Mayo-Led Researchers Discover Genetic Variants Modifying Breast Cancer Risk

Individuals with disrupting mutations in the BRCA1 gene are known to be at substantially increased risk of breast cancer throughout their lives. Now, discoveries from an international research team led by Mayo Clinic researchers show that some of those persons may possess additional genetic variants that modify their risk. These new findings enhancing individualized medicine appear in the current Nature Genetics.

"These findings should be useful in helping determine individual risk for breast cancer in BRCA1 carriers," says Fergus Couch, Ph.D., Mayo investigator and senior author of the study. "It also provides insights into hormone-receptor-negative breast cancer in the general population."

Genetic mutations in the BRCA1 gene give carriers of these mutations an increased risk for developing breast cancer. To determine if any genetic variations would modify or alter this risk among large populations of the mutation carriers, the researchers conducted genome-wide association studies (GWAS) that ultimately spanned 20 research centers in 11 different countries.

They first studied 550,000 genetic alterations from across the human genome in 1,193 carriers of BRCA1 mutations under age 40 who had invasive breast cancer and compared the alterations to those in 1,190 BRCA1 carriers of similar age without breast cancer. The 96 single nucleotide polymorphisms (SNPs) discovered were subsequently studied in a larger sample population of roughly 3,000 BRCA1 carriers with breast cancer and 3,000 carriers without cancer. Researchers found five SNPs associated with breast cancer risk in a region of chromosome 19p13.

Further studies of those SNPs in 6,800 breast cancer patients without BRCA1 mutations showed associations with estrogen-receptor-negative disease, meaning cancer in which tumors don't possess estrogen receptors. In another GWAS involving 2,300 patients, the five SNPs also were associated with triple-negative breast cancer, an aggressive form of the disease accounting for about 12 percent of all breast cancer. Triple-negative tumors don't express genes for estrogen or progesterone receptors or Her2/neu. The researchers also found that these SNPs were not related to risk for ovarian cancer in BRCA1 mutations carriers.

By locating these risk-modifying SNPs, the researchers have provided a target for better understanding the mechanisms behind the development of breast cancer. Furthermore, when combined with other risk-modifying SNPs that remain to be identified in ongoing studies by this group, it may be possible to identify certain BRCA1 carriers who are at lower risk of cancer and, also, carriers at particularly elevated risk of cancer who may decide to change their approach to cancer prevention.

Support for the research came from the Breast Cancer Research Foundation, Susan G. Komen for the Cure, the National Institutes of Health, and Cancer Research UK. In addition to first author Antonis Antoniou, Ph.D., of Cambridge University, over 180 individuals and several consortia contributed to the research and are co-authors.
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FDA Approves New Treatment for Late-Onset Pompe Disease

The U.S. Food and Drug Administration approved Lumizyme (alglucosidase alfa) for patients ages 8 years and older with late-onset (non-infantile) Pompe disease, a rare genetic disorder.

Pompe disease occurs in an estimated 1 in every 40,000 to 300,000 births. Its primary symptom is heart and skeletal muscle weakness, progressing to respiratory weakness and death from respiratory failure.

In Pompe disease, a gene mutation prevents the body from making an enzyme, or making enough of the enzyme called acid alpha-glucosidase (GAA), necessary for proper muscle functioning. GAA is used by the heart and muscle cells to convert a form of sugar called glycogen into energy. Without the enzyme action, glycogen builds up in the cells and, ultimately, weakens the heart and muscles.

Lumizyme is believed to work by replacing the deficient GAA, thereby reducing the accumulated glycogen in heart and skeletal muscle cells.

“Pompe disease is a devastating condition without the appropriate treatment,” said Julie Beitz, M.D., director of the Office of Drug Evaluation III in FDA’s Center for Drug Evaluation and Research. “The approval of Lumizyme will provide an important treatment for patients diagnosed later in life with Pompe disease.”

Lumizyme is being approved with a risk evaluation and mitigation strategy (REMS). It will only be available through a restricted distribution system called the Lumizyme ACE (Alglucosidase Alfa Control and Education) Program to ensure that it is used by the correct patient group.

Lumizyme will carry a Boxed Warning because of the risk of anaphylaxis, severe allergic reactions, and immune-mediated reactions.

