Monthly Archives: May 2017

Drug developer Spark Therapeutics said Thursday it has completed its biologics license application submission with the Food and Drug Administration for its experimental gene therapy for patients with rare inherited blindness.

If approved by the FDA, Sparks lead drug candidate, voretigene neparvovec, could be the first U.S. treatment that uses genes as medicine.

The Philadelphia biotech, spun out of Childrens Hospital of Philadelphia, said the FDA will have 60 days to determine if the application is complete. If the FDA decides the treatment should be given priority review, that would set a six-month target review period, said company spokeswoman Monique da Silva. The review period is still to be determined.

The gene therapy has received orphan, or rare-drug, designation in the United States and Europe. Companies that pursue a cure or treatment for a specific condition that affects a small percentage of the population fewer than 200,000 in the United States can receive tax reductions and an exclusive right to develop the medicine for seven years.

Sparks gene therapy also received breakthrough therapy designation by the FDA because it treats a serious or life-threatening disease or condition. The FDA will expedite the development and review of drugs designated as breakthrough therapies.

Sparks regulatory application includes data from three clinical trials that enrolled 41 participants. The therapy injects genes directly into the retina of the eye.

We look forward to working closely with the FDA, with the hope of bringing voretigene neparvovec, the first potential gene therapy for a genetic disease in the U.S., to patients as quickly as possible, said Jeffrey D. Marrazzo, chief executive officer.

Spark, spun out of decades of research led by Katherine A. High at Childrens Hospital, is also developing treatments for hemophilia and for an inherited retinal disease, choroideremia, that usually manifests during childhood in males as night blindness and a reduction of visual field.

Published: May 18, 2017 1:34 PM EDT

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Spark Therapeutics completes regulatory filing application for its experimental gene therapy medicine - Philly.com

By Robert F. ServiceMay. 17, 2017 , 2:30 PM

It takes more than a cast and a little time to heal many broken bones. Whether its a soldier wounded in battle, a car accident victim, or an elderly person who has fallen, bone damage can be so extensive that the bones never heal properly, leaving people crippled or with other severe problems. Now, researchers have combined ultrasound, stem cells, and gene therapy to stimulate robust bone repair. So far the work has only been performed in animals. But it has already been so successful that its expected to move quickly toward human clinical trials.

The new research has huge clinical significance, says David Kulber, who directs the Center for Plastic and Reconstructive Surgery at Cedars-Sinai Medical Center in Los Angeles, California, and who was not part of the study. The technology of being able to stimulate bone growth is really remarkable.

Its also one for which there is a glaring need. In the United States alone, some 100,000 people a year suffer from what is known as a nonunion fracture. In these cases, parts of a bone may be missing altogether or so badly splintered that the bone cant be reassembled. In such cases, doctors typically graft other bone into the site. Ideally this bone comes from the same personoften taken from the pelvis, a painful procedure that compounds a persons injuries and recovery time. When this isnt possible, physicians will turn to cadavers for the extra bone. But this bone must be sterilized before its implanted, robbing it of proteins and other signaling molecules that encourage its regrowth once transplanted, and lessening the chances of a full recovery.

Researchers have long tried to improve matters by growing new bone without use of a graft. To do so they typically first fill gaps in bone with a natural scaffolding material called collagen. This scaffolding encourages a persons own bone-forming stem cells, called mesenchymal stem cells (MSCs), to migrate into the area. The trouble is MSCs dont only differentiate into osteocytes, the bone-producing cells. They can also develop into either fat tissue cells or scar tissue.

Researchers have tried for years to steer MSCs into becoming osteocytes by exposing them to one or more bone morphogenetic proteins (BMPs), signaling molecules that trigger the cells to transform into bone-forming cells. But for this differentiation to occur, MSCs must be exposed to BMPs for up to a week. Yet if the BMPs are simply injected into the site of a fracture, they dissipate in just hours.

In an effort to produce a lasting BMP signal, researchers led by Dan Gazit, a regenerative medicine expert at Cedars-Sinai, as well as other groups, have previously turned to using viruses to introduce extra copies of BMP genes into MSCs so that the cells themselves will produce the proteins long enough to trigger their own differentiation. But success has been halting here, too.

