega Trends 4.5 Macroeconomic Indicators 4.6 Technology Trends & Assessment 5 Market Factor Analysis

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The report gives the clear picture of current market scenario which includes historical and projected market size in terms of value, technological advancement, macro economical and governing factors in the market. The report provides details information and strategies of the top key players in the industry. The report also gives a broad study of the different market segments and regions.

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Orphan Diseases Market Key Players analysis ... - Digital Journal - Digital Journal

Gene Editing in Human Embryos Leaps ForwardHere’s the Science – Singularity Hub

Gene Therapy Clinics | Posted by admin
Aug 22 2017

Imagine walking down the street with a ticking time bomb in your chest, never knowing when your heart may explode.

Or going through five decades of life, having kids, and always wondering when your mind will finally slip away from you. Or worse yet, knowing that one day the same will inevitably happen to your children and your grandchildren.

If there were a curea way to irreversibly correct the faulty biology in yourself and your offspringwould you do it? And knowing that there might be risks, would you be comfortable making that decision for generations to follow?

Last week, a remarkable study published in Nature brought these and other questions back into public discourse. For the first time, an international team led by US scientists used CRISPR, a genetic editing tool, to correct a mutation that leads to heart failure in viable human embryos.

This isnt the first time scientists have tinkered with human embryos. But it is the first that shows that certain off-target effectspreviously thought immensely challengingcan be dealt with in a relatively straightforward way.

In other words, the new technology just brought us one step closer to correcting genetic deficits in humans. And what can be used to right a disease can also be used to enhance a healthy babyartificially altering their intelligence or physical appearance.

To be clear, this study is a long way off from the complicated changes required to make designer babies. This isnt Brave New World or Gattaca.

This is for [the] sake of saving children from horrible diseases, says lead author Dr. Shoukhrat Mitalipov at the Oregon Health and Science University, who previously worked on Dolly the sheep and three-parent babies.

And with this milestone, says Dr. George Church at Harvard University, were one step closer.

The human body runs on the tens of thousands of genes that form the code of life. Sometimes, just a single faulty gene can have devastating consequences, such as Huntingtons disease or hypertrophic cardiomyopathya condition that often leads to heart failure.

For decades, scientists have tried hacking lifes code to cure these genetic diseases at the DNA level. The process seems straightforward: like programmers decoding a bug, scientists would read through the bodys encyclopedia of genes, identify the faulty member, cut and paste the correct code into the original spotand voil, fixed!

The promise of genetic cures seemed easily within reach when a technology called CRISPR came onto the scene in 2012. CRISPR itself isnt a cure. Rather, its a pair of molecular scissors that scientists can direct to almost any point on the human genome and make a precise cut.

The cut triggers a cell to activate a DNA repair program. Almost all cells do this, but embryos go about it slightly differently. If provided with a normal copy of the gene, embryos will use the blueprint gene to reconstruct the broken piece, essentially overwriting the mistaken code. In theory, this leads to fewer mistakes than a normal cells stitch it up repair program, which doesnt use templates.

In practice, however, embryonic DNAs been hard to hack. Just two years ago, Chinese scientists reported giving up on correcting a genetic abnormality in human embryos due to off-target effects, saying that the CRISPR-based technology was too immature.

And for good reason. The safety and ethical barriers are enormous when editing embryosso-called germline editing. The reason is this: after sperm meets egg, the resulting single cell will develop into a persons entire body. This means that any changes to an embryo will (in theory) be present in every single cell in the grown human, including reproductive cells.

In other words, any changes to the embryo will not only affect the person it will become, but also his or her children, and their children and so on. If any unwanted mutation sneaks in during the procedure, the harm is multi-generational.

Then theres the problem of mosaicism. Oftentimes, an edited embryo can lead to a mosaic of genotypes in the resulting cellssome fixed, some not, and the individual still ends up with the disease.

The new study tackles both problems head-on.

Mitalipovs team decided to focus on hypertrophic cardiomyopathy, an inherited disease due to a gene called MYBPC3. People with the condition have two copies of the gene: one normal, one faulty. This means they have a 50-50 chance of passing the condition to their children.

Because the embryo already contains a normal copy of MYBPC3, explain the authors, it already has a blueprint the cell could use to repair the abnormal one. The team recruited a dozen healthy egg donors and one sperm donor that carried the faulty MYBPC3.

Normally, scientists encode all CRISPR components into an external bit of DNA called a plasmid, put that into a cell and rely on the cell to make the necessary proteins and molecules. Mitalipovs team took a more unusual route: using a tiny syringe, they directly injected the CRISPR machinery into either a fertilized embryo or into the egg cell right before fertilization.

In the first case, the CRISPR machinery sticks around for a long time. This increases the chance that it might go rogue and snip parts of the DNA it wasnt designed to cut.

By directly injecting the components, the CRISPR scissors are chewed up by the recipient cell after they do their work: less random snipping, more precision.

The tactic worked. When the team analyzed the resulting embryos at the four- or eight-cell stage, they found 72 percent contained only normal copies of the MYBPC3 gene, compared to roughly 50 percent found in non-edited controls.

Even though the yield of wild type/wild type embryos is still higher, its not 100 percent. We have room to improve, says Mitalipov.

Heres the kicker: using a variety of modern genetic sequencing techniques, the team scrutinized the embryos genomes for off-target effects. They couldnt find any. For all intents and purposes, the edited embryos looked completely healthy.