Currently, the only other treatment for Pompe disease available in the United States is Myozyme, which is also manufactured by Genzyme at its manufacturing facilities in Framingham and Allston Landing, Mass. Myozyme has been in short supply due to limited manufacturing capacity. The manufacturer reserved Myozyme to treat infants and children with Pompe disease because younger patients generally have a much more aggressive form of the disease.

Some adult patients in the U.S. received Lumizyme under a temporary access program. The approval of Lumizyme will ensure that treatment is available for all U.S. adult Pompe patients in need of treatment. Lumizyme is manufactured at Genzyme facilities in Ireland and Belgium.

Lumizyme’s safety and effectiveness have not been evaluated in patients with infantile-onset Pompe disease or in patients ages 8 years and younger with late-onset disease. These patients should be treated with Myozyme, not Lumizyme.

The safety and efficacy of Lumizyme are based on a clinical study in 90 patients, ages 10 years to 70 years, with late-onset Pompe disease. The most commonly reported side effects for Lumizyme were infusion-related reactions and included severe allergic reactions, hives, diarrhea, vomiting, shortness of breath, itchy skin, skin rash, neck pain, partial hearing loss, flushing, pain in extremities, and chest discomfort.

Myozyme and Lumizyme are marketed by Cambridge, Mass.-based Genzyme.

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Studies Investigate Emerging Trends and Treatment Options for Patients With Sickle Cell Disease

/PRNewswire/ -- Sickle cell disease, a condition characterized by deformed and dysfunctional red blood cells, is one of the most common genetic blood disorders affecting millions of people around the world, including more than 70,000 Americans.(1) Research presented today at the 51st Annual Meeting of the American Society of Hematology highlights intriguing studies on the acute danger that the H1N1 pandemic presents for children with this blood disorder, evaluations of both new and standard treatments for common complications of sickle cell disease, and an expansion of the current understanding of hemoglobin expression in red blood cells that may lead to new treatments.

"Treatment for sickle cell disease consists primarily of life-long supportive care, with the only cure being bone marrow transplantation -- a risky procedure that is not readily available for most patients," said Alexis Thompson, MD, PhD, moderator of the press conference and Hematology Section Head at the Children's Memorial Hospital and Associate Professor of Pediatrics, at Northwestern University Feinberg School of Medicine, Chicago. "Therefore, research in this area is particularly important to help ensure that improved therapies continue to be developed and that patients with sickle cell disease have access to the best possible care."

NOTES:

(1) National Heart, Lung, and Blood Institute. Facts About Sickle Cell Anemia. Available at: http://www.nhlbi.nih.gov/health/public/blood/sickle/sca_fact.pdf.

Control of Hemoglobin Switching by BCL11A [Abstract #5]

As infants develop in the womb, the gamma-globin gene produces a fetal form of hemoglobin, the protein inside red blood cells that carries oxygen. Shortly after birth, a switch to beta-globin gene expression normally occurs, which leads to the production of adult hemoglobin. Both fetal and adult hemoglobin function similarly, though fetal hemoglobin has a greater affinity for binding with oxygen.

Patients with sickle cell disease have a defective form of adult hemoglobin that causes their red blood cells to become deformed and sickle shaped. As a result, the cells are unable to efficiently carry oxygen to the body's tissues and often stick together and jam vessels, causing blood flow obstruction and episodes of severe pain. If a patient with sickle cell could continue production of the fetal hemoglobin and produce less of their defective adult sickle hemoglobin, many of their complications could possibly be reduced or eliminated. A team of researchers from Harvard Medical School in Boston studied the therapeutic possibility of turning the genetic "switch" back on for the production of fetal hemoglobin to replace the defective adult hemoglobin and alleviate these devastating symptoms.

In previous studies, a gene called BCL11A was found to be involved in blocking the expression of fetal hemoglobin in adults. To test these findings in vivo and investigate the role of BCL11A in hemoglobin regulation at different developmental stages, the researchers performed genetic tests in both embryonic and adult mice that were genetically engineered to carry a complete human beta-globin gene cluster capable of producing adult hemoglobin.

In the embryonic mice, inactivation of the BCL11A gene led to a robust expression of gamma-globin (the fetal form of hemoglobin) during late gestation: more than 90 percent of the globin produced was of this type. Tissue-specific deletion of the BCL11A gene in the adult mice (8-10 weeks old) resulted in an increase of more than 1,000-fold in gamma-globin gene expression in the bone marrow erythroblasts (the precursors to red blood cells) of the experimental mice in comparison to control mice. This increase in the gamma-globin expression after inactivation of BCL11A was rapid and persisted during the course of the experiments (up until the mice were 25 weeks old).