Over the last several years, Gazits teamamong othershasdeveloped an alternative strategy for efficiently getting genes into MSCs without viruses. The researchers start by packing the wound with the usual collagen matrix and waiting for a couple of weeks for the stem cells to infiltrate the scaffold. They then create a solution containing numerous copies of their gene of interest alongside gas-filled micron-sized bubbles encased by a thin shell of fat molecules. After injecting this solution into the fracture site, they go over the area with an ultrasound wand, much as its done by obstetricians to check on the health of a fetus. The wands ultrasound pulses burst the microbubbles, briefly punching nano-sized holes in any adjacent stem cells, which allows the genes in the solution to enter.

In 2014, Gazit and his colleagues reported that they used this procedure to introduce nontherapeutic reporter genes into large fractures in animal models. But when they used the procedure to introduce genes for two different BMPsBMP-2 and BMP-7they detected some bone regrowth in the animals, but not enough to heal the fractures.

Gazits group has gotten better results by using the same approach to insert copies of the gene for BMP-6 into pigs that had been surgically given 1-centimeter gaps in a leg bone. After waiting 8 weeks, they found that the bone gap was closed and the leg fracture was healed in all of the treated animals. In fact, the procedure was so effective that the fractures healed as well as when bone grafts were carried out using bone from the same animal, the currently preferred treatment, they report today in Science Translational Medicine.

The results are just the type of thing we need to move this field forward, says Johnny Huard, an orthopedics researcher at the University of Texas Health Science Center in Houston. However, he notes, the pigs used in this study were all under 1 year in age. Younger animals, including people, tend to have far more MSCs than older ones, he says, yet large fractures are far more common in the elderly than the young. So Huard suggests that before the approach is ready for testing in people with bone fractures, it would be good to first see whether its equally successful in older animals.

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Tiny bubbles and a bit of gene therapy heal major bone fractures in pigs - Science Magazine

Medical students learn that the best way to treat a disease is to prevent it. That is certainly true for medical geneticists whose patients often include children with devastating genetic disorders for which there are no cures. In fact, these specialists are trained to actively seek for the molecular mechanism affecting patients who present with rare Mendelian disorders and apply conclusions from these individual cases to the larger population through screening campaigns.

To discuss the history of carrier screening and the tools being developed to overcome challenges in the field we spoke to Dr. Doron Behar, MD, Ph.D., CEO of Igentify, and CSO of Gene by Gene. Dr Behar recently helped to develop a pan-ethnic, high-throughput assay for the detection of sequence and structural variants with Thermo Fisher Scientific. As a population geneticist, his true interest lies in developing robust, low-priced genetic testing for the public that will enable the development of responsible, personalized genetic medicine for individuals worldwide.

Can you tell me a bit about the history of carrier screening and why the push for expanded carrier research?

The history of carrier screening for preconception purposes started with a scientific observation. In our case, it was observed that certain diseases and syndromes have a high prevalence in the general population or in a specific ethnicity. Accordingly, initial preconception screening programs focused on either specific diseases or specific targeted populations. In the genetic era, common principles for including a given mutation in a population screening campaign include the severity of the disease, the incidence of the disease in the population, the residual risk for an affected child after the test, the available technology for the screening efforts, and budgetary considerations.

A good example of the former is Cystic Fibrosis, reaching a prevalence of 1/2500 live births (1/25 carrier frequency) among the Caucasian population, and the Ashkenazi Jewish population for the latter. The push for expanded carrier screening stems from the will to increase the detection rate for rare Mendelian disorders among patients conceiving pregnancy and to reduce the residual risk as much as possible. The means to accomplish this mission is a direct and inevitable consequence of our ability to read larger and larger parts of our genome and to the demographic changes characterizing our era.

There is no doubt that one of the most straightforward and immediate applications of having genomic content as part of any medical record is the ability to know the risk each of us carries for having a child affected by one of the thousands of rare Mendelian disorders. This can be achieved by allowing expanded preconception screening comprising thousands of mutations (rather than dozens) via universal screening panels.