This doesnt necessarily mean the team avoided all unexpected mutations. It just means any genetic deletions or inserts didnt affect the embryos normal development.

Thats not all. The team also surprisingly found a way to minimize mosaicism. The key is to inject CRISPR components into the egg at the same time as they pumped in the sperm to fertilize it. This is much earlier in the developmental stage than anyone had previously attempted.

It worked. Out of the 58 treated eggs fertilized with the mutant sperm, 42 contained two normal copies of MYBPC3. Only one became a mosaic. In contrast, CRISPRing a fertilized embryo led to 13 out of 54 mosaics.

It makes previous work look pretty amateurish in terms of mosaicism and in terms of off-target effects, says Church.

Surprisingly, rather than bolstering a designer baby future, the study may have inadvertently doused a cold case of biological reality on the sci-fi idea.

Dr. Robin Lovell-Badge, a developmental biologist at the Francis Crick Institute in London, pointed out that the most unexpected result of the study is how the embryo chose to repair the gene.

In one experiment, the team tried introducing an artificial template of MYBPC3 in addition to the normal copy already present in the cell (from the healthy moms). But the cells completely ignored the researchers template, instead exclusively opting to use the maternal MYBPC3 to repair the mutation.

This suggests that you couldnt add anything that wasnt already there, says Lovell-Badge.

To Mitalipov, the crux of the conversation should be solidly based in therapy. My goal has always been to treat genetic diseases that have no cures, to save children, he says.

And there are still a lot of kinks that need ironing out before CRISPR could enter clinics. For one, scientists still hope to increase precision and accuracy. For another, IVF clinics already have solid screening protocols in place to weed out genetic abnormalities before implantation. While CRISPR can, in theory, boost the number of healthy embryos, it would have to work better to justify the cost.

To Dr. Richard Hynes, a cancer researcher at MIT who co-led a national committee that recently published a new guideline for editing embryos, the study is a big breakthrough.

What our report said was, once the technical hurdles are cleared, then there will be societal issues that have to be considered and discussions that are going to have to happen. Nows the time, he says.

Image Credit: University of Michigan via Flickr

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Gene Editing in Human Embryos Leaps ForwardHere's the Science - Singularity Hub

Global Cancer Biological Therapy Market 2017 Size, Development Status, Type and Application, Segmentation … – Digital Journal

Gene Therapy Clinics | Posted by admin
Aug 22 2017

""Cancer Biological Therapy Market""

WiseGuyReports.com adds Cancer Biological Therapy Market 2017 Global Analysis, Growth, Trends and Opportunities Research Report Forecasting to 2023reports to its database.

Cancer Biological Therapy Market:

Executive Summary

Biological therapy treatment is done with the help of living organisms, parts of living organisms or laboratory manufactured version of such content. There are various types of biological therapies, which inhibit specific molecules involved in development and growth of cancer tumor. Such therapies known as; cancer targeted therapies.

The global cancer biological therapy market is expected to reach USD 82,276.8 million by 2023 at a CAGR of 4.7% during the forecasted period.

The global cancer biological therapy market is segmented on the basis of phases, types, end users and regions. On the basis of phases, the market is segmented into phase I, phase II and phase III. In stage I & II the real impact of these therapies is seen and giving a success rate of 35% in Phase 1 and 20% in Phase II. The success rate of phase I is 35%.

On the basis on types, the global cancer biological therapy market is segmented into monoclonal antibodies, cancer growth blockers, interferons, interleukins, gene therapy, targeted drug delivery, colony stimulating factor, cancer vaccines and others. Monoclonal antibodies accounted for the largest market share of the global cancer biological therapy market. Colony stimulating factor is the fastest growing market at a CAGR of 5.2% during the forecasted period.

On the basis on end users, hospitals & clinics dominates the global cancer biological therapy market. Registering USD 26,790.6 million in 2016 and expected to reach at USD 38,471.9 million by 2023 at the rate of 4.4 % from 2016-2023.

On the basis of regions, the market is segmented into North America, Europe, Asia-Pacific and the Middle East & Africa. North America has the dominating market for cancer biological therapy. The cancer biological therapy market for North America is estimated at USD 19,481.2 million in 2016 and expected to reach by USD 29,516.9 million by 2023 at a fastest CAGR of 5.10%.

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Key Players

The leading market players in the global cancer biological therapy market include Merck Inc., F. Hoffmann-La Roche Ltd, Novartis AG, Amgen Inc., Bristol-Myers Squibb, Celgene, ELI Lilly and Company, EnGeneIC, and Pfizer

Study objectives

Target Audience

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Key Findings

The reports also covers regional analysis

o US

o Canada

o Germany

o France

o U.K.

o Italy

o Spain

o Rest of Europe

o Japan

o China

o India

o Republic of Korea

o Rest of Asia-Pacific

o Middle East

o Africa

Continued

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Traditional Therapy Clinics Ltd (TTC.AX) Money Flow Index Levels in Focus – Stock Daily Review

Gene Therapy Clinics | Posted by admin
Aug 22 2017

Traditional Therapy Clinics Ltd (TTC.AX) shares have seen theMoney Flow Indicator drop below 30, potentially spelling a near-term reversal if it crosses below the 20line. The Money Flow Indicatoris a unique indicator that combines momentum and volume with an RSI formula. Because of its incorporation of volume, the MFI is better suited to identify potential reversals using both overbought/oversold levels and bullish/bearish divergences. As with all indicators, the MFI should not be used by itself. A pure momentum oscillator, such as RSI, or pattern analysis can be combined with the MFI to increase signal accuracy.

