Category Archives: Gene Medicine

Sept. 28, 2014, 12:15 a.m.

This month the Federal Court decided that private companies have the right to control human genes in an important test case. A sensible win for private investment in research or a scary corporatisation of our shared genes? Jane Lyons sequences the debate.

This month the Federal Court decided that private companies have the right to control human genes in an important test case. A sensible win for private investment in research or a scary corporatisation of our shared genes? Jane Lyons sequences the debate.

Q. What was the "breast-cancer gene" court case about?

A.Social justice law firm Maurice Blackburn, which launched the court case in 2010, has gone two rounds with US biotech behemoth Myriad Genetics to invalidate its Australian patent for a mutation of the BRCA1 gene. This gives the patent holder a monopoly over the breast and ovarian cancer gene itself as well as its diagnostic test.

It lost the first Federal Court round last year and copped another beating in the appeal this month. But while this case was ostensibly about one patent, both sides have had their eyes firmly on the bigger prize.

For Maurice Blackburn, the BRCA1 case tests the controversial practice of gene patenting, which has been happening in Australia since the 1990s and has never been legally challenged here.

The lawyers arguethe practiceis based on an invalid premise:that isolating a gene from the body makes it an "artificial state of affairs" and therefore an invention (which can be protected by a patent), rather than a discovery (which cannot).

Their problem with these patents? Monopolies, higher test costs for patients, the stifling of genetic research and the questionable ethics of a company owning the rights to our genes.

Over in the other corner, Myriad has been fighting not only for its future but also for the biotech industry, which has anxiously watched the outcome. Myriad's 20-year BRCA1 patent expires next August, but it has more gene-patent irons in the fire. It argues that the isolation and chemical modification of BRCA1 needed to analyse it in the laboratory makes it an innovation worthy of patent protection.

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Explainer: cancer gene legal case a win for corporate medicine or common sense?

Pfizer Inc. (PFE)s Xalkori for advanced lung cancer shrunk tumors in those with a rare genetic mutation, according to a study that may provide the first targeted treatment for these patients.

Xalkori reduced the size of tumors in 36 of 50 patients in the study while halting tumor growth in another nine, according to company-funded research released today at the European Society for Medical Oncology meeting in Madrid and online in the New England Journal of Medicine.

About 15,000 people, or 1 percent of the estimated 1.5 million annual new cases of non-small-cell lung cancer, have an abnormality to the ROS1 gene, according to New York-based Pfizer. Todays findings also showed that Xalkori was effective for about 18 months in patients, longer than the average eight to 12 months seen for some other targeted treatments, said Alice Shaw, a lead study author.

Were seeing much longer durations of remissions, Shaw, an associate professor of medicine at Harvard Medical School and Massachusetts General Hospital in Boston, said in a telephone interview. This points to being a very good target in lung cancer and this drug being a very effective targeted therapy for these patients.

Xalkori helps shut off the ROS1 gene that is causing cancer tumors to grow, she said. It was approved in 2011 to treat non-small-cell lung cancers in patients with mutations to the ALK gene, which has structural similarities to the ROS1 gene. The National Comprehensive Cancer Network, an alliance of 25 cancer centers, already recommends that doctors use Xalkori in patients who have this gene defect.

Pfizer continues to support clinical research of Xalkori in patients with ROS1 rearrangements to better understand the compounds activity in this population, Sally Beatty, a company spokeswoman, said in an e-mail.

The cancer drug generated $282 million in 2013 sales, according to data compiled by Bloomberg. The drug may produce revenue of more than $812 million in 2017, according to the average of five analysts estimates.

Patients with a mutation to the ROS1 gene are often younger and usually arent smokers, Shaw said.

Todays study is an expansion of the original Phase 1 clinical trial of Xalkori in patients with the ALK gene mutation. Researchers enrolled 50 patients who were ROS1 positive starting in late 2010 through August 2013. Those in the study received Xalkori two times daily.

By the end of the trial, half of the patients were still getting Xalkori and had no signs of their tumors growing, the authors said.

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Pfizers Lung Cancer Drug Helps Patients With Gene Defect

PUBLIC RELEASE DATE:

25-Sep-2014

Contact: Leslie Ridgeway lridgewa@usc.edu 323-442-2823 University of Southern California - Health Sciences

LOS ANGELES Keck Medicine of USC scientists have discovered new clues about a drug instrumental in treating a certain blood cancer that may provide important targets for researchers searching for cures.

The team investigated whether demethylation of gene bodies induced by the drug 5-Aza-CdR (decitabine), which is used to treat pre-leukemia, could alter gene expression and possibly be a therapeutic target in cancer.

