New Genetic And Stem-Cell Technology To Grow Sheets Of Skin

Somewhere in Germany’s Ruhr valley, a nine-year-old boy is doing what children do: playing football, joking around with friends and going to school. Two years ago, he was confined to a hospital bed, dying of a rare and cruel genetic skin disease. The boy had junctional epidermolysis bullosa, or JEB. He, like other people with the disease, carried a mutation in a gene that controls the integrity of the skin. Doctors could only try to ease his suffering as some 80% of his skin simply fell away.

A team of Italian researchers came to his aid by combining stem-cell techniques with gene therapy. As a young scientist at Harvard Medical School in Boston, Massachusetts, in the 1980s, Michele De Luca — the lead author of the new study — watched pioneers in skin regeneration learn to grow small sheets of skin from cells taken from burns patients, and to use them in grafts. He extended the work in Italy, applying new genetic and stem-cell technologies. He developed ways to generate stem cells from human skin, replace disease-causing genes in them and grow sheets of healthy skin on scaffolds in the lab.

He chose JEB for his first clinical trial, which he registered with the Italian Medicines Agency in 2002. Four years later, he reported his first success, in which he created healthy skin patches from biopsies to replace small areas of sloughed-off skin on the legs of a patient with a form of JEB (F. Mavilio et al. Nature Med. 12, 1397–1402; 2006). New European Commission regulations introduced in 2007 required him to pause the project while he created facilities adhering to ‘good manufacturing practices’ (GMPs) and a spin-off company to meet the demands for strengthened oversight of cell-based therapies.

Having a company refocused his team’s attention on a different type of stem-cell therapy, one likely to yield a product for the market faster. Holoclar, a treatment that replaces the eye’s cornea in a form of blindness, became the world’s first commercial stem-cell therapy in 2015.

A few months later, at the University of Modena, De Luca got a call out of the blue from doctors in Germany who were trying to treat the little boy. Because the therapy had been in a clinical trial, albeit one on hold at the time, and because De Luca could provide GMP services, German regulatory authorities quickly approved the one-off compassionate use of the JEB therapy. Surgeons in Germany sent a skin biopsy to Modena, and two major skin transplants followed. Six months after the initial biopsy, the boy returned to school. During the many months since, he has not had so much as a blister, and loves to show off his ‘new skin’. By their nature, highly personalized treatments using gene therapies and products derived from an individual’s stem cells are likely to be applicable to only a subset of patients.

Scientists and clinicians have presented the details of the recovery in Nature (T. Hirsch et al.Nature http://dx.doi.org/10.1038/nature24487; 2017). This major clinical development was based on decades of basic research. The clinical data gathered during 21 months of follow-up after the boy’s treatment have also led to major insights into human skin biology, as discussed in an accompanying News & Views (M. Aragona and C. Blanpain Naturehttp://dx.doi.org/10.1038/nature24753; 2017). For example, normal regeneration of the epidermis is directed by only a few stem-cell clones that can self-renew.

Source: http://www.nature.com/

Cancer: A Giant Step For Immunotherapy

A Food and Drug Administration (FDA) panel opened a new era in medicine, unanimously recommending that the agency approve the first-ever treatment that genetically alters a patient’s own cells to fight cancer, transforming them into what scientists call “a living drug” that powerfully bolsters the immune system to shut down the disease.

If the F.D.A. accepts the recommendation, which is likely, the treatment will be the first gene therapy ever to reach the market. Others are expected: Researchers and drug companies have been engaged in intense competition for decades to reach this milestone. Novartis is now poised to be the first. Its treatment is for a type of leukemia, and it is working on similar types of treatments in hundreds of patients for another form of the disease, as well as multiple myeloma and an aggressive brain tumor.

To use the technique, a separate treatment must be created for each patient — their cells removed at an approved medical center, frozen, shipped to a Novartis plant for thawing and processing, frozen again and shipped back to the treatment center.

A single dose of the resulting product has brought long remissions, and possibly cures, to scores of patients in studies who were facing death because every other treatment had failed. The panel recommended approving the treatment for B-cell acute lymphoblastic leukemia that has resisted treatment, or relapsed, in children and young adults aged 3 to 25.