The MFI was created by Gene Quong and Avrum Soudack and they believed a reading above 70-80 would signify Overbought territory where a reading below 20-10 would indicate that the conditions wereindicative of an Oversold price level.

Investors might be interested in taking a closer look at additional stock technical levels. After a recent check, Traditional Therapy Clinics Ltd (TTC.AX) has a 14-day ATR of 0.02. The average true range indicator was created by J. Welles Wilder in order to measure volatility. The ATR may help traders to determine the strength of a breakout or reversal in price. It is important to mention that the ATR was not designed to calculate price direction or to predict future prices.

Currently, the 14-day ADX for Traditional Therapy Clinics Ltd (TTC.AX) is sitting at 23.62. Generally speaking, an ADX value from 0-25 would indicate an absent or weak trend. A value of 25-50 would support a strong trend. A value of 50-75 would identify a very strong trend, and a value of 75-100 would lead to an extremely strong trend. ADX is used to gauge trend strength but not trend direction. Traders often add the Plus Directional Indicator (+DI) and Minus Directional Indicator (-DI) to identify the direction of a trend.

Checking in on some other technical levels, the 14-day RSI is currently at 32.37, the 7-day stands at 23.25, and the 3-day is sitting at 9.65. Many investors look to the Relative Strength Index (RSI) reading of a particular stock to help identify overbought/oversold conditions. The RSI was developed by J. Welles Wilder in the late 1970s. Wilder laid out the foundation for future technical analysts to further investigate the RSI and its relationship to underlying price movements. Since its inception, RSI has remained very popular with traders and investors. Other technical analysts have built upon the work of Wilder. The 14-day RSI is still a widely popular choice among technical stock analysts.

Investors may be watching other technical indicators such as the Williams Percent Range or Williams %R. The Williams %R is a momentum indicator that helps measure oversold and overbought levels. This indicator compares the closing price of a stock in relation to the highs and lows over a certain time period. A common look back period is 14 days. Traditional Therapy Clinics Ltd (TTC.AX)s Williams %R presently stands at -100.00. The Williams %R oscillates in a range from 0 to -100. A reading between 0 and -20 would indicate an overbought situation. A reading from -80 to -100 would indicate an oversold situation.

Taking a closer look from a technical standpoint, Traditional Therapy Clinics Ltd (TTC.AX) presently has a 14-day Commodity Channel Index (CCI) of -229.42. Typically, the CCI oscillates above and below a zero line. Normal oscillations tend to stay in the range of -100 to +100. A CCI reading of +100 may represent overbought conditions, while readings near -100 may indicate oversold territory. Although the CCI indicator was developed for commodities, it has become a popular tool for equity evaluation as well.

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Traditional Therapy Clinics Ltd (TTC.AX) Money Flow Index Levels in Focus - Stock Daily Review

Sodium Iodide Symporter for Nuclear Molecular Imaging and …

Gene Therapy Clinics | Posted by admin
Aug 13 2017

Theranostics 2012; 2(4):392-402. doi:10.7150/thno.3722

Review

Byeong-Cheol Ahn

Department of Nuclear Medicine, Kyungpook National University School of Medicine and Hospital, Daegu, South Korea

Molecular imaging, defined as the visual representation, characterization and quantification of biological processes at the cellular and subcellular levels within intact living organisms, can be obtained by various imaging technologies, including nuclear imaging methods. Imaging of normal thyroid tissue and differentiated thyroid cancer, and treatment of thyroid cancer with radioiodine rely on the expression of the sodium iodide symporter (NIS) in these cells. NIS is an intrinsic membrane protein with 13 transmembrane domains and it takes up iodide into the cytosol from the extracellular fluid. By transferring NIS function to various cells via gene transfer, the cells can be visualized with gamma or positron emitting radioisotopes such as Tc-99m, I-123, I-131, I-124 and F-18 tetrafluoroborate, which are accumulated by NIS. They can also be treated with beta- or alpha-emitting radionuclides, such as I-131, Re-186, Re-188 and At-211, which are also accumulated by NIS. This article demonstrates the diagnostic and therapeutic applications of NIS as a radionuclide-based reporter gene for trafficking cells and a therapeutic gene for treating cancers.

Keywords: sodium iodide symporter, molecular imaging, radionuclide-based imaging, gene therapy, radionuclide.

The ability of the thyroid gland to concentrate iodide has long provided the basis for diagnosis and therapeutic management of benign thyroid diseases and thyroid cancer [1]. Thyroid scintigraphy with radioiodines or technetium-99m (Tc-99m) pertechnetate has played a key role in the evaluation of thyroid nodules with its ability of providing anatomical and functional information since the advent of modern endocrinology [2]. Radioiodine via an 'atomic cocktail' was first used medically for thyroid cancer treatment under the Atomic Energy Act since 1946 [3]. Thereafter, millions of patients with benign or malignant thyroid diseases have been given radioiodine for diagnostic and therapeutic purposes with successful outcomes. However, the uptake mechanism of radioiodine into thyroid tissue or thyroid cancers was not fully elucidated until 1996, when the sodium iodide symporter (NIS) was finally cloned [4]. This not only improved understanding of thyroid pathophysiology tremendously, but also offered promising molecular biological strategies of imaging and treatment. Clinical theranostic application of NIS function using radioiodine was projected to biologic preclinical experimental studies after the NIS cloning. NIS expression can be imaged feasibly with simple radiotracers, such as radioiodines or Tc-99m. By the easy imaginable characteristic of NIS, it has been used as an imaging reporter to monitor gene transfer.[5, 6] In addition to the potential as the imaging reporter gene, NIS has been used as a therapeutic gene to treat cancers through its ability to concentrate therapeutic doses of radionuclides in target cells [7-10].

