Regenerative Medicine ⯀  

Researchers have developed a device that can switch cell function to rescue failing body functions with a single touch. The technology, known as Tissue Nanotransfection (TNT), injects genetic code into skin cells, turning those skin cells into other types of cells required for treating diseased conditions.

Researchers at The Ohio State University Wexner Medical Center and Ohio State’s College of Engineering have developed a new technology, Tissue Nanotransfection (TNT), that can generate any cell type of interest for treatment within the patient’s own body. This technology may be used to repair injured tissue or restore function of aging tissue, including organs, blood vessels and nerve cells.

In a new study published in Nature Nanotechnology, first author Daniel Gallego-Perez of Ohio State demonstrated that the technique worked with up to 98 percent efficiently.

"It takes just a fraction of a second. You simply touch the chip to the wounded area, then remove it."

“By using our novel nanochip technology, injured or compromised organs can be replaced. We have shown that skin is a fertile land where we can grow the elements of any organ that is declining,” said Dr. Chandan Sen, director of Ohio State’s Center for Regenerative Medicine & Cell Based Therapies, who co-led the study with L. James Lee, professor of chemical and biomolecular engineering with Ohio State’s College of Engineering in collaboration with Ohio State’s Nanoscale Science and Engineering Center.

Researchers studied mice and pigs in these experiments. In the study, researchers were able to reprogram skin cells to become vascular cells in badly injured legs that lacked blood flow. Within one week, active blood vessels appeared in the injured leg, and by the second week, the leg was saved. In lab tests, this technology was also shown to reprogram skin cells in the live body into nerve cells that were injected into brain-injured mice to help them recover from stroke.

“It takes just a fraction of a second. You simply touch the chip to the wounded area, then remove it,” said Chandan Sen, PhD, director of the Center for Regenerative Medicine and Cell-Based Therapies at The Ohio State University Wexner Medical Center. “At that point, the cell reprogramming begins.”

In a series of lab tests, researchers applied the chip to the injured legs of mice that vascular scans showed had little to no blood flow. “We reprogrammed their skin cells to become vascular cells,” Sen said. “Within a week we began noticing the transformation.” By the second week, active blood vessels had formed, and by the third week, the legs of the mice were saved—with no other form of treatment.

“It extends the concept known as gene therapy, and it has been around for quite some time,” said study collaborator James Lee, PhD, a professor of chemical and biomolecular engineering at Ohio State. “The difference with our technology is how we deliver the DNA into the cells.”

The nanochip, loaded with specific genetic code or certain proteins, is placed on the skin, and a small electrical current creates channels in the tissue. The DNA or RNA is injected into those channels where it takes root and begins to reprogram the cells.

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“What’s even more exciting is that it not only works on the skin, but on any type of tissue,” Sen said. In fact, researchers were able to grow brain cells on the skin surface of a mouse, harvest them, then inject them into the mouse’s injured brain. Just a few weeks after having a stroke, brain function in the mouse was restored, and it was healed. Because the technique uses a patient’s own cells and does not rely on medication, researchers expect it to be approved for human trials within a year.

“This is difficult to imagine, but it is achievable, successfully working about 98 percent of the time. With this technology, we can convert skin cells into elements of any organ with just one touch. This process only takes less than a second and is non-invasive, and then you're off. The chip does not stay with you, and the reprogramming of the cell starts. Our technology keeps the cells in the body under immune surveillance, so immune suppression is not necessary,” said Sen, who also is executive director of Ohio State’s Comprehensive Wound Center.

TNT technology has two major components: First is a nanotechnology-based chip designed to deliver cargo to adult cells in the live body. Second is the design of specific biological cargo for cell conversion. This cargo, when delivered using the chip, converts an adult cell from one type to another, said first author Daniel Gallego-Perez, an assistant professor of biomedical engineering and general surgery who also was a postdoctoral researcher in both Sen’s and Lee’s laboratories.

TNT doesn’t require any laboratory-based procedures and may be implemented at the point of care. The procedure is also non-invasive. The cargo is delivered by zapping the device with a small electrical charge that’s barely felt by the patient.

“The concept is very simple,” Lee said. “As a matter of fact, we were even surprised how it worked so well. In my lab, we have ongoing research trying to understand the mechanism and do even better. So, this is the beginning, more to come.”

SOURCE  Ohio State University

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Gene Therapy  

If early data is accurate, the world’s first successful example of telomere lengthening via gene therapy in a human individual has been undertaken. The gene therapy was completed on BioViva CEO Elizabeth Parrish.

Elizabeth Parrish, CEO of BioViva USA Inc. has become the first human being to be successfully rejuvenated by gene therapy, after her own company’s experimental therapies reversed 20 years of normal telomere shortening.