Modern molecular techniques have revealed how the human genome is constantly evolving and developing, even today. But, how is our genetic make-up changing and what's driving this change?

Humans are constantly going through a process of evolution. Demographic changes represent the major forces shaping the contemporary genomic makeup and changes among humans. Phenomena such as massive population migrations and inter-community marriages shuffle the genomic content among various ethnic groups so that the link between specific mutations and the populations they were first identified in becomes obscured.

Since 2007, I was carefully reading the literature and collecting information about each newly discovered deleterious mutation affecting the population I work with in Israel. There is an abundance of rare deleterious diseases in my region as many Jewish communities went through a founder event followed by rapid population expansion that has resulted in the accumulation of deleterious mutations for well-recognized diseases such as Tay-Sachs, Bloom, and Cystic Fibrosis. In addition, consanguinity is commonly practiced by many other populations residing in the region. Universal panels might eliminate the need to verify the ethnic background of each tested individual which might be very complex and sometimes unknown.

What challenges are we facing in carrier screening and what effect does globalization have?

Carrier screening, as any medical procedure, must be taken cautiously. Large challenges include the need to educate patients and their healthcare providers to the advantages of expanded preconception screening. The decision on the appropriate diseases that should be included is challenging as well.

For medical geneticists working in the field of preconception, it can feel a bit like being part of Charlie in the Chocolate Factory. Clearly, some candies are delightful while others can be dangerous. The ability to screen more conditions and mutations challenges the first criteria for severity as we can check milder phenotypes. While we do not want to deprive the public of information, we do not want to create unnecessary anxiety among couples conceiving pregnancy as some of these milder phenotypes, might not be labeled as actionable by many individuals worldwide.

Even more serious, is the problem of identifying variants of unknown clinical significance that each of us carries as part of his genome. Do we want such changes to be part of a preconception screening? The ability to create a comprehensive panel comprising mutations relevant to all global populations is a difficult task. The establishment of an accessible and affordable test to all individuals worldwide must be a declared goal. CarrierScan will overcome all of these obstacles.

The American College of Obstetricians and Gynaecologists recently updated their screening recommendations. How would adopting these new standards help?

The ACOG statements are a landmark, well-timed, and cautiously made recommendations. They clearly put expanded pre-conception screening under the spotlight as an appropriate approach. These recommendations are clearly in line with the aims of CarrierScan.

How do you think carrier screening will evolve into the future? What role will pan-ethnic assays like CarrierScan play?

I was looking for a solution aiming to be truly complete. I envisioned a test that can allow us to responsibly screen simultaneously for thousands of deleterious mutations irrespective of their population frequency as that is the direct promise of the genomic revolution screen for any mutation you can. The product should allow easy expansion to meet changing data in the literature or changing regulatory requests. The product must be flexible and allow the inclusion of commonly screened point mutations alongside dosage (deletion/ duplication) mutations such as the ones causing spinal muscular atrophy or Duchenne muscular dystrophy.

The result was CarierScan - an easily integrated, comprehensive and expanded preconception screening array, which is robust and inexpensive enough to be offered at the population level to any individual worldwide.

One of the major principles leading the molecular design of CarrierScan is to establish a comprehensive but finite list of mutations that can be safely offered to individuals worldwide while avoiding the parental anxiety that might be associated with counseling for various variants of unknown clinical significance. CarrierScan will keep on evolving to include more and more mutations of known clinical significance, relevant to an ever-growing number of world-wide populations. We see CarrierScan becoming a standard of care offered to each couple at the preconception state. Our aim is to make the CarrierScan expanded preconception screening accessible and affordable globally.

Dr Behar will be speaking about this novel assay at the upcoming European Society of Human Genetics (ESHG) annual meeting on Sunday, May 28 at 11:15 a.m.

CarrierScan Assay is for research use only; not for use in diagnostic procedures.

Dr. Doron Behar was speaking to Jack Rudd, Senior Editor for Technology Networks.