This review is mainly focused on the theranostic application of NIS for radionuclide-based molecular imaging and radionuclide gene therapy in in vivo animal models.

NIS is an intrinsic plasma membrane glycoprotein with 13 transmembrane domains that actively mediates iodide transport into the thyroid follicular cells and several extrathyroidal tissues [11]. This protein plays an essential role in thyroid physiology by mediating iodide uptake into the thyroid follicular cells, a key step in thyroid hormone synthesis. NIS belongs to the sodium/solute symporter family or solute carrier family 5, which drives negatively-charged solutes into the cytoplasm using an electrochemical Na+ gradient [12]. The symporter co-transports two sodium ions (Na+) along with one iodide (I-), with the transmembrane sodium gradient serving as the driving force for iodide uptake; therefore, NIS functionality is dependent on the electrochemical sodium gradient that is maintained by the oubaine-sensitive Na+/K+ATPase pump (Fig. 1) [13].

NIS needs to be localized in the plasma membrane for efficient transportation of iodide into thyroid follicular cells. Poor iodide uptake in thyroid cancer cells compared to thyroid follicular cells is related to impaired targeting and retention of NIS at the membrane. Membrane localization of NIS requires thyroid stimulating hormone (TSH) stimulation; through TSH deprivation, NIS is not retained at the membrane, leading to a decrease in iodide uptake. Although TSH stimulation is essential for efficient NIS trafficking to plasma membrane of thyroid follicular cells, it is possible that TSH-independent mechanisms for the trafficking exist because non-thyroidal tissues also retain NIS at the membrane in the absence of TSH stimulation. One suggested mechanism of NIS targeting to the membrane is the phosphorylation of NIS at serine residues in the carboxy terminus. Protein-protein interaction is another suggested mechanism for the trafficking. NIS contains PDZ, dileucine and dipeptide motifs which might be associated with trafficking [1, 13]. Non-thyroidal cancer tissues also can express NIS; however, only 20-25% of NIS-positive tumors showed iodide uptake partly due to the intracytoplasmic location of NIS [14].

Although expression of NIS is also detectable in normal extrathyroidal tissues such as the salivary glands, gastric mucosa and lactating mammary glands, the expression is not regulated by TSH and is present at lower levels in these tissues than in thyroid tissue. Iodide organification is a particular and unique characteristic of the thyroid gland, and long-term retention of iodide does not occur in the extrathyroidal tissues expressing NIS [15].

Iodide uptake function of NIS. NIS transports 2 sodium ions and 1 iodide ion into the cytoplasm together. The electrochemical sodium gradient generated by the oubaine-sensitive Na+/K+ ATPase pump provides energy for this transfer.

NIS has marked advantages as an imaging reporter gene and as a therapeutic gene compared to other reporter or therapeutic genes due to the wide availability of radiopharmaceuticals and its well understood metabolism and clearance of these radiopharmaceuticals from the body [16].

NIS actively takes up radioiodine and Tc-99m; therefore, its function can be imaged with I-123, I-131, I-124 and Tc-99m [7, 15, 17]. No issues of labeling processes and stability arise when using these radiopharmaceuticals, whereas they may be a major concern of the radiolabeled ligands of other radionuclide-based reporter genes, such as the dopamine D2 receptor or herpes simplex virus thymidine kinase (HSV-tk) genes [16].

I-123 is produced in a cyclotron by proton irradiation of enriched xenon-124 (Xe-124) in a capsule, decays by electron capture to tellurium-123 (Te-123) with a half-life of 13.2 hours, and emits gamma rays with predominant energies of 159 keV (the gamma ray is primarily used for imaging) and 127 keV. I-123, mainly a gamma emitter, has a high counting rate compared with I-131 and provides a higher lesion-to-background signal, thereby improving sensitivity and imaging quality. Moreover, with the same administered activity, I-123 delivers an absorbed radiation dose that is approximately one-fifth that of I-131 to NIS-expressing tissues [18].

I-124 is a proton-rich isotope of iodine produced in a cyclotron by numerous nuclear reactions and decays to Te-124 with a half-life of 4.2 days. Its modes of decay are 74.4% electron capture and 25.6% positron emission. It emits gamma radiation with energies of 511 and 602 keV [19].

I-131 is produced in a nuclear reactor by neutron bombardment of natural Te-127, decays by beta emission with a half-life of 8.0 days to Xe-133, and emits gamma rays as well. It most often (89% of the time) expends its 971 keV of decay energy by transforming into the stable Xe-131 in two steps, with gamma decay following rapidly after beta decay. The primary emissions of I-131 decay are beta particles with a maximal energy of 606 keV (89% abundance, others, 248-807 keV) and 364 keV gamma rays (81% abundance, others 723 keV) [19]. As I-131 emits both beta and gamma rays, it can be used to image NIS gene expression; however, it is not recommended for imaging due to poor image quality (by high energy of the gamma rays) and the high radiation burden (by the beta rays) compared to I-123.

