Category Archives: Gene Medicine

PUBLIC RELEASE DATE:

1-Dec-2014

Contact: David Slotnick newsmedia@mssm.edu The Mount Sinai Hospital / Mount Sinai School of Medicine @mountsinainyc

(NEW YORK - December 1, 2014) Kidneys donated by people born with a small variation in the code of a key gene may be more likely, once in the transplant recipient, to accumulate scar tissue that contributes to kidney failure, according to a study led by researchers at the Icahn School of Medicine at Mount Sinai and published today in the Journal of Clinical Investigation.

If further studies prove the variation to cause fibrosis (scarring) in the kidneys of transplant recipients, researchers may be able to use it to better screen potential donors and improve transplant outcomes. Furthermore, uncovering the protein pathways that trigger kidney fibrosis may help researchers design drugs that prevent this disease process in kidney transplant recipients, and perhaps in all patients with chronic kidney disease.

"It is critically important that we identify new therapeutic targets to prevent scarring within transplanted kidneys, and our study has linked a genetic marker, and related protein pathways, to poor outcomes in kidney transplantation," said Barbara Murphy, MD, Chair, Department of Medicine, Murray M. Rosenberg Professor of Medicine (Nephrology) and Dean for Clinical Integration and Population Health at the Icahn School of Medicine at Mount Sinai. "Drug designers may soon be able to target these mechanisms."

A commonly used study type in years, the genome-wide association study (GWAS) looks at differences at many points in the genetic code to see if, across a population, any given variation in the genetic code is found more often in those with a given trait; in the case of the current study, with increased fibrosis in recipients of donated kidneys.

Even the smallest genetic variations, called single nucleotide polymorphisms (SNPs), can have a major impact on a trait by swapping just one of 3.2 billion "letters" making up the human DNA code. The current study found a statistically significant association between SNP identified as rs17319721 in the gene SHROOM3 and progressive kidney scarring (fibrosis) and function loss in a group of kidney donors, mostly of European descent. In many cases, certain SNPs will be more common in families or ethnic groups.

The kidneys filter the blood to remove extra blood sugar and waste products that trickle down the kidney tubes to become urine, while re-absorbing key nutrients. The build-up of scar tissue in these delicate structures over time interferes with proper renal function.

Chronic kidney disease already affects 10 percent of US adults and its prevalence is increasing. Along with leading to kidney failure in many cases, chronic kidney disease increases the risk of cardiovascular disease. Fibrosis in kidney tubules is a common pathogenic process for many types of chronic kidney disease, and a central part of chronic disease in donated kidneys (chronic allograft nephropathy, or CAN).

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Genetic marker may help predict success of kidney transplants

PUBLIC RELEASE DATE:

1-Dec-2014

Contact: Glenna Picton picton@bcm.edu 713-798-4710 Baylor College of Medicine @bcmhouston

HOUSTON -- (Dec. 1, 2014) - Most genes are inherited as two working copies, one from the mother and one from the father. However, in a few instances, a gene is imprinted, which means that one copy is silenced. This is called genomic imprinting. If the active copy is mutated, then disease results, even though the silenced gene copy may be normal.

Angelman syndrome, which causes learning difficulties, speech problems, seizures, jerky movements and an unusually happy disposition, results when a gene inherited from the mother in a particular area of chromosome 15 is mutated and the other copy of the gene, inherited from the father, is silenced. In a report that appears online in the journal Nature Dr. Arthur Beaudet, professor of molecular and human genetics at Baylor College of Medicine and a clinical geneticist at Texas Children's Hospital, and colleagues answer the question: "Can we turn on the activity of the paternal gene?"

Angelman syndrome occurs when an infant inherits a mutated copy of the imprinted gene UBE3A from his or her mother. He or she also has a paternal copy of the gene, but it is silenced by a long ribbon of RNA called the UBE3A anti-sense transcript. (Antisense, in this case, is complementary to the ribbon of RNA, which means it binds to it and silences any activity.)

In an earlier experiment, Dr. Ben Philpott of the University of North Carolina showed that a type of drug called a topoisomerase could activate the father's copy of the gene, but the drug itself was toxic and it did not limit activation to the Angelman gene but affected all long genes.

One of Beaudet's graduate students - Linyan Meng - was writing her dissertation on Angelman syndrome and was wrestling with this problem when a member of her dissertation committee, Dr. Thomas Cooper, professor of pathology & immunology at Baylor, said he was working with a Carlsbad, Calif.-based company called Isis Pharmaceuticals that had anti-sense oligonucleotides that could turn off the antisense transcript that silenced the paternal copy of the gene. She bred a mouse in which the antisense transcript was "knocked down" and the paternal copy of the gene turned on.