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We believe that when this treatment is approved it will save thousands of children’s lives around the world,” Emily’s father, Tom Whitehead, told the panel. “I hope that someday all of you on the advisory committee can tell your families for generations that you were part of the process that ended the use of toxic treatments like chemotherapy and radiation as standard treatment, and turned blood cancers into a treatable disease that even after relapse most people survive.”

The main evidence that Novartis presented to the F.D.A. came from a study of 63 patients who received the treatment from April 2015 to August 2016. Fifty-two of them, or 82.5 percent, went into remission — a high rate for such a severe disease. Eleven others died.

It’s a new world, an exciting therapy,” said Dr. Gwen Nichols, the chief medical officer of the Leukemia and Lymphoma Society, which paid for some of the research that led to the treatment. The next step, she said, will be to determine “what we can combine it with and is there a way to use it in the future to treat patients with less disease, so that the immune system is in better shape and really able to fight.” She added, “This is the beginning of something big.”

Source: http://www.chop.edu/
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https://www.nytimes.com/

How To Prevent Alzheimer’s

Researchers from Imperial College London (ICL) have prevented the development of Alzheimer’s disease in mice by using a virus to deliver a specific gene into the brain. The early-stage findings by scientists open avenues for potential new treatments for the disease. In the study, published in the journal Proceedings of the National Academy of Sciences, the team used a type of modified virus to deliver a gene to brain cells.

Previous studies by the same team suggest this gene, called PGC1 – alpha, may prevent the formation of a protein called amyloid-beta peptide in cells in the lab. Amyloid-beta peptide is the main component of amyloid plaques, the sticky clumps of protein found in the brains of people with Alzheimer’s disease. These plaques are thought to trigger the death of brain cellsAlzheimer’s disease affects around 520,000 people in the UK. Symptoms include memory loss, confusion, and change in mood or personality. Worldwide 47.5 million people are affected by dementia – of which Alzheimer’s is the most common form. There is no cure, although current drugs can help treat the symptoms of the disease.

Dr Magdalena Sastre, senior author of the research from the Department of Medicine at Imperial, hopes the new findings may one day provide a method of preventing the disease, or halting it in the early stages.

alzheimer_s_disease_vs_normal-spl

She explained: “Although these findings are very early they suggest this gene therapy may have potential therapeutic use for patients. There are many hurdles to overcome, and at the moment the only way to deliver the gene is via an injection directly into the brain. However this proof of concept study shows this approach warrants further investigation.”

The modified virus used in the experiments was called a lentivirus vector, and is commonly used in gene therapy explained Professor Nicholas Mazarakis, co-author of the study from the Department of Medicine: “Scientists harness the way lentivirus infects cells to produce a modified version of the virus, that delivers genes into specific cells. It is being used in experiments to treat a range of conditions from arthritis to cancer. We have previously successfully used the lentivirus vector in clinical trials to deliver genes into the brains of Parkinson’s disease patients.

Source: http://www3.imperial.ac.uk/

How To Fight Brain Cancer

Despite improvements in the past few decades with surgery, chemotherapy and radiation therapy, a predictably curative treatment for glioma (brain and spine cancer) does not yet exist. New insights into specific gene mutations that arise in this often deadly form of brain cancer have pointed to the potential of gene therapy, but it’s very difficult to effectively deliver toxic or missing genes to cancer cells in the brain. Now, Johns Hopkins researchers report they have used nanoparticles to successfully deliver a new therapy to glioma cells in the brains of rats, prolonging their lives.
Previous research on mice found that nanoparticles carrying genes can be taken up by brain cancer cells, and the genes can then be turned on. However, this is the first time these biodegradable nanoparticles have effectively killed brain cancer cells and extended survival in animals.
For their studies, the Johns Hopkins team designed and tested a variety of nanoparticles made from different polymers, or plastics. When they found a good candidate that could deliiver genes to rat brain cancer cells, they filled the nanoparticles with DNA encoding an enzyme, a potent therapy that kills brain cancer cells. When combined with the compound, called ganciclovir, these loaded nanoparticles were 100 percent effective at killing glioma cells grown in laboratory dishes.
brain cancer
We then evaluated the system in rats with glioma and found that our nanoparticles could penetrate completely throughout the tumor following a single injection,” says Jordan Green, Ph.D, associate professor of biomedical engineering, neurosurgery and ophthalmology at Johns Hopkins and a member of the Institute for NanoBioTechnology. “When combined with systemic administration of ganciclovir, rats with malignant glioma lived significantly longer than rats that did not receive this treatment.”
A draft of the study has been published on the website of the journal ACS Nano.
Source: http://www.hopkinsmedicine.org/