Tc-99m, a metastable nuclear isomer of Tc-99, has a half-life of 6.0 hours and emits 140 keV gamma rays which is an optimal energy for scintigraphic imaging. Tc-99m, the most commonly used radionuclides in routine nuclear medicine imaging, is usually extracted from Tc-99m generators which contain parent nuclide molybdenum-99 (Mo-99) [2].

Recently, F-18 tetrafluoroborate (F-18 TFB) was developed as a positron-emitting radiopharmaceutical that is actively taken up by NIS [20]. The rapid uptake and efflux of F-18 TFB in the rat thyroid cell line parallels the behavior of Tc-99m pertechnetate, which is known to be taken up in cells expressing NIS [20]. Uptake of F-18 TFB to thyroid follicular cells is stimulated by TSH and blocked by perchlorate. It was suggested that F-18 TFB transport occurs with little or no coupling to sodium transport, or that TFB occupies a binding site on NIS but is transported very inefficiently.

I-131, rhenium-188 (Re-188), Re-186 and astatine-211 (At-211), which emit particles from their nuclei, are used for radionuclide therapy on cells expressing NIS [1, 8-10, 13, 21]. Re-188 is an important therapeutic radionuclide, which is obtained on demand as a carrier-free sodium perrhenate by saline elution of the tungsten-188 (W-188)/Re-188 generator system. With a half-life of 17.0 hours and emission of a high-energy beta ray (maximal energy of 2.12 MeV) and gamma ray (155 keV, 15%) for imaging, Re-188 offers the prospect of cost-effective preparation of radiopharmaceuticals for cancer treatment [22]. Cyclotron-driven neutron activator may be an alternative for on-demand supply of Re-188 [23].

Currently, At-211 is the most promising alpha-emitter that has been studied for cancer therapy. It is the heaviest halogen, with no stable isotope. It decays via a double-branch pathway with a mean alpha-energy of 6.7 MeV (42% 5.9 MeV and 58% 7.5 MeV) and a half-life of 7.2 hours. As a consequence of its electron capture branching to its daughter polonium-211, X-rays of 77 to 92 keV in sufficient abundance are emitted, enabling external imaging (including single photon emission computed tomography [SPECT]) and gamma counting of blood samples as additional advantages. However, its widespread use in therapeutic doses is hindered as a result of limited availability of medium-energy cyclotrons with an alpha-particle beam for its production, which is currently feasible at only a few research centers [24]. Table 1 summarizes characteristics of radionuclides which can be used with NIS for diagnostic or therapeutic purposes.

Gamma camera imaging with radioiodine (I-131 or I-123) can visualize metastatic lesions in differentiated thyroid cancer patients who have undergone total thyroidectomy because the lesions are highly efficient at trapping circulating iodine by expression of NIS (Fig. 2) [25]. Radioiodine scintigraphy, once the mainstay of post-therapy imaging surveillance, has largely been replaced by neck ultrasonography as the modality of choice for long-term imaging surveillance, although it still may be used for the detection of occult or distant metastases, particularly in the setting of a newly elevated serum thyroglobulin level [26]. Routine use of radioiodine scintigraphy for surveillance is not recommended for low-risk patients. However, it is still used in patients with intermediate or high risk of recurrence, as well as to assess patients for evidence of recurrence in the setting of an elevated thyroglobulin level with a negative neck ultrasonography. Scintigraphy performed after empiric treatment with high doses of I-131 is more sensitive than the usual diagnostic I-131 scanning [26].

I-124 positron emission tomography (PET) has higher sensitivity for the detection of thyroid cancer lesions with NIS expression compared with I-131 whole body scintigraphy due to lower background noise and the higher resolution of PET imaging than gamma camera imaging. Additionally, PET images can be fused with CT and/or magnetic resonance imaging [27].

Detection and localization of metastatic thyroid cancer lesions by radioiodine scintigraphy or PET rely on the expression of NIS in the cancer cells which accumulate radioiodine [27].

Radionuclides used for diagnostic or therapeutic purposes associated with NIS.

T1/2: half-life, PET: positron emission tomography

A 21-year-old female who underwent total thyroidectomy due to papillary thyroid cancer. Chest simple radiography and CT did not demonstrate any metastatic lesion of the cancer in the neck and chest regions. However, a radioiodine whole body scan revealed lymph node metastases (white arrow) in the right supraclavicular area and diffuse lung metastases (black arrows).

Molecular imaging, defined as the visual representation, characterization and quantification of biological processes at the cellular and subcellular levels within intact living organisms, can be obtained by various imaging technologies, such as optical imaging, nuclear imaging, magnetic resonance imaging (MRI), ultrasound imaging and computed tomography (CT) [28]. Molecular imaging has the potential to provide unique information that will guarantee the safety and efficacy of biotherapies which utilize antibodies, bacteria or cells in humans, and also will contribute to the future development of novel biotherapies [15].

With the emergence of cell therapies in regenerative medicine, it is important to track cells injected into subjects. In this context, NIS has been used in preclinical studies. With transfer of the NIS gene into therapeutic cells such as cytotoxic T or natural killer cells, nuclear molecular imaging modalities can image the cells with a relevant radiotracer, such as I-123, I-124, I-131, Tc-99m or F-18 TFB. The NIS-expressing cells have been imaged with planar scintigraphy, SPECT or PET according to the administered radiotracers [15].