"Currently, there are only a limited number of therapies available for patients with sickle cell disease and thalassemia, another disorder involving abnormal hemoglobin," said senior study author Stuart H. Orkin, MD, David G. Nathan Professor of Pediatrics at Dana-Farber Cancer Institute, Children's Hospital Boston, and Harvard Medical School in Boston. "This research opens up a new avenue for treatment, a way to genetically activate healthy fetal hemoglobin in the red blood cells of patients with these lifelong blood disorders."


Hydroxyurea in Children With Sickle Cell Disease: Practice Patterns and Barriers to Utilization

[Abstract #242]

Sickle cell disease is often marked by episodes of severe and incapacitating pain called vaso-occlusive painful events, which can sometimes require hospitalization. Hydroxyurea, an oral drug that is most commonly taken once daily, was approved by the U.S. Food and Drug Administration for use in sickle cell disease patients in 1998. While hydroxyurea remains the standard of care for reducing these painful events in adults, little is known about its practice patterns in children. Researchers from the Medical College of Wisconsin and Children's Research Institute of the Children's Hospital of Wisconsin in Milwaukee investigated the patterns and barriers to hydroxyurea use in children with sickle cell disease.

In this study, researchers surveyed members of the American Society of Pediatric Hematology/Oncology about their practices and patients. Of the 1,128 surveys disseminated, 31 percent (350 surveys) were returned.

To standardize and increase the quality of care for both adults and children with sickle cell disease, the National Heart, Lung, and Blood Institute (NHLBI) provides clinical practice guidelines for the management of this blood disorder. Most of the survey respondents had heard of (87 percent) and read (78 percent) these guidelines, and provider utilization of hydroxyurea correlated with awareness of the NHLBI recommendations.

The survey found that only 8 percent of providers had half or most (50 to 90 percent) of their pediatric patients with sickle cell disease on hydroxyurea. Another 54 percent of providers had 10 to 30 percent of pediatric patients on the therapy, and 10 percent of providers had fewer than 10 percent of pediatric patients on hydroxyurea. Although a majority of providers (90 percent) felt that hydroxyurea was effective or very effective for the prevention of pain, some still did not prescribe the drug to eligible children because of apprehension about future reproductive issues (birth defects and infertility in males), despite insufficient evidence to support this concern. Low patient compliance was cited by 86 percent of providers as another reason they did not prescribe hydroxyurea. Providers reported that children and their families refused hydroxyurea because of a fear of cancer or other possible side effects, concerns that the drug would not work, compliance with required laboratory monitoring, or because they simply did not want to take medication.

The study also found that many providers prescribed hydroxyurea for reasons other than that for which it was intended, despite insufficient evidence of its efficacy for other complications of the disease.

"Our survey suggests a substantial variation in hydroxyurea utilization in children with sickle cell disease with barriers to its use found on the part of both providers and patients," said lead study author Amanda M. Brandow, DO, MS, Assistant Professor of Pediatrics at the Medical College of Wisconsin and the Children's Research Institute of the Children's Hospital of Wisconsin in Milwaukee. "To alleviate this problem, future research in the following areas may help: continued funding of studies to determine the efficacy of hydroxyurea for complications other than pain, evaluating unconfirmed toxicities of the drug that influence practice, exploring how access to care contributes to noncompliance, and research on methods to promote patient adherence to recommended medical care."

Dr. Brandow will present this study during an oral session on Monday, December 7, at 7:15 a.m. in Room 388-390.

Increased Severity of Pandemic H1N1 Influenza in Children and Young Adults With Sickle Cell Disease [Abstract #264]

Patients with sickle cell disease are more susceptible to infection than the general population. In particular, influenza, a viral disease that affects the respiratory system, is more than 50 times more frequent in children with sickle cell disease than in the general population, according to research conducted by John J. Strouse, MD, PhD, the lead author on this study, and colleagues. As H1N1 influenza, which began circulating in the United States in April 2009, has been reported to cause more severe illness in children and young adults than seasonal flu, researchers from The Johns Hopkins University School of Medicine in Baltimore sought to compare the clinical characteristics and complications associated with these infections in sickle cell disease patients under the age of 21 through a prospective analysis of patient discharge and billing records from September 1993 through July 2009.