RNA Molecules Deliver Drugs To Silence Cancerous Genes

Researchers at Sanford-Burnham Medical Research Institute have developed nanoparticles that appear to solve a big challenge in delivering the RNA molecules, called small interfering RNA, or siRNA, to the cells where they are needed. By synthesizing a nanoparticle that releases its siRNA cargo only after it enters targeted cells, Dr. Tariq M. Rana and colleagues showed in mice that they could deliver drugs that silenced the genes they wanted.

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Our study describes a strategy to reduce toxic effects of nanoparticles, and deliver a cargo to its target,” said Dr. Rana, whose paper, “In Vivo Delivery of RNAi by Reducible Interfering Nanoparticles (iNOPs),” also included contributions from researchers at the University of Massachusetts Medical School and the University of California at San Diego. “We’ve found a way to release the siRNA compounds, so it can be more effective where it’s needed,” Dr. Rana said.

Source: http://beaker.sanfordburnham.org/

Targeting Parkinson’s Disease At Its Roots

Researchers at Northeastern University in Boston have developed a gene therapy approach that may one day stop Parkinson’s disease (PD) in it tracks, preventing disease progression and reversing its symptoms. Each year, 60,000 adults are newly diag­nosed with Parkinson’s dis­ease, a neu­rode­gen­er­a­tive dis­order that causes a slew of symp­toms, including tremors, slowed move­ments, and changes in speech. The drugs cur­rently avail­able to treat PD patients help them regain some of the motor con­trol lost through the dis­ease, but don’t treat the under­lying cause, said Bar­bara Waszczak, a pro­fessor of phar­ma­ceu­tical sci­ences in the Bouvé Col­lege of Health Sci­ences.

parkinson's
Parkinson’s is caused by the death of dopamine neu­rons in a key motor area of the brain called the sub­stantia nigra,” said Waszczak. If you want to treat PD at its roots, she added, then you have to stop the death of these neural cells. In research reported ear­lier this week at the Exper­i­mental Biology 2013 con­fer­ence in Boston, Waszczak and grad­uate stu­dent Brendan Harmon pro­posed a treat­ment approach that does exactly that. What’s more, the method is simple and easy to use.“If we can get at it in the early stages of the dis­ease, when patients are just starting to develop symp­toms, then we might be able to stop the dis­ease from get­ting worse or at least delay the onset of severe symp­toms,” Waszczak explained.

Source: http://www.northeastern.edu/
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http://www.eurekalert.org/

Lipid Nanoparticles Ideal For Delivering Drugs

A research team from the Faculty of Pharmacy of the Basque Public University(UPV/EHU) – Spain – is using nanotechnology to develop new formulations that can be applied to drugs and gene therapy. Specifically, they are using nanoparticles to design systems for delivering genes and drugs; this helps to get the genes and drugs to the point of action so that they can produce the desired effect. The scientists have shown that lipid nanoparticles are ideal for acting as vectors in gene therapy. Gene therapy is a highly promising alternative for diseases that so far have no effective treatment. It consists of delivering a nucleic acid, for example, a therapeutic gene, to modulate the expression of a protein that is found to be altered in a specific disease, thus reversing the biological disorder.
lipid nanoparticle
“Using lipid nanoparticles conducts to new formulations to deliver drugs that are not particularly soluble or which are difficult to absorb”, Dr Rodriguez explained. “40% of the new pharmacologically active molecules are reckoned to be insoluble or not very soluble in water; that prevents many of these potentially active molecules from ever reaching the clinic because of the problems involved in developing a safe, effective formulation.” explains Dr Alicia Rodriguez.

Source: http://www.basqueresearch.com/

Gene Delivery Vehicle Goes To The Heart Of The Target.