"When we put the drug in cancer cells, we found it not only reactivated some tumor suppressor genes, but it down-regulated the overexpressed oncogene (cancer gene)," said Gangning Liang, Ph.D., associate professor of research, Keck School of Medicine of USC Department of Urology, who is corresponding author on the research. "Overexpression is what turns cancer 'on.' The mechanism by which the drug accomplishes this dual action is by removing DNA methylation in the gene body, which we didn't expect."

DNA methylation is an epigenetic signaling tool used by cells use to turn genes off. DNA methylation is an important component in many cellular processes, including embryonic development. Mistakes in methylation are linked to several human diseases, including cancer.

The research builds upon past research by Peter Jones, Ph.D., D.Sc., former director of the USC Norris Comprehensive Cancer Center, Distinguished Professor of Urology and Biochemistry & Molecular Biology, and now director of research at the Van Andel Institute.

"The beginnings of epigenetic therapy, which is now the standard of care for myelodysplastic syndrome, can be traced back to the discovery of the DNA demethylating effects of 5-Azacytidine at Children's Hospital Los Angeles in 1980," Jones said. "Since that time we have always assumed that the drugs act by switching genes on, thus reapplying the 'brakes' to cancer cells. In this paper we show that they may also work by turning down the levels of genes, which have become overexpressed in cancer. In other words, they may also decrease the 'gasoline' and this two pronged mechanism, which was entirely unexpected, may help explain why patients respond to epigenetic therapy."

The research, "Gene body methylation can alter gene expression and is a therapeutic target in cancer," was published online Sept. 25, 2014 in Cancer Cell.

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USC researchers discover dual purpose of cancer drug in regulating expression of genes

PUBLIC RELEASE DATE:

25-Sep-2014

Contact: Sandy Van sandy@prpacific.com 808-526-1708 Cedars-Sinai Medical Center @cedarssinai

LOS ANGELES (Sept. 25, 2014) Investigators at the Cedars-Sinai Board of Governors Regenerative Medicine Institute have received a grant from the National Institutes of Health to participate in a consortium taking the study of motor neuron disorders such as Lou Gehrig's disease and spinal muscular atrophy to a new, comprehensive perspective.

"We will be working as part of an NIH initiative to create databases of disease 'signatures' by generating and analyzing thousands of data points. Scientists often focus on very small things, such as a single signaling pathway in cells or a single gene or protein that is involved in some way with disease development, but identifying and correcting one component rarely leads to a cure. This is especially true in the brain because its networks are very complex," said Clive Svendsen, PhD, professor and director of the Board of Governors Regenerative Medicine Institute, principal investigator of Cedars-Sinai's part of the study.

Svendsen, the Kerry and Simone Vickar Family Foundation Distinguished Chair in Regenerative Medicine, compares this shift in perspective to the way meteorologists began predicting weather years ago viewing global trends and collecting vast amounts of data to create a forecast for a specific place and time.

The grant is part of an NIH initiative called the Library of Integrated Network-based Cellular Signatures, or LINCS, program, which aims to develop a "library" of molecular signatures that describes how different cells respond to proteins, genes, chemicals essentially anything that may come in contact with or change the cell or its activity.

Cedars-Sinai is a member of a group, NeuroLINCS, studying motor neuron disorders, which include Lou Gehrig's disease, also known as amyotrophic lateral sclerosis, or ALS, and spinal muscular atrophy. The NeuroLINCS study will be coordinated by researchers at the University of California, Irvine, with additional collaborators at the Gladstone Institutes at the University of California, San Francisco, Johns Hopkins University and the Broad Institute.

NeuroLINCS is one of six consortiums recently funded through NIH's LINCS program to study diabetes, cancers and other diseases using cell lines and specialized stem cells called induced pluripotent stem cells. Derived from a patient's own skin samples and "sent back in time" through genetic manipulation to an embryonic state, these cells can be made into any cell of the human body.

The Board of Governors Regenerative Medicine Institute, which has developed a national reputation for the quality of its induced pluripotent stem cells, was asked to provide the stem cells for all of the consortiums. The cells are produced in the Regenerative Medicine Institute's Induced Pluripotent Stem Cell Core Facility, directed by Dhruv Sareen, PhD, assistant professor of biomedical sciences and faculty research scientist with the Department of Biomedical Sciences.

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With NIH grant, Cedars-Sinai helps bring big data to neuro disease research

Drug Des Devel Ther. 2008; 2: 115122.

Published online Feb 6, 2009.