During the study period, 99 patients who were seen at The Johns Hopkins Hospital in Baltimore were identified as having both sickle cell disease and influenza (89 with seasonal influenza and 10 with H1N1 influenza). Clinical symptoms, such as fever, cough, and runny nose, were similar between the two groups, although those with H1N1 influenza were at an estimated three-fold increased risk for life-threatening complications, such as acute chest syndrome (a severe lung illness), and nine times more likely to require intensive care, such as ventilator support.

"Our findings underscore that receiving a vaccination against H1N1 influenza, in addition to seasonal influenza, is extremely important for the health and safety of children and young adults with sickle cell disease," said lead author John J. Strouse, MD, PhD, Assistant Professor of Pediatrics and Medicine at The Johns Hopkins University School of Medicine in Baltimore.

Dr. Strouse will present this study in an oral session on Monday, December 7, at 8:15 a.m. in Room 220-222.

Safety and Efficacy of Sildenafil Therapy for Doppler-Defined Pulmonary Hypertension in Patients With Sickle Cell Disease: Preliminary Results of the Walk-PHaSST Clinical Trial [Abstract #571]

As patients with sickle cell disease have a high rate of hemolysis (red blood cell destruction), excessive amounts of hemoglobin are released into the blood stream that react with and destroy nitric oxide, a critical regulator that dilates blood vessels and inhibits clotting. This can lead to pulmonary hypertension, or abnormally high blood pressure in the arteries of lungs that also affects the heart. Approximately 10 to 30 percent of patients with sickle cell disease are suspected to have this life-threatening condition.

While the oral drug sildenafil (known as Revatio®) is approved to treat pulmonary arterial hypertension, it is unknown whether it is a safe and effective treatment for pulmonary hypertension in those with sickle cell disease. Therefore, a 16-week, double-blind clinical trial, known as the Walk-PHaSST study (treatment of Pulmonary Hypertension and Sickle cell disease with Sildenafil Therapy) was conducted in 10 medical centers in the United States and United Kingdom to test this application in adults and children over 12 years of age with sickle cell disease.

Before starting treatment, potential study participants were given baseline tests, including a Doppler echocardiogram and a six-minute walk test to measure heart and lung function. Seventy-four patients who had a tricuspid regurgitant jet velocity (TRV) of greater than or equal to 2.7 m/s (a sign of suspected high pulmonary blood pressure) and a six-minute walking distance of only 150-500 meters (reflecting decreased exercise capacity) were included in the study. The researchers then randomly assigned the study participants into two groups of 37 patients each. Half of the patients were treated with sildenafil at escalating doses from 20, 40, and 80 mg three times per day, and the other half received a placebo three times per day. In previous studies of patients with primary pulmonary hypertension, the highest dose of sildenafil (80 mg) had the greatest effect on blood circulation; however, to monitor for possible adverse effects associated with escalating doses, the sildenafil doses in this study were increased slowly, with dose increases made every four weeks.

The study was prematurely stopped when a significant number of the patients in the sildenafil treatment arm (46 percent) began experiencing serious side effects (primarily sickle cell pain crises requiring hospitalization), compared with only 22 percent of those in the placebo arm. Headache and blurred vision, which were expected side effects of sildenafil, were also experienced. The patients in the sildenafil group had more headaches (27 percent versus 14 percent) and more blurred vision (11 percent versus 3 percent) than the placebo group.

Prior to stopping the study, 33 patients had completed the 16-week assessment and were found to have no change in TRV value or in the walking distance test. On pain questionnaires, patients on the sildenafil treatment also reported worsening pain during walking and less enjoyment of life when compared to the patients on placebo.

"Although sildenafil is approved by the U.S. Food and Drug Administration and by the European Medicines Agency for patients with pulmonary arterial hypertension, the Walk-PHaSST study was prematurely stopped for safety concerns. However, these preliminary data should not be interpreted as implying that sildenafil may not be efficacious and safe in select sickle cell patients with documented pulmonary hypertension who are at low risk for vaso-occlusive events," said lead study author Mark Gladwin, MD, Chief of the Division of Pulmonary, Allergy, and Critical Care Medicine and Director of the Vascular Medicine Institute at the University of Pittsburgh Medical Center. "Further investigations are critically needed to find a safe and effective treatment for this patient population at high risk for death from this debilitating condition."