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Bringing the Genomic Revolution to Reproductive Health - Technology Networks

May 18, 2017 Dr. Chad Creighton. Credit: Baylor College of Medicine

Looking to improve cancer treatment, a multi-institutional research team has taken a comprehensive approach to evaluating which molecular changes in cancer cells are most likely involved in the development of the disease. This approach resulted in the confirmation of previously known cancer molecular changes and in the discovery of others that had not been typically linked to cancer before. Targeting particular patient alterations with specific drugs might help one day improve response to treatment. The report appears in Cancer Cell.

"We studied the PI3K pathway, one of the most important pathways of the cell," said senior author Dr. Chad Creighton, associate professor of medicine and member of the Dan L Duncan Comprehensive Cancer Center Division of Biostatistics at Baylor College of Medicine. "A cellular pathway is a chain of events involving several proteins. The PI3K pathway has a number of diverse functions, including altering the cell's metabolism and driving cell growth and proliferation."

"PI3K is the most commonly mutated pathway in cancer that can be targeted by drugs. Thus, understanding how the pathway and mutations in cancer affect the many different cancer lineages is important," said co-author Dr. Gordon Mills, professor of medicine and immunology at MD Anderson Cancer Center.

Previous studies had identified a number of the genes, proteins and processes involved in the PI3K pathway in cells grown in the lab.

"In this study, we have taken what we have learned in the lab regarding how the pathway works and analyzed it together with information about the genes and the proteins present in cancer cells taken from human patients," Creighton said. "We looked at nearly 11,000 human cancers representing 32 major types. This is the largest study of its kind, and it was possible in part thanks to the Cancer Genome Atlas, a publicly available dataset of genomic changes in 32 types of cancer."

To carry out the complex analysis of this vast amount of data, the research team pulled the resources of experts in cancer protein data, in molecular biology of the pathway, and in the use of powerful analytical tools that provided genomic analysis and integration of the protein data.

The challenge is to know which mutations in cancer are important

To assess which cancer mutations are important, the researchers carried out a comprehensive analysis that allowed them to distinguish which of the altered genes and proteins were more likely to affect the normal function of the PI3K pathway.

"What makes this analysis complex is that there is a large number of gene and protein alterations that can be present in a given patient's tumor, and it is possible that different alterations are present in different patients," Creighton said. "In addition, not all mutations necessarily cause disease. The challenge is to find out which mutations are altering the pathway in a way that can lead to cancer. We hope that one day we will be able to apply this knowledge to personalized medicine."

There were a few surprises in the study.

"For some genes there was previous work indicating they were implicated in this pathway, but we discovered other genes, such as IDH1 and VHL, which had not been typically associated with the pathway in cancer before," Creighton said. "These genes, as well as others that may be discovered in the future, may now be incorporated into the group of genes linked to the PI3K pathway and considered as potential candidates for targeted therapy."

"Finding several cancers and mutations that we didn't know before could activate this pathway supports moving up the priority of testing drugs toward the new mutations found in specific cancer types," said co-author Dr. David Kwiatkowski, professor of medicine at Harvard Medical School and senior physician at Brigham and Women's Hospital and the Dana Farber Cancer Institute.

The future of personalized medicine

"The comprehensive nature of this project that integrates information from multiple levels has the potential to impact patient management and to eventually improve outcomes for the large population of patients with abnormalities in this very important pathway," Mills said.

"This comprehensive approach expands our knowledge regarding which types of cancer this pathway is activated and why, and that's important in terms of thinking about therapies that go after this pathway," Kwiatkowski said.

Imagine the following possible future scenario in a personalized medicine setting: a patient provides a sample of tumor and the physician sends it to a lab that runs a sequencing assay that shows where the genetic changes are located and the type of changes. Then, from the protein data, the team of physicians and scientists can determine which genetic changes are associated with greater activation of the PI3K pathway and which may not. These data would help the team in terms of selecting patients for whom specific drugs may be effective.

Explore further: New subtypes of lung cancer can lead to personalized therapies with better outcome

More information: Cancer Cell (2017). DOI: 10.1016/j.ccell.2017.04.013

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Comprehensive cancer study assesses potential targets for personalized medicine and finds new ones - Medical Xpress

One treatment for neovascular or wet age-related macular degeneration neutralizes the protein linked to the disease using repeated eye injections, an uncomfortable, onerous regimen that causes much anxiety for patients. Gene therapy - if proven to be safe and effective - offers an attractive alternative because one injection could provide lasting effects. Now, a small clinical trial shows that one experimental gene therapy for this significant cause of vision loss in older people appears to be safe and well tolerated.