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Telomere score is calculated according to telomere length of white blood cells (T-lymphocytes). This result is based on the average T-lymphocyte telomere length compared to the American population at the same age range. The higher the telomere score, the “younger” the cells.

In September 2015, then 44 year-old Parrish received two of her own company’s experimental gene therapies: one to protect against loss of muscle mass with age, another to battle stem cell depletion responsible for diverse age-related diseases and infirmities.

The treatment was originally intended to demonstrate the safety of the latest generation of the therapies. But if early data is accurate, it is already the world’s first successful example of telomere lengthening via gene therapy in a human individual. Gene therapy has been used to lengthen telomeres before in cultured cells and in mice, but never in a human patient.

Telomeres are short segments of DNA which cap the ends of every chromosome, acting as ‘buffers’ against wear and tear. They shorten with every cell division, eventually getting too short to protect the chromosome, causing the cell to malfunction and the body to age.

In September 2015, telomere data taken from Parrish’s white blood cells by SpectraCell‘s specialised clinical testing laboratory in Houston, Texas, immediately before therapies were administered, revealed that Parrish’s telomeres were unusually short for her age, leaving her vulnerable to age-associated diseases earlier in life.

In March 2016, the same tests were taken again by SpectraCell revealed that her telomeres had lengthened by approximately 20 years, from 6.71kb to 7.33kb. This implies that Parrish’s white blood cells (leukocytes) have become biologically younger. These findings were independently verified by the Brussels-based non-profit HEALES (HEalthy Life Extension Company), and the Biogerontology Research Foundation, a UK-based charity committed to combating age-related diseases.

"BioViva has the potential to create breakthroughs in human gene therapy research, while leapfrogging companies in the biotech market."

Parrish’s reaction: “Current therapeutics offer only marginal benefits for people suffering from diseases of aging. Additionally, lifestyle modification has limited impact for treating these diseases. Advances in biotechnology is the best solution, and if these results are anywhere near accurate, we’ve made history”, Parrish said.

Bioviva will continue to monitor Parrish’s blood for months and years to come. Meanwhile, BioViva will be testing new gene therapies and combination gene therapies to restore age related damage. It remains to be seen whether the success in leukocytes can expanded to other tissues and organs, and repeated in future patients. For now all the answers lie in the cells of Elizabeth Parrish, ‘patient zero’ of restorative gene therapy.

Since her first gene therapy injections BioViva has received global interest from both the scientific and investment communities. Earlier this month BioViva became a portfolio company of Deep Knowledge Life Sciences (DKLS), a London-based investment fund which aims to accelerate the development of biotechnologies for healthy longevity.

Dmitry Kaminskiy, founding partner of DKLS, said “BioViva has the potential to create breakthroughs in human gene therapy research, while leapfrogging companies in the biotech market.”

SOURCE  Bioviva

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 Gene Therapy  

By using a a new gene-editing system based on bacterial proteins, researchers have effectively cured mice of a rare liver disorder caused by a single genetic mutation.

Using a new gene-editing system based on bacterial proteins, MIT researchers have cured mice of a rare liver disorder caused by a single genetic mutation.

The findings, described in Nature Biotechnology, offer the first evidence that this gene-editing technique, known as CRISPR, can reverse disease symptoms in living animals.

CRISPR, which offers an easy way to snip out mutated DNA and replace it with the correct sequence, holds potential for treating many genetic disorders, according to the research team.

“What’s exciting about this approach is that we can actually correct a defective gene in a living adult animal,” says Daniel Anderson, the Samuel A. Goldblith Associate Professor of Chemical Engineering at MIT, a member of the Koch Institute for Integrative Cancer Research, and the senior author of the paper.

The recently developed CRISPR system relies on cellular machinery that bacteria use to defend themselves from viral infection. Researchers have copied this cellular system to create gene-editing complexes that include a DNA-cutting enzyme called Cas9 bound to a short RNA guide strand that is programmed to bind to a specific genome sequence, telling Cas9 where to make its cut.

At the same time, the researchers also deliver a DNA template strand. When the cell repairs the damage produced by Cas9, it copies from the template, introducing new genetic material into the genome. Scientists envision that this kind of genome editing could one day help treat diseases such as hemophilia, Huntington’s disease, and others that are caused by single mutations.

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Scientists have developed other gene-editing systems based on DNA-slicing enzymes, also known as nucleases, but those complexes can be expensive and difficult to assemble.

“The CRISPR system is very easy to configure and customize,” says Anderson, who is also a member of MIT’s Institute for Medical Engineering and Science. He adds that other systems “can potentially be used in a similar way to the CRISPR system, but with those it is much harder to make a nuclease that’s specific to your target of interest.”

"What’s exciting about this approach is that we can actually correct a defective gene in a living adult animal."