1 Division of Pathology, Chiba Cancer Center Research Institute

2 Division of Gastroenterological Surgery, Chiba Cancer Center, Chiba, Japan

3 Department of Environmental Biochemistry

4 Department of Diagnostic Pathology

5 Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan

Loss of p53 function compromises genetic homeostasis, which induces deregulated DNA replication, damages DNA, and subsequently results in increased resistance to anticancer agents. Pharmacological approaches using recombinant adenoviruses (Ad) have been developed to restore the p53 functions. Another approach for gene medicine is to modify Ad replication in a tumor-specific manner, which induces tumor cell death without damaging normal tissues in the vicinity. The Ad-derived gene medicines, Ad expressing the wild-type p53 gene and replication-competent Ad defective of the E1B-55kDa gene, have been tested for their clinical feasibility and became commercially available in China. These agents demonstrated their antitumor activities as a monotherapy and in combination with conventional chemotherapeutic agents. In this article, we summarize the outcomes of clinical trials in China, most of which have been published in domestic Chinese journals, and discuss potential directions of cancer gene therapy with these agents.

Keywords: gene therapy, cancer, clinical trials, p53, adenovirus, E1B

Cancer is currently one of the main causes of death in Western and Asian societies. Treatments for advanced-stage cancer are often difficult with a limited efficacy despite multimodal therapeutic strategies. Novel approaches are required to improve the prognosis. A molecular targeting with small-sized synthetic chemicals in a certain type of cancer is currently available and furthermore many candidate molecules are under investigation. Gene therapy is also a possible treatment modality and over the past decades has been investigated preclinically and clinically for their feasibility. According to data published in the Journal of Gene Medicine, there have been 1309 approved clinical trials in the world until July 2007 and 66.5% of the trials targeted cancer. Historically, a number of clinical trials have been conducted in the Western world but none of the gene medicines have yet been approved by governmental authorities for commercialization. In contrast, adenoviruses (Ad) expressing the human wild-type p53 gene and Ad defective of the E1B-55 kDa molecule, both of which were originally developed and clinically examined for the efficacy in USA, have been admitted in China. The Ad agents have become the first commercially available gene medicine in the world.

Excerpt from:
Gene medicine for cancer treatment: Commercially available ...

One of the inventors of gene editing says scientists should proceed cautiously before testing it in people.

Feng Zhang

Citing the risk of deadly mistakes, a leading researcher speaking at MIT Technology ReviewsEmTech conferenceon Tuesday said the risks of gene editing need to be better understood before the technology can be used in medical studies.

Feng Zhang, a researcher at MIT, helped invent a powerful new way to alter DNA that he compared in his talk to a search-and-replace function for the genome.

Several startups have already sprung up to turn the technology into new kinds of gene-therapy drugs, including CRISPR Therapeutics and Editas Medicine, a biotechnology company that Zhang cofounded last year with venture capitalists who invested $43 million.

These companies hope to correct diseases, like cystic fibrosis, caused by faulty DNA. In other cases, Zhang said, changing a persons DNA could provide a protective effectfor instance, conferring immunity to HIV.

The concept is very powerful, but to make any correction in the body is very challenging, he said.

Looming over researchers is the 1999 death of Jesse Gelsinger, a volunteer in an early gene therapy study in Pennsylvania. That failure dealt a huge setback to genetic drugs. Later it was shown that such treatments, even when they work, could sometimes cause cancer by making unwanted changes to a persons genome.

One of the early lessons from gene therapy is to go slowly, said Zhang. The lesson is that we need to understand a system carefully before putting it into a person.

Gradually, however, gene therapy has staged a comeback. In 2012, a treatment called Glybera was the first to be approved in Europe. Its not yet for sale in the U.S., but numerous gene treatments are being tested in patients.

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EmTech: Risks of Gene-Editing Drugs Need Study, Pioneer Says

Posted by Jennifer Schutz (@jschutz) 6 day(s) ago

Mayo Clinic Center for Regenerative Medicine Forms Collaboration with National University Ireland Galway

ROCHESTER, Minn. The Mayo Clinic Center for Regenerative Medicine and colleagues at the National University Ireland Galway have signed a formal memorandum of understanding (MOU) to pave the way for joint clinical trials using regenerative therapies.

The MOU follows years of close collaboration with NUI Galways Regenerative Medicine Institute (REMEDI) and the Network of Excellence for Functional Biomaterials (NFB) and will focus on adult stem cell therapy, gene therapy, biomaterials and biomedical engineering. Furthermore, the agreement facilitates ongoing student and staff exchange between Galway and the United States.

MEDIA CONTACT:Jennifer Schutz, Mayo Clinic Public Affairs, 507-284-5005, newsbureau@mayo.edu

Journalists: Sound bites withDr. Windebankare in the downloads.