Dr. Gladwin will present this study in an oral session on Monday, December 7, at 2:45 p.m. in Room 220-222.

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New Rules Protect Patients' Genetic Information

Individuals' genetic information will have greater protections through new regulations issued today by the U.S. Departments of Health and Human Services (HHS), Labor, and the Treasury.

The interim final rule will help ensure that genetic information is not used adversely in determining health care coverage and will encourage more individuals to participate in genetic testing, which can help better identify and prevent certain illnesses.

"Echoing the late Senator Ted Kennedy, our efforts to protect Americans undergoing genetic testing from having the results of that testing used against them by their insurance companies is one of the 'first major new civil rights' of the new century," said HHS Secretary Kathleen Sebelius. "Consumer confidence in genetic testing can now grow and help researchers get a better handle on the genetic basis of diseases. Genetic testing will encourage the early diagnosis and treatment of certain diseases while allowing scientists to develop new medicines, treatments, and therapies."

The interim final rule with request for comments and the notice of proposed rulemaking implement Title I of the Genetic Information Nondiscrimination Act of 2008 (GINA). Under GINA, and the interim final rule, group health plans and issuers in the group market cannot:
increase premiums for the group based on the results of one enrollee's genetic information; deny enrollment; impose pre-existing condition exclusions; or do other forms of underwriting based on genetic information. In the individual health insurance market, GINA prohibits issuers from using genetic information to deny coverage, raise premiums, or impose pre-existing condition exclusions.

Further, under GINA and the new interim final regulations, group health plans and health insurance issuers in both the group and individual markets cannot request, require or buy genetic information for underwriting purposes or prior to and in connection with enrollment.
Finally, plans and issuers are generally prohibited from asking individuals or family members to undergo a genetic test.

"Today's genetic technologies yield data that are vital to helping Americans make personal, medical decisions. It is essential that we protect such information and ensure it is not misused by health plans or insurers," said Labor Secretary Hilda L. Solis. "The rules issued today protect individuals against the unwarranted use of information related to their personal health because no one should have to fear that disclosure of their medical data will put their job or health coverage at risk."

Additionally, HHS, through its Office for Civil Rights (OCR), issued a notice of proposed rulemaking with a 60-day comment period, to propose changes to the Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule to prohibit health plans from using or disclosing genetic information for underwriting purposes.

The proposed rule published today modifies the HIPAA Privacy Rule pursuant to GINA Title I to clarify that genetic information is health information and to prohibit the use and disclosure of genetic information by covered health plans for eligibility determinations, premium computations, applications of any pre-existing condition exclusions, and any other activities related to the creation, renewal, or replacement of a contract of health insurance or health benefits. In combination with the new penalties for violations of the HIPAA Privacy Rule, as provided for by the American Recovery and Reinvestment Act of 2009, a use or disclosure of genetic information in violation of the HIPAA Privacy Rule could result in a fine of $100 to $50,000 or more for each violation.

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The HRSA Genetics Collaboratives are Bringing Genetic and Newborn Screening Services to Local Communities Around the United States

/PRNewswire/ -- Overcoming the challenges of bringing quality and cutting edge genetic and newborn screening (NBS) services to local communities and to children and families with hereditary diseases is extremely complex. It requires coordinated, multifaceted and multidisciplinary efforts that are national, regional, and local and include public, private and not-for-profit partnerships. In order to meet these challenges, the Health Resources and Services Administration/Maternal and Child Health Bureau (HRSA/MCHB) awarded the American College of Medical Genetics (ACMG) a cooperative agreement in 2004 and later renewed it until 2012 to serve as the National Coordinating Center (NCC) for seven similarly-funded Regional Genetics Collaboratives known as the HRSA Genetics Collaboratives (http://www.nccrcg.org/).

These seven HRSA/MCHB-funded HRSA Genetics Collaboratives and their National Coordinating Center (NCC) are working to improve access to local genetic and newborn screening services, information, and resources for individuals and families with heritable disorders. A major component of the NCC/Genetics Collaboratives system involves using a variety of approaches to link primary care providers, geneticists and other specialist providers, and public health services into a comprehensive medical home that meets all the needs of individuals and families with heritable conditions. Activities at all levels engage consumers and families, with new opportunities for partnerships continually emerging.