Nuclear imaging modalities, such as PET and SPECT, provide the 3-dimensional distribution of radiopharmaceuticals and have excellent sensitivity and high resolution with excellent tissue penetration depth [29]. These advantages permit these imaging techniques for use in translational research, from cell culture to preclinical animal models to clinical applications [28]. Both PET and SPECT give quantitative and non-invasive information on NIS gene expression or the number of NIS-expressing cells [15, 28].

As a gene reporter, NIS is able to be used for monitoring of gene and vector biodistribution and for trafficking of therapeutic cells [6, 15]. Contrary to the diagnostic application of radioiodine nuclear imaging using NIS gene expression for the detection of thyroid cancer recurrence or metastases, NIS gene transfer is a prerequisite for radionuclide-based molecular imaging (Fig. 3). Non-invasive imaging of NIS expressing nonthyroidal cells with a gamma camera or PET upon viral gene transfer has been demonstrated feasible and safe in experimental animals and humans as well (Fig. 4) [6, 8].

Cells without NIS gene expression obtain the function of iodine uptake with NIS gene transduction by viral or non-viral vector delivery. The cells can be imaged by radionuclide-based molecular imaging techniques using gamma ray or positron-emitting radiotracers and be cleared by beta or alpha particle-emitting radionuclides.

Visualization of macrophages expressing NIS with radionuclide-based molecular imaging. Inflammation at the right thigh (yellow arrow) was well visualized in F-18 FDG microPET imaging. Migration of microphages expressing NIS to the inflammation site (white arrow) was clearly visualized on I-124 microPET imaging [7].

Visualization of tumor cells expressing NIS with optical molecular imaging using I-124. Tumor xenografts of anaplastic thyroid cancer cells expressing NIS were well visualized on both microPET imaging (white arrows) and Cerenkov luminescence imaging (black arrows) after intravenous administration of I-124 [17].

Recently, I-131 and I-124, which are commonly used for thyroid imaging, were reported to have sufficient energy to result in Cerenkov radiation that can be visualized with sensitive optical imaging equipment and cells transfected with NIS gene were successfully imaged with the radioiodines using an optical imaging instrument in an in vivo animal model (Fig. 5) [17].

Radioiodine accumulation in NIS-expressing organs such as the thyroid is a deterrent to scintigraphic visualization of NIS-expressing cells in various animal models. To remove radioiodine uptake in the thyroid gland and better visualize NIS-expressing cells, the animal can be prepared with surgical total thyroidectomy or radioiodine ablation before administration of the NIS-expressing cells [30].

Molecular radionuclide-based therapy of differentiated NIS-expressing thyroid cancer with I-131 was the cornerstone on which nuclear medicine was built and it has been a very successful example of targeted therapy to reduce recurrence and mortality for almost 70 years (Fig. 6) [31, 32]. Therapeutic application of I-131 for hyperthyroidism and thyroid cancer was implemented in the early 1940s, and success of the applications resulted in the approval of medical radioisotope use and initiation of atomic medicine, later re-named nuclear medicine [31, 33].

Radioiodine therapy for thyroid diseases relies on the fact that thyroid follicular cells and differentiated thyroid cancer are efficient at trapping circulating radioiodine than other tissues [25]. I-131 treatment has been the most preferred therapeutic modality by physicians for hyperthyroidism in the United States and it has been one of the key treatment modalities for differentiated thyroid cancers worldwide [34, 35]. However, I-131 treatment is not very effective in de-differentiated thyroid cancer, which down-regulates NIS expression, and is meaningless in anaplastic thyroid and medullary thyroid cancers, which do not express NIS. One possible treatment option for de-differentiated thyroid cancer is the induction of re-differentiation with differentiating agents such as retinoic acid and thiazolidinedione [31, 36].

Expression of NIS is not uncommon in breast and stomach cancers, and some reports have shown visualization of primary or metastatic lesions of such cancers with radioiodine or Tc-99m scintigraphy [37-40]. The possibility of radioiodine treatment for cancers with sufficient NIS expression has been suggested; however, as far as the author knows, clinical reports on such treatment with successful outcome have yet to be published, likely due to insufficient NIS expression [16].

Although it has not been clinically attempted, anaplastic or medullary thyroid cancers lacking NIS expression can be treated with I-131 after NIS gene transfer to the tumors. Additionally, other tumor entities which do not express NIS can also be treated with the same strategy [31].

A 26-year-old female who underwent total thyroidectomy due to papillary thyroid cancer. (A) Chest simple radiograph did not demonstrate any observable metastatic lesions of the cancer. (B) CT scan of the chest demonstrated several metastatic lesions of the cancer in both lung fields (white arrows). TSH-stimulated serum thyroglobulin was 65.0 ng/mL. The patient was diagnosed with metastatic thyroid cancer of the lung. (C) A post initial high dose I-131 treatment (150 mCi) scan revealed numerous metastatic lung lesions. (D) A post 2nd high dose I-131 treatment (200 mCi) scan revealed fewer but still several metastatic lung lesions (black arrows). (E, F) A post 3rd high dose I-131 treatment (200 mCi) scan revealed no remarkable radioiodine uptake in both lung fields and chest CT showed only tiny lung nodules having no clinical significance. TSH-stimulated serum thyroglobulin was 1.4 ng/mL after the third treatment. The patient had achieved complete remission with three times of high dose I-131 treatment and her status still remains disease-free at 7 years follow-up.