Anthony Windebank, M.D., deputy director for Discovery, Mayo Clinic Center for Regenerative Medicine, and Professor Timothy OBrien, director of the REMEDI, were among those present at the signing in Galway.

Both the National University Ireland Galway and the Mayo Clinic Center for Regenerative Medicine have laboratories which are compliant with current good manufacturing practice (GMP) regulations as it applies to cell manufacturing, says Professor OBrien. This allows us to initiate joint trials of regenerative therapies that will produce identical cell products.

The U.S. Food and Drug Administration and the European Medicines Agency are making efforts to streamline and facilitate introduction of new therapies on both sides of the Atlantic Ocean. Carrying out these approval processes and completing joint studies will facilitate more rapid introduction of new therapies for patients.

Pictured at the signing: Prof. Lokesh Joshi, Vice President for Research, NUI Galway; Dr. Jim Browne, President, NUI Galway; Dr. Anthony Windebank, Deputy Director for Discovery, Mayo Clinic Center for Regenerative Medicine; and Prof. Tim OBrien, Director of REMEDI NUI Galway.

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Mayo Clinic Center for Regenerative Medicine Forms Collaboration with National University Ireland Galway

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Newswise Philadelphia, Sept. 23, 2014 An international team of scientists has identified a gene mutation that causes aplastic anemia, a serious blood disorder in which the bone marrow fails to produce normal amounts of blood cells. Studying a family in which three generations had blood disorders, the researchers discovered a defect in a gene that regulates telomeres, chromosomal structures with crucial roles in normal cell function.

Identifying this causal defect may help suggest future molecular-based treatments that bypass the gene defect and restore blood cell production, said study co-leader Hakon Hakonarson, M.D., Ph.D., director of the Center for Applied Genomics at The Childrens Hospital of Philadelphia (CHOP).

Hakonarson and CHOP colleagues collaborated with Australian scientists on the study, published online Sept. 9 in the journal Blood.

Were thrilled by this discovery which has advanced our understanding of certain gene mutations and the causal relationship to specific diseases, said study co-leader Tracy Bryan, Ph.D., Unit Head of the Cell Biology Unit at the Childrens Medical Research Institute in Westmead, New South Wales, Australia.

The research team studied an Australian family with aplastic anemia and other blood disorders, including leukemia. Hakonarson and lead analyst Yiran Guo, Ph.D., along with genomics experts from BGI-Shenzhen, performed whole-exome sequencing on DNA from the families and identified an inherited mutation on the ACD gene, which codes for the telomere-binding protein TPP1.

Telomeres, complex structures made of DNA and protein, are located on the end of chromosomes, where they protect the chromosomes stability. They are sometimes compared to plastic tips at the end of shoelaces that prevent the laces from fraying.

Telomeres shorten after each cell division, and gradually lose their protective function. Aging cells, with their shortened telomeres, become progressively more vulnerable to DNA damage and cell death. Separately from the aging process, certain inherited and acquired disorders may shorten telomeres and injure rapidly dividing blood-forming cells produced in bone marrow. This leads to bone marrow failure, one example of which is aplastic anemia.

Bryans team investigated the function of the ACD gene. They determined that the mutation shortened telomeres and interrupted the ability of telomeres to attract the enzyme telomerase, which counteracts telomere shortening and thus protects cells.

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Gene Mutation Discovered in Blood Disorder

Analysis of circulating tumor cells (CTCs) in a mouse model of pancreatic cancer identified distinct patterns of gene expression in several groups of CTCs, including significant differences from the primary tumor that may contribute to the ability to generate metastases. In their study reported in the Sept. 25 issue of Cell Reports, investigators from the Massachusetts General Hospital (MGH) Cancer Center identified several different classes of pancreatic CTCs and found unexpected factors that may prove to be targets for improved treatment of the deadly tumor.

"Our ability to combine a novel microfluidic CTC isolation device, developed here at MGH, with single-cell RNA sequencing has given us new biological insights into these cells and revealed novel avenues to try and block the spread of cancer," says lead author David T. Ting, MD, MGH Cancer Center.

Pancreatic cancer is among the most deadly of tumors because it spreads rapidly via CTCs carried in the bloodstream. The earliest technologies for isolating CTCs from blood samples relied on interactions with known tumor-specific marker proteins, potentially missing cells that did not express those particular markers. The device used in the current study, called the CTC-iChip, enables the isolation of all CTCs in a blood sample, regardless of the proteins they express on their surface, by removing all other components. Since the CTCs collected are in solution, unlike with previous CTC capture devices, they are suitable for advanced RNA sequencing techniques to reveal the gene expression patterns of each individual cell.