"Hundreds of professionals including public health officials, newborn screening program staff members, primary care providers, physician geneticists, genetic counselors, consumer advocates, and families are active in the HRSA Genetics Collaboratives. The Collaboratives are bringing genetic discoveries into local communities in every state in the country and are working hard to improve local access to newborn screening and genetic services for everyone by addressing the unique needs of the community," says Judith Benkendorf, MS, CGC, a genetic counselor and Project Director of the NCC. "Each regional Genetics Collaborative has fostered a variety of approaches to building linkages between public health, genetics specialists, primary care/the Medical Home and families. Some of activities are even being replicated nationally. A benefit of the current coordinated system is that each HRSA Genetics Collaborative has access to national expertise, positioning it to be a 'go to' resource for information about genetic and newborn screening services," added pediatrician Tracy L. Trotter, MD, FAAP, Senior Partner, San Ramon Valley Primary Care.

The NCC also facilitates collaborations between the HRSA Genetics Collaboratives and national projects, using local communities to pilot materials and programs for policymakers, health professionals and families. Many national organizational partners contribute additional resources.

NCC initiatives include:
-- building national capacity in the use of telegenetics;
-- establishing a searchable national network of genetic service and
subspecialty providers experienced in the diagnosis and management of
infants with heritable disorders detected through NBS programs;
-- collecting and disseminating data that establish the value of genetic
services to payers and policymakers;
-- developing disaster preparedness strategies to ensure that NBS
programs and treatment of patients with metabolic conditions are not
interrupted in the case of an emergency;
-- developing and distributing of management guidelines and "just in
time" resources for providers caring for patients with heritable
disorders;
-- addressing the transition of patients with heritable conditions from
pediatric to adult care; and
-- developing resources for state policymakers.

National data collection efforts include tracking pilot NBS programs and establishing and maintaining a patient follow-up database useful in rare disease research. Maximizing collaboration between the genetic services, primary care, NBS and public health communities is critical to the success of each of these efforts and to the collective impact of the NCC and the Genetics Collaboratives.

The Seven Regional HRSA Genetics Collaboratives

Region 1: The New England Regional Genetics Collaborative (NEGC), with CT, MA, ME, NH, RI and VT (www.negenetics.org/)

Region 2: New York-Mid-Atlantic Consortium for Genetic and Newborn Screening Services, with DC, DE, MD, NJ, NY, PA, VA, and WV (www.wadsworth.org/newborn/nymac/)

Region 3: The Southeast NBS and Genetics Collaborative, with AL, FL, GA, LA, MI, NC, SC, TN, PR, and USVI (http://southeastgenetics.org/)

Region 4: The Region 4 Genetics Collaborative with IL, IN, KY, MI, MN, OH, WI (http://region4genetics.org/)

Region 5: The Heartland Regional Genetics and Newborn Screening Collaborative, with AR, IA, KS, MO, ND, NE, OK, and SD (www.heartlandcollaborative.org/)

Region 6: Mountain States Genetics Regional Collaborative Center, with AZ, CO, MT, NM, NV, TX, UT, and WY (www.msgrcc.org/)

Region 7: Western States Genetic Services Collaborative, with AK, CA, HI, OR, WA, and US Pacific Basin (www.westernstatesgenetics.org/)

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HHS Issues Second Report on Personalized Health Care

HHS Secretary Mike Leavitt today released the second report from his
Initiative on Personalized Health Care, examining the potential for new
findings in genetics and other molecular-level medicine to improve the
quality and cost-effectiveness of health care.

The report, "Personalized Health Care: Pioneers, Partnerships,
Progress," includes reports from 10 institutions where personalized
health care techniques are beginning to be used. It also includes seven
commissioned papers examining the opportunities and challenges for
personalized health care from the perspectives of different stakeholders
in the health care sector.

"These sample case studies reflect a broad scope of approaches that are
already being tried, as well as partnerships for achieving higher levels
of effectiveness and personalization in health care," Secretary Leavitt
writes in a "Prologue" chapter in the report.

Personalized health care envisions medical care that is increasingly
differentiated between patients based on variations in their individual
biology. For example, differences in metabolism or other factors cause
a given prescription medication to work well with some individuals, but
not others. By measuring such individual variations in patients before
prescribing, drugs could be used more safely, effectively and at lower
cost.