"If you blocked the antisense, you could turn on the paternal copy," said Beaudet, also the Henry and Emma Meyer Chair in Molecular Genetics at Baylor. The treatment worked both in cells in the laboratory and in the live animals. The effect of the injection of the antisense oligonucleotides lasted about 16 weeks.

"It was clear from the molecular data that we were turning on the paternal copy of the gene," said Beaudet. "It is not clear how much we are able to reverse the behavioral abnormalities."

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Taking the 'mute' off silenced gene may be answer to Angelman syndrome

The western worlds first gene therapy drug is set to go on sale in Germany with a 1.1m ($1.4m) price tag. Photograph: Eliseo Fernandez/Reuters

The western worlds first gene therapy drug is set to go on sale in Germany with a 1.1m ($1.4m) price tag, a new record for a medicine to treat a rare disease.

The sky-high cost of Glybera, from Dutch biotech firm UniQure and its unlisted Italian marketing partner Chiesi, shows how single curative therapies to fix faulty genes may upend the conventional pharmaceutical business model.

After a quarter century of experiments and several setbacks, gene therapy is finally throwing a life-line to patients by inserting corrective genes into malfunctioning cells but paying for it poses a challenge.

The new drug fights an ultra-rare genetic disease called lipoprotein lipase deficiency (LPLD) that clogs the blood with fat. The medicine was approved in Europe two years ago but its launch was delayed to allow for the collection of six-year follow-up data on its benefits.

Now Chiesi has filed a pricing dossier with Germanys federal joint committee, or G-BA, which will issue an assessment of the drugs benefits by the end of April 2015.

The company is seeking a retail price of 53,000 per vial, or 43,870 ex-factory.

That equates to 1.11m for an typical LPLD patient, averaging 62.5kg in clinical trials, who will need 42 injections from 21 vials. This price will be subject to a standard 7% discount under Germanys drug pricing system.

Under German rules, the launch price for a new drug is valid for the first 12 months.

A Chiesi spokeswoman confirmed the launch price, in response to inquiries from Reuters, prompted by information from health insurance sources.

Originally posted here:
World's most expensive medicine Glybera goes on sale with $1m price tag

FRANKFURT/LONDON The Western worlds first gene-therapy drug is set to go on sale in Germany with a price of 1.1 million ($1.4 million), a new record for a medicine to treat a rare disease.

The sky-high cost of Glybera, from the Dutch biotechnology firm UniQure and its unlisted Italian marketing partner, Chiesi, shows how targeted therapies to fix faulty genes may upend the conventional pharmaceutical business model.

After a quarter of a century of experiments and several setbacks, gene therapy is finally throwing a lifeline to patients by inserting corrective genes into malfunctioning cells but paying for it poses a challenge.

The new drug fights an ultra-rare genetic disease called lipoprotein lipase deficiency (LPLD), which clogs the blood with fat. The medicine was approved in Europe two years ago, but its launch was delayed to allow for the collection of six-year follow-up data on its benefits.

Now Chiesi has filed a pricing dossier with Germanys Federal Joint Committee (G-BA), which will issue an assessment of the drugs benefits by the end of April 2015. The company is seeking a retail price of 53,000 (66,000) per vial, or 43,870 ($54,800) ex-factory.

That equates to 1.11 million for a typical LPLD patient, who will need 42 injections from 21 vials. This price will be subject to a standard 7 percent discount under Germanys drug pricing system.

Under German rules, the launch price for a new drug is valid for the first 12 months.

A Chiesi spokeswoman confirmed the launch price. She added that a final figure would be set after the G-BA gives its verdict and negotiations are held with statutory health insurance funds.

First commercial treatments are expected in the first half 2015, she said.

UniQure, which will get a net royalty of between 23 and 30 percent on sales, said EU pricing is a matter for its Italian partner, although the Dutch firm does plan to discuss Glybera pricing during an investor meeting in New York on Dec. 1.

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London - The Western world's first gene therapy drug is set to go on sale in Germany with a 1.1m ($1.4m) price tag, a new record for a medicine to treat a rare disease.

The sky-high cost of Glybera, from Dutch biotech firm UniQure and its unlisted Italian marketing partner Chiesi, shows how single curative therapies to fix faulty genes may upend the conventional pharmaceutical business model.