Using a well-known mouse model of pancreatic cancer, the researchers first isolated 168 single CTCs from the bloodstreams of five individual mice. Analysis of the RNA transcripts of each CTC revealed several different subsets of CTCs, based on gene expression patterns that were different from each other and from the primary tumor. The largest subset, which the authors call 'classic CTCs,' was found to have elevated expression of a stem cell gene called Aldh1 a2, along with genes characteristic of two basic cell types -- epithelial and mesenchymal -- transition between which has been associated with tumor metastasis. Another gene expressed by almost all classic CTCs, Igfbp5, is only expressed in primary tumor at locations where epithelial cancer cells interface with the supporting stromal cells that provide a nurturing microenvironment, an observation that suggests that those regions may be the source of CTCs.

The research team was most surprised to observe that extracellular matrix (ECM) genes in general -- usually expressed primarily in stromal cells -- were highly expressed in all classic CTCs. Previous studies have suggested that the establishment of metastases depends on the appropriate cellular microenvironment -- 'soil' in which CTCs can plant themselves as 'seeds'- and that the expression of ECM genes is an important aspect of that environment. Expression of ECM genes by CTCs themselves suggests that the blood-borne cells may provide or help prepare their own 'soil.'

Analysis of CTCs from blood samples of human patients with pancreatic, breast or prostate cancer also found elevated expression of several ECM genes. One particular gene, SPARC, was highly expressed in all pancreatic CTCs as well as in 31 percent of breast CTCs. Further experiments revealed that suppressing SPARC expression in human pancreatic cancer cells reduced their ability to migrate and invade tissue, and significantly fewer metastases were generated when SPARC-suppressed pancreatic tumors were implanted into a mouse model, supporting the protein's role in a tumor's metastatic potential.

"Given our limited therapeutic options for pancreatic cancer, understanding the role of the ECM in this tumor seems to be of great importance," says Ting, who is an assistant professor of Medicine at Harvard Medical School. "Much effort has been focused on targeting the microenvironment to improve the efficacy of chemotherapy, and data indicating that environmental stromal cells can enhance a tumor's metastatic ability indicate that ECM proteins are important whether they are produced in stroma or within the tumor cells themselves. Now we need to investigate whether therapeutically targeting ECM can destroy both the tumor microenvironment and CTCs before they have a chance to metastasize."

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The above story is based on materials provided by Massachusetts General Hospital. Note: Materials may be edited for content and length.

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Gene expression patterns in pancreatic circulating tumor cells revealed

Published: Monday, September 22, 2014 at 10:17 p.m. Last Modified: Monday, September 22, 2014 at 10:17 p.m.

Right now a registry is being built through free testing for people in the United States with the two main types of hemophilia A and B. It is gathering information to help in their clinical care and to advance scientific research that is expected to lead to new treatments.

Hemophilia is a chronic bleeding disorder in which one of the proteins needed to form blood clots is missing or reduced. It can cause internal bleeding for long periods. Treatment usually involves a patient injecting himself with the missing clotting factor regularly as prevention or to stop an episode of bleeding. The condition usually occurs in males, with rare exceptions.

The program, known as "My Life, Our Future," is a partnership of the National Hemophilia Foundation, the Puget Sound Blood Center in Seattle, the pharmaceutical company Biogen Idec and the American Thrombosis and Hemostasis Network. It offers free genotyping to patients getting care at hemophilia treatment centers around the country.

In each sample, the genetic makeup of each person will be noted, including the clotting-factor mutations that are part of their type of hemophilia. Genes in hemophilia A have a factor VIII deficiency; hemophilia B has a factor IX deficiency.

Hematologist Barbara A. Konkle, director of clinical and translational research at Puget Sound, said recently that more than 1,000 patients have enrolled in the program. Once 5,000 people agree to participate in the research, scientists can apply to study the data and samples.

Dr. Konkle said before this, it was thought that only 20 percent of patients had their genotype determined for their hemophilia.

"We increased that. In the last week, we received 100 new samples. Right now we have 46 different hemophilia treatment centers (that) are ready to enroll or are enrolling. We continue to have sites coming on board."

A patient's genotype will be determined in the Puget Sound laboratory and then, with the patient's consent, it will be added to a database of the thrombosis network, where researchers also will have access to phenotypic information how a person's genes are expressed and environmental influences. No data will identify the patient.

"There aren't special therapies for specific genotypes," Dr. Konkle said. "But knowing the genotype can help us understand a couple of things."

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Registry Offers Help for Hemophilia Patients