Genetic and molecular medicine should also help spot diseases before
symptoms appear, enabling treatments to delay or preempt the disease and
avoid costly late-stage treatments. Personal genomic profiles may also
enable patients to learn their particular predisposition to disease and
take more effective disease prevention steps.

Secretary Leavitt says in the report that the potential for personalized
health care techniques to improve health and increase value in health
care make personalized health care a factor that should be targeted as
part of any plan to reform the nation's health care system. In
addition, current models of paying for health care, which reward volume
of care over value or quality, may hinder promising new avenues that
would avoid expensive late-stage treatments or prevent disease.

Secretary Leavitt launched his special Initiative on Personalized Health
Care in 2006. The report is available at www.hhs.gov/myhealthcare.

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Memories Selectively, Safely Erased in Mice

New and old memories have been selectively and safely removed from mice by scientists.

"While memories are great teachers and obviously crucial for survival and adaptation, selectively removing incapacitating memories, such as traumatic war memories or an unwanted fear, could help many people live better lives," says Dr. Joe Z. Tsien, brain scientist and co-director of the Brain & Behavior Discovery Institute at the Medical College of Georgia School of Medicine.

"Our work reveals a molecular mechanism of how that can be done quickly and without doing damage to brain cells," says the Georgia Research Alliance Eminent Scholar in Cognitive and Systems Neurobiology.

Dr. Tsien's research team, in collaboration with scientists at East China Normal University in Shanghai, were able to eliminate new and old memories alike by over-expressing a protein critical to brain cell communication just as the memory was recalled, according to research featured on the cover of the Oct. 23 issue of Neuron.

Dr. Tsien had already created a mouse that couldn't form memories by eliminating the NMDA receptor, which receives messages from other neurons. He then garnered international acclaim by making "Doogie," a smart mouse in which a subunit of the NMDA receptor is over-expressed. Younger brains have higher amounts of this NR2B subunit which leaves communication channels between brain cells open longer. That is why young people can learn faster than older adults.

This time he was examining downstream cascades of the NMDA receptor to learn more about memory formation. An abundant protein found only in the brain, called αCaMKII, was a logical place to look because it's a major signaling molecule for the NMDA receptor. He found that when he over-expressed αCaMKII while a memory was being recalled, that single memory was eliminated.

Receptors such as the NMDA receptor are like front doors to cells, providing an opening for signaling molecules such as calcium. Synapses are the point of communication between two cells, and NMDA receptors are on the receiving end of the message. Like people, neurons change with the signals they receive. "Learning changes the way cells connect to each other," says Dr. Tsien. To form a memory, the NMDA receptor is activated, which results in the insertion of AMPA receptors into those synapses and subsequent strengthening of the synaptic connections among hundreds of thousands of neurons. Scientists believe that αCaMKII plays an important role in the insertion of AMPA receptors into synapses during learning and subsequent strengthening of connections between neurons to create a memory.

Memory has four distinct stages: learning, consolidation, storage and recall. It has been difficult to dissect the molecular mechanisms of these stages because researchers lacked techniques to manipulate proteins quickly. For example, when researchers disable a gene suspected to play a role in the memory process, the deletion typically occurred throughout the entire period so it was impossible to tell which parts of processes were impaired. Previous technology would take several days to switch off a protein, which is the product of a gene.

So Dr. Tsien’s team developed a powerful chemical-genetic method that allows him to use a pharmacologic inhibitor to instantly turn αCaMKII off and on in a mouse that he genetically engineered to over express this signaling molecule. That enabled him to study exactly what happened if he threw off the natural balance during the retrieval stage.

Much as a war veteran remembers a fateful patrol when he was fired upon, mice can establish a very long-lasting emotional memory about a place if, for example, they receive a mild shock to the paws while there. The researchers showed if they over-expressed αCaMKII, this powerful memory was rapidly erased as the animals tried to retrieve them while other memories remained intact.

A similar approach was taken with object recognition memory, giving mice a couple of toys to play with then erasing their memory of one of them. "You will feel like every time, it's a new toy," says Dr. Tsien.

While the ability to rapidly erase a selective memory is exciting, he cautions that its translation to humans would be difficult at this stage. “We are barely at the foot of a huge mountain,” says Dr. Tsien. A possible strategy for humans would be a drug that mimics the αCaMKII over expression that researchers accomplished through genetic manipulation. Or, further downstream substrates that αCaMKII acts upon could become possible drug targets.