A paper on the trial, which was led by Johns Hopkins University School of Medicine in Baltimore, MD, and funded by Sanofi Genzyme of Framingham, MA, is published in The Lancet.

Senior author Peter Campochiaro, a professor of ophthalmology at Johns Hopkins, says: "Even at the highest dose, the treatment was quite safe. We found there were almost no adverse reactions in our patients."

Age-related macular degeneration (AMD) is the third most common global cause of visual deficiency in industrialized countries.

In the United States, National Eye Institute estimates suggest that the number of people affected by AMD will rise to 5.44 million by 2050 - more than double the 2.07 million figure for 2010.

People with AMD lose the ability to see objects clearly and find it increasingly difficult to do everyday things, such as read, drive, recognize faces, and use a computer. As the disease progresses, it destroys the macula, the central part of the retina at the back of the eye that provides sharp, central vision.

The study concerns a type of AMD known as neovascular or wet AMD, which arises when abnormal blood vessels grow beneath the retina. These new blood vessels - neovascular means "new vessels" - can leak fluids that cause swelling and damage to the macula.

Although wet AMD is less common among cases of AMD, it accounts for a high proportion of cases of severe vision loss in AMD.

In their study paper, the authors explain that wet AMD is linked to high levels of vascular endothelial growth factor (VEGF), a protein that promotes growth and leakiness of blood vessels.

Treatments that successfully treat wet AMD include injections into the eye of anti-VEGF compounds. However, these need to be given regularly, because after a month or so, the compounds leave the eye and the VEGF levels start rising again.

Eye specialists suggest that the distress and discomfort of such an onerous regimen - often involving repeat injections every 6 to 8 weeks - is likely a main reason patients do not come for injections as often as they should, and their vision gets worse.

Gene therapy is an experimental approach that treats disease by inserting, deleting, or altering genes in the patient. The aim is for doctors to be able use it to treat diseases by "correcting" the underlying genetic causes instead of using drugs or surgery.

Although gene therapy is showing promise in the treatment of some diseases, it is still a risky method and needs to be approached with great caution, which is why at present it is only being tested as a treatment for diseases that currently have no cure.

In this phase I clinical trial, the researchers tested the safety and tolerance of a gene therapy that inserts a gene into retinal cells that causes them to produce sFLT01 - a protein that binds to VEGF and stops it promoting growth and leakage of abnormal blood vessels.

The hope is that, once proven, one treatment of the gene therapy will be enough to cause the cells to become permanent producers of the anti-VEGF protein.

The vehicle or "vector" the researchers used to deliver the gene is a disabled version of the AAV2 virus that causes the common cold. Viruses are ideal vectors for gene therapy because by their nature they insert genetic material into host cells.

The team enrolled 19 men and women aged 50 and older who had been diagnosed with wet AMD, and assigned them to five groups who received the following doses of viral particles (vector genomes, or vg) in 0.05 milliliters of fluid: 2X10^8 vg (group 1), 2X10^9 vg (group 2), 6X10^9 vg (group 3) and 2X10^10 vg (groups 4 and 5).

The patients were not all treated at the same time. The researchers waited for at least 4 weeks and examined each group to see if there were any adverse reactions before treating the next highest dose group.

The highest dose was not given until the researchers had established there was no dose-limiting toxicity in the first three groups. They found no serious adverse effects in the final two maximum dose groups.

The experimental nature of the trial meant it could only treat patients who were unlikely to regain vision following standard treatment. Because of this, it meant that only 11 of the 19 were likely to show fluid reduction.

The results show that four of these 11 patients experienced dramatic reduction in fluid levels. The levels dropped from severe to almost zero, which Prof. Campochiaro says is what might be expected from standard treatment. Two others from the 11 showed some reduction in fluid in the eyes.