After a quarter century of experiments and several setbacks, gene therapy is finally throwing a life-line to patients by inserting corrective genes into malfunctioning cells - but paying for it poses a challenge.

The new drug fights an ultra-rare genetic disease called lipoprotein lipase deficiency (LPLD) that clogs the blood with fat. The medicine was approved in Europe two years ago but its launch was delayed to allow for the collection of six-year follow-up data on its benefits.

Now Chiesi has filed a pricing dossier with Germany's Federal Joint Committee, or G-BA, which will issue an assessment of the drug's benefits by the end of April 2015. The company is seeking a retail price of 53 000 per vial, or 43 870 ex-factory.

That equates to 1.11m for an typical LPLD patient, averaging 62.5 kg in clinical trials, who will need 42 injections from 21 vials. This price will be subject to a standard 7% discount under Germany's drug pricing system.

Under German rules, the launch price for a new drug is valid for the first 12 months.

A Chiesi spokeswoman confirmed the launch price, in response to inquiries from Reuters, prompted by information from health insurance sources. She added that a final figure would be set after the G-BA gives its verdict and negotiations are held with statutory health insurance funds.

"First commercial treatments are expected in the first half 2015," she said.

UniQure, which will get a net royalty of between 23 and 30% on sales, said EU pricing was a matter for its Italian partner, although the Dutch firm does plan to discuss Glybera pricing during an investor meeting in New York on December 1.

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Fin24.com | First gene therapy drug sets price record

FRANKFURT/LONDON - The Western world's first gene therapy drug is set to go on sale in Germany with a 1.1 million euro ($1.4 million) price tag, a new record for a medicine to treat a rare disease.

The sky-high cost of Glybera, from Dutch biotech firm UniQure and its unlisted Italian marketing partner Chiesi, shows how single curative therapies to fix faulty genes may upend the conventional pharmaceutical business model.

After a quarter century of experiments and several setbacks, gene therapy is finally throwing a life-line to patients by inserting corrective genes into malfunctioning cells - but paying for it poses a challenge.

The new drug fights an ultra-rare genetic disease called lipoprotein lipase deficiency (LPLD) that clogs the blood with fat. The medicine was approved in Europe two years ago but its launch was delayed to allow for the collection of six-year follow-up data on its benefits.

Now Chiesi has filed a pricing dossier with Germany's Federal Joint Committee, or G-BA, which will issue an assessment of the drug's benefits by the end of April 2015. The company is seeking a retail price of 53,000 euros per vial, or 43,870 euros ex-factory.

That equates to 1.11 million euros for an typical LPLD patient, averaging 62.5 kg in clinical trials, who will need 42 injections from 21 vials. This price will be subject to a standard 7 percent discount under Germany's drug pricing system.

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First gene therapy drug sets million-euro price record

PUBLIC RELEASE DATE:

25-Nov-2014

Contact: Amy Blustein ablustein@wihri.org 401-681-2822 Women & Infants Hospital @womenandinfants

There has been much recent debate on the benefits and risks of screening for breast cancer using BRCA1 and BRCA2 mutations in the general adult population. With an estimated 235,000 new breast cancer diagnoses each year in the U.S. and more than 40,000 deaths, it is clearly important to be able to determine which women may be genetically predisposed to breast cancer.

Glenn E. Palomaki, PhD, associate director of the Division of Medical Screening and Special Testing in the Department of Pathology and Laboratory Medicine at Women & Infants Hospital of Rhode Island has recently published an invited commentary in the November issue of Genetics in Medicine. The commentary is entitled "Is it time for BRCA1/2 mutation screening in the general adult population? Impact of population characteristics."

A family history of breast or ovarian cancer or a personal history of early-onset cancer are strong risk factors for breast cancer. Systematic criteria when caring for a patient with a positive family history have been well established by such agencies as the U.S. Preventive Services Task Force and the National Comprehensive Cancer Network.

Dr. Palomaki said, "With the identification of the tumor suppressor genes BRCA1 and BRCA2 in the 1990s, the scientific community has extensively explored both the personal and population impact of carrying a deleterious mutation in these genes. Any new population-based screening test, such as testing for BRCA1 and BRCA2 mutations, requires consideration of key performance characteristics that evaluate both strengths and shortcomings before its introduction."

In his commentary, Dr. Palomaki cited two recent publications that present perspectives on routine, population-based screening for breast cancer using BRCA1/2 mutations in different populations.