The research was funded by the National Institute of Mental Health, the National Institute on Aging and the Georgia Research Alliance.

By Toni Baker

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FDA Licenses for Marketing New Therapy for Rare Genetic Disease

The U.S. Food and Drug Administration today licensed for marketing the first product in the United States intended to protect people with hereditary angioedema (HAE), a rare and potentially life-threatening genetic disease. HAE affects about 6,000 to 10,000 individuals in the United States.

The product, called Cinryze, is licensed for the prevention of HAE attacks, which can occur spontaneously or during stress, surgery, or infection in patients diagnosed with the disease. Attacks can produce rapid swelling of the hands, feet, limbs, face, intestinal tract or airway. Swelling of the larynx can lead to asphyxiation.

"Cinryze should greatly enhance treatment options for those with hereditary angioedema and potentially save lives," said Jesse Goodman, M.D., M.P.H., director of the FDA’s Center for Biologics Evaluation and Research.

Cinryze is a C1-esterase inhibitor product derived from human plasma. This plasma protein regulates clotting and inflammatory reactions that, when impaired, can lead to local tissue swelling. C1-esterase inhibitor is low or does not function properly in individuals with HAE. In clinical trials, Cinryze was effective in preventing or decreasing the frequency of attacks in most but not all HAE patients. Adverse reactions reported in the study were considered mild or moderate in severity.

Cinryze is administered intravenously and can be used every three or four days for routine prevention of HAE attacks. It is manufactured by Lev Pharmaceuticals Inc., New York, N.Y., through a contract manufacturing agreement with Sanquin Blood Supply Foundation in The Netherlands.

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FDA Clears Test that Helps Identify Type of Cancer in Tumor Sample

The U.S. Food and Drug Administration has cleared for marketing a test that can help health care professionals determine what type of cancer cells are present in a malignant tumor.

The Pathwork Tissue of Origin test compares the genetic material of a patient’s tumor with genetic information on malignant tumor types stored in a database.

It uses a microarray technology to analyze thousands of pieces of genetic material at one time. The test considers 15 common malignant tumor types, including bladder, breast, and colorectal tumors.

"The clearance of the Pathwork test is another step in the continued integration of molecular-based medicine into standard practice," said Daniel Schultz, M.D., director of the FDA's Center for Devices and Radiological Health, which oversees medical diagnostics. "In the past, scientists have classified different types of cancers based on the organs in which the tumors develop. With the help of microarray technology, they will be able to classify these types of cancers in a standardized non-reader dependent manner based on the patterns of gene activity in the tumor cells."

The Pathwork Tissue of Origin test is the second in vitro diagnostic multivariate index assay (IVDMIA) device to be cleared by the FDA. In July 2007, the FDA issued a draft guidance document to address premarket pathways and postmarket requirements for IVDMIAs. IVDMIA tests combine the values of multiple variables to yield a single, patient-specific result.

Nearly every cell of the body contains a full set of chromosomes and identical genes but only a fraction of these genes are turned on or expressed in any given cell. Gene expression occurs when certain molecular information contained within DNA is transcribed to create molecules known as RNA. These molecules in turn make the proteins that perform most of the critical functions of cells.

Microarray technology can simultaneously measure gene expression levels of large numbers of genes. Small DNA fragments are placed or arrayed on a slide and then RNA, which has been extracted from the tumor tissue and labeled with a fluorescent marker, is spread over this "microarray."

Since RNA binds to its complementary DNA strand, how much binding occurs indicates how active the gene being evaluated is. This can be determined by putting the array under a scanning microscope and measuring the intensity of the fluorescent light at each point on the array.

Pathwork’s proprietary software converts the scanned image data to gene expression measurements. The gene expression patterns are compared with known gene expression patterns in the database that correspond to different tumor types.

The Pathwork Tissue of Origin test has been found to provide patterns that confirm existing tissue of origin of the 15 common tumor types using standard clinical and pathological information. This accuracy of this test is similar to that achieved by expert pathologists using current standards of practice.

PathChip, the gene expression array used in the Pathwork Tissue of Origin test, is custom-designed for Pathwork Diagnostics of Sunnyvale, Calif., by Affymetrix Inc., of Santa Clara, Calif. PathChip is the first custom Affymetrix gene expression array to be cleared for diagnostic use.