In addition to its imaging potential, NIS can be used as a therapeutic gene through its ability to concentrate therapeutic doses of radionuclides in target cells [15]. Contrary to the therapeutic application of I-131 using NIS gene expression for treating thyroid cancer recurrence or metastases, NIS gene transfer is a prerequisite for tumors without NIS gene expression. After the transfer of the NIS gene into various cancer cells, they can be treated with beta or alpha particle-emitting radionuclides including I-131, Re-186, Re-188 and At-211, which are accumulated via NIS (Fig. 3) [31].

Right after NIS was cloned by Carrasco et al. in 1996, many researchers started to use the gene for therapeutic purposes with I-131, and in general, the results were effective. The effect of I-131 NIS gene therapy was enhanced with higher doses of I-131 and intervention with retinoic acid or dexamethasone, which increase radioiodine uptake [41]. Transcription factors such as Pax-8 and TTF-1 could induce or promote iodide uptake and specifically prolong iodide retention time in cancer cells [42, 43].

Re-188 and At-211 were also used as therapeutic radionuclides with NIS gene therapy to nonthyroidal tumors. Re-188 has advantages over I-131, as its beta ray energy is higher and has a shorter half-life, which makes it a more suitable radionuclide for NIS-expressing tumors. In addition, it is conveniently obtained from a W-188/Re-188 generator [44]. At-211, which emits extremely cytotoxic alpha-particles, is known to be taken up by NIS in thyroid tissue and has been used as a therapeutic radionuclide for NIS-expressing tumors in cell culture and animal experiments [21, 45, 46]. In addition to very effective tumoricidal effects, At-211 has the advantages of alpha-particle's short range and a short half-life, which allow for a minimal radiation burden to the surrounding environment, including people [46].

However, single radionuclide NIS gene therapy might have limited therapeutic effects and can produce serious adverse effects positively related to the amount of administered radionuclide dose. Reducing the radionuclide dose for NIS gene therapy is able to reduce the adverse effects, but might lead to limited effectiveness [47]. Combined treatment of radionuclide NIS gene therapy with other therapeutic approaches could be more efficient to improve therapeutic outcomes and can reduce adverse effects of radionuclide NIS gene therapy by reducing the radionuclide dose. Chemotherapy, genciclovir HSV-tk gene therapy, immunotherapy, external beam radiotherapy and siRNA therapy have been combined with radionuclide NIS gene therapy, and the results were almost always successful [8-10, 47].

Even though radionuclide NIS gene therapy has been shown to be effective in in vivo animal models, several issues must be resolved before this novel strategy can be useful clinically. First of all, vector systems having safe, effective and specific NIS gene delivery to the tumor are needed. The optimal time interval between NIS gene transfer and therapeutic radionuclide administration should be determined to obtain the most effective therapeutic results. Organs that normally express NIS, such as the thyroid gland and the salivary glands, are inevitably damaged by the therapeutic radionuclide; therefore, protecting or managing strategies for the organs need to be developed [13, 31, 48].

Even though radionuclide NIS gene therapy is only performed in the preclinical setting at the moment, clinical trials of the treatment are likely to happen in the not-too-distant future with advances in efficiency and safety of the therapy by close communication between these basic biological studies and clinical experiences of thyroid cancer treatment with I-131.

NIS provides an advantage of both as reporter and therapeutic genes and therefore, NIS gene transfer makes it possible to image, monitor and treat the tumor with appropriate radionuclides, just as in differentiated thyroid cancer. Another advantage of NIS is wide availability of appropriate diagnostic and therapeutic radiopharmaceuticals. Although NIS is one of the best theranostic genes, there are several pending questions that must be answered before its clinical use.

Tissues that normally express endogenous NIS such as the thyroid gland, salivary glands and stomach, are an obstacle for NIS-based imaging or treatment. Uptake of imaging radiotracers to the tissues conceals trafficking target cells expressing NIS which are located near the tissues. Uptake of therapeutic radionuclides to the normal tissues can damage the organs and may reduce tracer uptake to the target cells expressing exogenous NIS.

Retention time of radioiodine is generally short in NIS-transduced cells by rapid washout of the radioiodine, therefore absorbed dose and toxicity to the target cells might be limited and it precludes successful radioiodine NIS gene therapy. To prolong the retention time, drugs such as lithium carbonate, or co-transfer of the thyroid peroxidase gene was introduced, however, results were conflicting and not very effective [13]. Co-transfer of the thyroglobulin gene was also suggested to increase retention time [42]. Efflux of iodine from the cell is known to be related to pendrin, SLC5A8 and ClCn5, and even though not verified by experiments, down-regulation of these proteins can delay iodine efflux from the cell [42]. Ablation of the thyroid gland and low iodine diet are able to prolong the retention time in NIS transduced tumor cells, however applicability of this strategy is limited in a clinical situation. It can be feasibly applied only in thyroid cancer patients receiving previous thyroidectomy. Enhancement of radioiodine uptake by up-regulation of NIS expression has been tried with drugs such as retinoic acid or dexamethasone, troglitazone and external radiation [49, 50]. Histone deacetylase inhibitors (e.g. depsipeptide, trichosatin A and valproic acid) and demethylating agents (5-azacytidine) have been used to restore endogenous NIS expression [1]. In addition to increasing radiation dose to the NIS expressing cells, radiosensitization can enhance the biological effect of the same radiation dose. DNA damage repair inhibitors revealed a therapeutic benefit with radionuclide NIS gene therapy [51]. Further studies are needed for validation and optimization of the pharmacological approaches for prolonging the retention time, delaying iodine efflux, restoring/up-regulation of NIS expression and enhancing radiosensitization before practical use.