"Together, these two publications offer an unusual opportunity to compare and contrast how distinct population differences, such as the mutations carrier rate, might influence the feasibility of population-based screening," said Dr. Palomaki. "Because founder mutations are more common in Ashkenazi Jewish women, are more easily identified and account for a higher proportion of all breast cancer cases, pilot trials in that population are indicated before launching widespread screening in Israel to identify and resolve implementation issues. Such screening in the United States, however, is more complicated, tilting the balance away from routine population screening, as least for the moment."

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Pathology specialist contributes to debate on breast cancer gene screening

PUBLIC RELEASE DATE:

24-Nov-2014

Contact: Vanessa Wasta wasta@jhmi.edu 410-614-2916 Johns Hopkins Medicine @HopkinsMedicine

After mining the genetic records of thousands of breast cancer patients, researchers from the Johns Hopkins Kimmel Cancer Center have identified a gene whose presence may explain why some breast cancers are resistant to tamoxifen, a widely used hormone treatment generally used after surgery, radiation and other chemotherapy.

The gene, called MACROD2, might also be useful in screening for some aggressive forms of breast cancers, and, someday, offering a new target for therapy, says Ben Ho Park, M.D., Ph.D., an associate professor of oncology in the Kimmel Cancer Center's Breast Cancer Program and a member of the research team.

The drug tamoxifen is used to treat estrogen receptor-positive breast cancers. Cells in this type of breast cancer produce protein receptors in their nuclei which bind to and grow in response to the hormone estrogen. Tamoxifen generally blocks the binding process of the estrogen-receptor, but some estrogen receptor-positive cancers are resistant or become resistant to tamoxifen therapy, finding ways to elude its effects. MACROD2 appears to code for a biological path to tamoxifen resistance by diverting the drug from its customary blocking process to a different way of latching onto breast cancer cell receptors, causing cancer cell growth rather than suppression, according to a report by Park and his colleagues published online Nov. 24 in the Proceedings of the National Academy of Sciences.

Specifically, the team's experiments found that when the gene is overexpressed in breast cancer cells--producing more of its protein product than normal--the cells become resistant to tamoxifen.

One piece of evidence for the gene's impact was demonstrated when the Johns Hopkins scientists blocked MACROD2's impact in breast cancer cell cultures by using an RNA molecule that binds to the gene to "silence," or turn off, the gene's expression. But the technique only partially restored the cells' sensitivity to tamoxifen.

To conduct the study, the scientists examined two well-known databases of breast cancer patients' genetic information, The Cancer Genome Atlas and the Molecular Taxonomy of Breast Cancer International Consortium study. Patients who had MACROD2 overexpressed in primary breast cancers at the original breast cancer site had significantly worse survival rates than those who did not, according to an analysis of the patient databases.

With this in mind, the Johns Hopkins scientists suggest that clinicians may be able to look at MACROD2 activity to help them identify aggressive breast cancers at early stages of growth.

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Johns Hopkins scientists link gene to tamoxifen-resistant breast cancers

Chuck Bednar for redOrbit.com Your Universe Online

A new stem cell gene therapy developed by researchers at UCLA is set to begin clinical trials early next year after the technique reportedly cured 18 children who were born without working immune systems due to a condition known as ADA-deficient Severe Combined Immunodeficiency (SCID) or Bubble Baby disease.

The treatment was developed by Dr. Donald Kohn, a member of the UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, and his colleagues, and according to the university, it is able to identify and correct faulty genes by using the DNA of the youngsters born with this life-threatening condition.

Left untreated, ADA-deficient SCID is often fatal within the first year of a childs life, reports Peter M. Bracke for UCLA. However, after more than three decades of research, Dr. Kohns team managed to develop a gene therapy that can safely restore the immune systems of children with the disease by using their own cells and with no noticeable side effects.

All of the children with SCID that I have treated in these stem cell clinical trials would have died in a year or less without this gene therapy, instead they are all thriving with fully functioning immune systems, Dr. Kohn, who is also a professor of pediatrics and of microbiology, immunology and molecular genetics, said in a recent statement.

Children born with SCID have to be isolated in a controlled environment for their own safety, because without an immune system, they are extremely vulnerable to illnesses and infections that could be deadly. While there are other treatments for ADA-deficient SCID, Dr. Kohn noted that they are not always optimal or feasible for many children. The new technique, however, provides them with a cure, and the chance to live a full healthy life.