Many types of tumor form a compact mass, like the phalanx formation of Greek antiquity. And although many drugs are known to be toxic to cancer cells, they are often unable to percolate into the inner recesses of the tumor. Upon intravenous administration, for instance, cytotoxic drugs may only be able to penetrate the outermost layers of a solid tumor. A team led by Ludwig Maximilians Universitat Munchen LMU-Germany – pharmacologist Dr Manfred Ogris has now developed a new type of gene delivery vehicle, which is designed to open up a route through the vascular network that supplies the tumor so that drugs can reach their target. A new strategy employing gene therapy could provide a solution to this problem. The idea is to deliver the gene for TNFα directly and specifically to the tumor cells. If this worked, the tumor cells themselves could produce and secrete the cytokine, ensuring that its local concentration becomes sufficiently high to permeabilize the blood vessels only in the immediate vicinity of the tumor.

We first designed a version of the TNFα gene that allows for the production of large amounts of the protein,” Dr. Baowei Su, first author on the study, explains.
Source: http://www.en.uni-muenchen.de/

Gene Therapy For Cardiac Repair

Researchers have established a novel gene therapy strategy which is an excellent substitute for the current expensive and uncontrollable Vascular endothelial growth factor (VEGF) gene delivery system. The discovery of the hyperbranched poly(amidoamine) (hPAMAM) nanoparticle based hypoxia regulated vascular endothelial growth factor (HRE-VEGF) gene therapy strategy, by Dr Changfa Guo, Professor Chunsheng Wang and their co-investigators from Zhongshan hospital Fudan University, Shanghai, China, provides an economical, feasible and biocompatible gene therapy strategy for cardiac repair.

 

Transplantation of VEGF gene manipulated mesenchymal stem cells (MSCs) has been proposed as a promising therapeutic method for cardiac repair after myocardium infarction. However, the gene delivery system, including the VEGF gene and delivery vehicle, needs to be optimized. 

Zhongshan hospital Fudan University, Shanghai:
 
 http://www.zs-hospital.sh.cn/e/intro/index.htm

Source: http://www.researchgate.net/publication/228062762_Novel_vascular
_endothelial_growth_factor_gene_delivery_system-anipulated_mesenchymal_stem_cells_repair_infarcted_myocardium

Gene therapy to rejuvenate

Several studies have demonstrated that the average life of organisms, including that of mammals, can be lengthened by acting on different genes. Until now this has included permanent modifications in animal genes starting in the embryonic phase, something which is not intended to be carried out with humans. Researchers at CNIO and CBATEG now have proved it possible to prolong the life of mice using a treatment which acts directly on the genes, but is used in adult animals and is applied only once. This is achieved through gene therapy, a strategy never before used to fight the aging process.

The therapy demonstrated to be safe and effective in mice. Researchers worked with adult mice aged one year and older mice aged two. In both cases the gene therapy had a "rejuvenating" effect. The mice which were treated at one year of age on average lived 24% longer.

This research is led at the Spanish National Cancer Research Centre (CNIO) by director Maria A. Blasco, in collaboration with Eduard Ayuso and Fátima Bosch, of the Centre for Animal Biotechnology and Gene Therapy (CBATEG) at the Universitat Autonoma de Barcelona UAB, Spain.

Sourcehttp://www.uab.es/servlet/Satellite/latest-news/news-detail/lifespan-of-mice-grows-by-24–1096476786473.html?noticiaid=1337064121411

Gene therapy without a needle

For the first time, researchers have found a way to inject a precise dose of a gene therapy agent directly into a single living cell without a needle.

The technique uses electricity to “shoot” bits of therapeutic biomolecules through a tiny channel and into a cell in a fraction of a second.

L. James Lee and his colleagues at Ohio State University describe the technique in the online edition of the journal Nature Nanotechnology, where they report successfully inserting specific doses of an anti-cancer gene into individual leukemia cells to kill them.

L. James Lee

They have dubbed the method “nanochannel electroporation,” or NEP.

NEP allows us to investigate how drugs and other biomolecules affect cell biology and genetic pathways at a level not achievable by any existing techniques,” said Lee, who is the Helen C. Kurtz Professor of Chemical and Biomolecular Engineering and director of the NSF Nanoscale Science and Engineering Center for Affordable  Nanoengineering of Polymeric Biomedical Devices at Ohio State.