However, the other five patients from the 11 that might be expected to benefit from the therapy showed no reductions in the fluid in their eyes.

Further tests showed that these patients all had antibodies to the strain of AAV2 virus used in the gene therapy. The researchers suggest that the antibodies may have destroyed the virus particles carrying the therapeutic gene before they could insert it into the retinal cells.

However, due to the small number of patients in the trial, they cannot be sure if this is really the cause or just a coincidence.

Should further studies show that the presence of AAV2 antibodies in patients renders the treatment ineffective, then it could mean that as it stands, the gene therapy may have limited use in the U.S., where around 60 percent of people are likely to have antibodies to the family of viruses that AAV2 belongs to.

However, the trial achieved its main purpose in showing that this particular gene therapy, regardless of effectiveness, is safe and well tolerated, and it moves the search for a new treatment for wet AMD forward. Prof. Campochiaro concludes:

"This preliminary study is a small but promising step towards a new approach that will not only reduce doctor visits and the anxiety and discomfort associated with repeated injections in the eye, but may improve long-term outcomes because prolonged suppression of VEGF is needed to preserve vision, and that is difficult to achieve with repeated injections because life often gets in the way."

Discover how gut microbes influence the development of wet AMD.

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Wet AMD: Small trial shows new gene therapy is safe in humans - Medical News Today

May 18, 2017 Defect of the medial cerebellum in Rac1/Rac3-DKO mouse. Credit: Kobe University

Opitz G/BBB (Opitz) syndrome is a hereditary disorder that affects people in different ways, causing malformations in medial (midline) organs and structures, intellectual disability and developmental disorders. Scientists have revealed a new control mechanism for the gene that causes this disorder, a discovery that could help in developing treatment for the syndrome. The findings were published on May 16 in the online edition of Development.

A group of scientists led by Associate Professor UEYAMA Takehiko and Professor SAITO Naoaki (both from the Kobe University Biosignal Research Center) and members of Kyoto Prefectural University of Medicine carried out this research.

Professor Ueyama expressed his hopes that this discovery would contribute to "revealing the underlying mechanism that explains the range of symptoms caused by Opitz syndrome, a disease that has different effects on individual patients, even within the same family".

Opitz syndrome occurs for at least 1 in every 10,000-50,000 people. It is a hereditary disorder that causes a wide range of physical malformations in midline structures of organs, including in the brain, the face, the heart, the larynx and pharynx, the trachea and esophagus, urinary organs and genitals.

Previous findings identified Midline 1 (MID1) as the gene responsible for Opitz syndrome. The functional decline of MID1 causes the congenital disorders described above, but it is still unclear why these symptoms are so varied among individual patients. Treatment methods are yet to be fixed, and surgical therapy is currently the main treatment.

The research team focused on cerebellar granule neurons, a type of neurons with the largest population in the brain, and a signaling protein/molecule called Rac which functions in cerebellar granule neurons during cerebellar development. The team created a "knockout" mouse with the Rac protein deleted. They discovered that this mouse experienced severe walking impairment because of the loss of the internal granule layer in the medial cerebellum. Next, they extracted the cerebellar granule neurons affected by the deleted Rac from the medial cerebellum. Using DNA microarrays they examined these neurons and discovered reduced expression of MID1, the causative gene of Opitz syndrome. This showed that Rac had been regulating the expression of Mid1, and when Rac was deleted, MID1 stopped functioning correctly in the mouse.

They also discovered a cell signaling pathway in which Rac-Mid1-mTOR form a complex and contribute to the differentiation and maturation of cerebellar granule cells.

The individual variability in these cell signaling pathways could be a cause of the broad range in the symptoms caused by Opitz syndrome. These findings could lead to development of a new treatment for Opitz syndrome that targets cell signaling.

Explore further: Scientist models Smith-Lemli-Opitz syndrome in adult stem cells

More information: Takashi Nakamura et al. Novel role of Rac-Mid1 signaling in medial cerebellar development, Development (2017). DOI: 10.1242/dev.147900

Journal reference: Development

Provided by: Kobe University

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Control mechanism unveiled for gene that causes Opitz syndrome - Medical Xpress