SCID is an inherited immunodeficiency that is typically diagnosed about six months after birth, the researchers said, and children with the condition are so vulnerable to infectious diseases that even the common cold could prove fatal to them. This particular form of the condition causes cells to not create ADA, an enzyme essential for the production of the white blood cells which are a vital component of a healthy, normally-functioning immune system.

Approximately 15 percent of all SCID patients are ADA-deficient, according to the university, and these youngsters are typically treated by being injected twice per week with the required enzyme. This is a process that must continue throughout a patients entire life, and even then it doesnt always work to bring their immune systems to optimal levels. Alternately, they could undergo bone marrow transplants from matched siblings, but those matches are rare and the transplanted cells themselves are often rejected by the childs body.

Dr. Kohn and his colleagues tested two therapy regimens on 18 ADA-deficient SCID over the course of two multi-year clinical trials starting in 2009. During the trials, the blood stem cells of the patients were removed from their bone marrow and genetically modified in order to correct the defect. All 18 of the patients were cured.

The technique used a virus delivery system first developed in Dr. Kohns laboratory in the 1990s a technique which inserts the corrected gene that produces the ADA into the blood forming stem cells in the bone marrow. The genetically corrected blood-forming stem cells will then produce the T-cells required to combat infections.

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New Stem Cell Treatment Found To Cure 'Bubble Baby' Disease

Gene therapy developed at St. Jude Children's Research Hospital, University College London (UCL) and the Royal Free Hospital has transformed life for men with a severe form of hemophilia B by providing a safe, reliable source of the blood clotting protein Factor IX that has allowed some to adopt a more active lifestyle, researchers reported. The results appear in the November 20 edition of The New England Journal of Medicine.

In this study, participants received one of three doses of gene therapy that used a modified adeno-associated virus (AAV) 8 as the vector to deliver the genetic material for making Factor IX. The vector was administered as a single infusion into a peripheral vein in the arm of each participant.

Factor IX levels rose in all 10 men with severe hemophilia B following gene therapy and have remained stable for more than four years. Overall, episodes of spontaneous bleeding declined 90 percent. Use of Factor IX replacement therapy dropped about 92 percent in the first 12 months after the treatment with the investigational therapy.

In the six participants who received the highest gene therapy dose, levels of the blood-clotting protein increased from less than 1 percent of normal levels to 5 percent or more. The increase transformed their disease from severe to mild and enabled participation in sports such as soccer without the need for Factor IX replacement therapy or an increase in the risk of bleeding. Episodes of spontaneous bleeding and use of Factor IX replacement therapy declined for these patients more than 94 percent in the next 12 months.

Liver enzymes rose in four of the six patients who received the highest dose, possibly due to an immune response against the vector. The men had no symptoms and remained otherwise healthy. Their liver enzymes returned to the normal range following brief treatment with steroids.

Hemophilia B is caused by a mutation in the Factor IX gene that can result in dangerously low levels of the essential clotting protein. The disorder affects about 1 in 30,000 individuals, mostly men. For those with severe disease marked by Factor IX levels less than 1 percent of normal, scrapes and bumps are medical emergencies. Painful episodes of spontaneous bleeding can result in crippling joint damage early in life and an increased risk of potentially fatal bleeding within the brain.

"This study provides the first clear demonstration of the long-term safety and efficacy of gene therapy," said senior author Andrew Davidoff, M.D., chair of the St. Jude Department of Surgery. "The results so far have made a profound difference in the lives of study participants by dramatically reducing their risk of bleeding."

The paper's first and corresponding author, Amit Nathwani, M.D., Ph.D., added: "The data we are reporting mark a paradigm shift in treatment of hemophilia B and lay the groundwork for curing this major bleeding disorder." Nathwani is a faculty member at the UCL Cancer Institute, Royal Free Hospital and NHS Blood and Transplant. "The results also provide a solid platform for developing this gene transfer approach for treatment of other disorders ranging from other congenital clotting deficiencies like hemophilia A to inborn errors of metabolism such as phenylketonuria."

Prior to receiving gene therapy, seven of the 10 men received Factor IX replacement therapy at least once a week in order to prevent bleeding episodes. Others used replacement therapy as needed to halt bleeding or prior to surgeries.

Since joining the trial, four of the seven men ended the routine Factor IX injections. None have suffered spontaneous bleeding despite increased physical activity. "Some patients have not required clotting factor injections for more four years, which has been life changing," Nathwani said. Researchers estimated that overall spending on Factor IX replacement therapy for study participants is down more than $2.5 million.

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Gene therapy provides safe, long-term relief for patients with severe hemophilia B