For this study, the researchers designed three guide RNA strands that target different DNA sequences near the mutation that causes type I tyrosinemia, in a gene that codes for an enzyme called FAH. Patients with this disease, which affects about 1 in 100,000 people, cannot break down the amino acid tyrosine, which accumulates and can lead to liver failure. Current treatments include a low-protein diet and a drug called NTCB, which disrupts tyrosine production.

In experiments with adult mice carrying the mutated form of the FAH enzyme, the researchers delivered RNA guide strands along with the gene for Cas9 and a 199-nucleotide DNA template that includes the correct sequence of the mutated FAH gene.

Using this approach, the correct gene was inserted in about one of every 250 hepatocytes — the cells that make up most of the liver. Over the next 30 days, those healthy cells began to proliferate and replace diseased liver cells, eventually accounting for about one-third of all hepatocytes. This was enough to cure the disease, allowing the mice to survive after being taken off the NCTB drug.
“We can do a one-time treatment and totally reverse the condition,” says Hao Yin, a postdoc at the Koch Institute and one of the lead authors of the Nature Biotechnology paper.

Gene therapy is one area of science that has consistently failed to achieve its therapeutic potential. Now, our abilities may finally be able to unlock some of the promise of real-world DNA manipulation, making hereditary and acquired genetic disease much more treatable. This study marks the beginning of a new era of usability in genetic manipulation, and everyone with DNA stands to benefit.


SOURCE  MIT News Top Image - Christine Daniloff/MIT

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 Regenerative Medicine  

A University of Utah doctor has performed the historic first procedure using new regenerative medicine technique called retrograde gene therapy to restore function to a human heart severely damaged by cardiac arrest.

Aman in Utah has become the first patient in the world to undergo retrograde gene therapy at University of Utah Hospital, a novel procedure designed to deliver stem cells to the heart to repair damaged muscle and arteries in the most minimally invasive way possible.

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Amit Patel, M.D., director of Clinical Regenerative Medicine and Tissue Engineering and an associate professor in the Division of Cardiothoracic Surgery at the University of Utah School of Medicine. started investigating cell and gene-based therapies for the treatment of heart disease 12 years ago, but only recently received FDA approval to try the therapy on Ernie Lively, who was the first of several patients anxious to receive the treatment.

More than 6 million people are currently living with heart failure. As the condition progresses, patients’ options are usually limited to a heart transplant or assist devices, such as an artificial heart. Patel wanted to find a way to intervene in the progression of heart failure before a patient advanced to the point of needing a heart transplant or device.

Patel and his team came up with the idea of retrograde heart therapy, a concept that has been discussed for 50 years. The first successful procedure was performed on Lively on November. 7.

“It’s incredible. Imagine having a heart procedure that can potentially regenerate or rejuvenate your heart muscle — and it’s done as an outpatient procedure,” said Patel.

Patel used a minimally invasive technique where he went backwards through a patient’s main cardiac vein, or coronary sinus, and inserted a catheter. He then inflated a balloon in order to block blood flow out of the heart so that a very high dose of gene therapy could be infused directly into the heart.

The unique gene therapy did not involve viruses (a rarity for gene therapy, Patel notes) and is pure human DNA infused into patients. The DNA, called SDF-1, is a naturally occurring substance in the body that becomes a homing signal for a patient’s body to use its own stem cells to go to the site of an injury.

Once the gene therapy was injected, the genes acted as “homing beacons.” When the genes are put into patients with heart failure, they marinate the entire heart and act like a look out, Patel said.

“The genes basically act like a light house with a bright signal. They say, ‘ How can we help the ships that need to get to the port — which is the heart –get there. When the signal, or the light from the SDF-1, which is that gene, shows up, the stem cells from not inside your own heart and from those that circulate from your blood and bone marrow all get attracted to the heart which is injured, and they bring reinforcements to make it stronger and pump more efficiently,” said Patel.

After becoming the first patient in the world to undergo the procedure, Lively returned home and is recovering. Before the technique Patel used was available, Lively’s other option would have been a three-to-five day hospital stay. Instead, he is recuperating while daydreaming about what it will be like to be able to ski and enjoy life fully again. He said he has noticed an immediate difference in his health following the procedure.

“I woke up this morning and told my wife, ‘I haven’t felt this good in years,” said Lively. “I moved to Utah because of the snow, but I haven’t been able to ski. I literally didn’t have the heart to do it. Now, I’m excited about living the rest of my life instead of sitting around.”

Patel said watching Lively recover successfully from the surgery is both rewarding and exciting for what the future holds for the procedure and those who may benefit from it. He is already training other physicians around the U.S. to model what he accomplished first this month. He is overseeing a trial of the procedure in which 72 patients will participate over the next few months.

“This is one of the great moments in biological therapy for the heart,” said Patel. “We are providing options for patients who have no possible solutions. This is one of the safest and most reproducible therapies out there for these very sick patients.”



SOURCE  University of Utah

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