Several new diagnostic or therapeutic radiopharmaceuticals for NIS were recently studied. Cells expressing NIS can be imaged with F-18 FTB PET instead of radioiodine scintigraphy and be treated more effectively with Re-188, Re-186 or At-211 instead of I-131. Some of the radiopharmaceuticals are not suitable at present due to scarce availability and nontrivial safety issues related to their production and handling. Technical advancement of the production and handling skills for the radiopharmaceuticals is warranted.

With administration of I-131, the thyroid gland takes up I-131 and retains it within the gland for a long time by organification of the radioiodine. This will end in permanent hypothyroidism by radioablation of normal thyroid tissue. The salivary gland also accumulates the radionuclide and xerostomia can occur by radiation sialoadenitis related to uptake of the radionuclide. To maintain sufficient radioiodine uptake to the extrathyroidal cancer tissues expressing NIS, uptake of radioiodine to the thyroid gland can be suppressed by thyroid hormone replacement and antithyroidal drugs [52]. Stable iodine administration before administration of radioiodine can reduce radioiodine to the gland as well [13]. Radioiodine uptake in the salivary gland can be expelled by manual massage of the gland and may reduce incidence of xerostomia related to radiation-induced sialoadenitis [53]. Strategies for preventing or reducing side effects to normal tissues expressing NIS by radionuclides uptake must be developed and optimized before common clinical application of NIS-based radionuclide theranostics.

Although diagnostic and therapeutic use of the NIS gene began in clinics more than half a century ago, understanding of the biology of NIS has been advancing rapidly the last two decades. NIS-based molecular imaging and radionuclide gene therapy, cutting edge technologies in molecular imaging and gene therapy arenas, were born with imitation of diagnostic and therapeutic applications in the field of clinical thyroid practice. With fast advancement of molecular imaging and gene therapy with active research, these bench technologies are likely to be used in the clinical setting in the near future.

This study was supported by a grant (A102132) of the Korea Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea and the Ministry of Knowledge Economy (MKE), and a grant of the Korea Institute for Advancement of Technology (KIAT) and Daegyeong Leading Industry Office through the Leading Industry Development for Economic Region.

The authors have declared that no competing interest exists.

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Biological bypass shows promise in coronary artery disease – Medical Xpress

Gene Therapy Clinics | Posted by admin
Aug 12 2017

August 8, 2017

A new gene therapy that targets the heart and requires only one treatment session has been found safe for patients with coronary artery disease, according to a successful trial carried out in Finland. Enhancing circulation in the oxygen-deficient heart muscle, the effects were visible even one year after the treatment.

The randomised, blinded, placebo-controlled phase 1/2a trial was carried out in collaboration between the University of Eastern Finland, Kuopio University Hospital and Turku PET Centre as part of the Centre of Excellence in Cardiovascular and Metabolic Diseases of the Academy of Finland.

The biological bypass is based on gene transfer in which a natural human growth factor is injected into the heart muscle to enhance vascular growth. The trial was the first in the world to use a novel vascular growth factor that has several beneficial effects on circulation in the heart muscle. The trial also developed a novel and precise method for injecting the gene into the oxygen-deficient heart muscle area. A customised catheter is inserted via the patient's groin vessels to the left ventricle, after which the gene solution can be injected directly into the heart muscle. The method is as easy to perform as coronary balloon angioplasty, which means that it is also suitable for older patients and patients who are beyond a bypass surgery or other demanding surgical or arterial operations.

The biological bypass constitutes a significant step forward in the development of novel biological treatments for patients with severe coronary artery disease. A new blood test biomarker was also discovered, making it possible to identify patients who are most likely to benefit from the new treatment.

The biological bypass was developed by Academy Professor Seppo Yl-Herttuala's research group at the A.I. Virtanen Institute for Molecular Sciences of the University of Eastern Finland. At the Kuopio University Hospital Heart Centre, Professor Juha Hartikainen was responsible for the trial.

Securing six million euros of funding from the European Union, research into the biological bypass will continue, and a new phase 2b trial will start at Kuopio University Hospital in early 2018. This trial will also include five other cardiology clinics from Denmark, the UK, Austria, Spain and Poland. The multi-centre trial will be coordinated by the Kuopio University Hospital Heart Centre, and the gene therapy drug will be manufactured in the clean room facilities of FinVector Therapies Ltd. in Kuopio.

Explore further: Novel mapping technique targets gene therapy to hibernating heart muscle

More information: Juha Hartikainen et al. Adenoviral intramyocardial VEGF-DNC gene transfer increases myocardial perfusion reserve in refractory angina patients: a phase I/IIa study with 1-year follow-up, European Heart Journal (2017). DOI: 10.1093/eurheartj/ehx352

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Biological bypass shows promise in coronary artery disease - Medical Xpress