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Research ENews Vol 1 No 8 September 2006 Welcome to the National Information and Advice Centre for Metabolic Diseases Research News Sheet - Vol 1 No 7. The contents of this news sheet has been gathered from around the globe during our research to update our information on metabolic diseases. The contents are general and not specific to our cause.
Shire’s ELAPRASE™ (idursulfase) Approved by the Food and Drug Administration (FDA) for Hunter Syndrome 24 Jul 2006 - Basingstoke, UK and Philadelphia, US – July 24, 2006 – Shire plc (LSE: SHP, NASDAQ: SHPGY, TSX: SHQ) today announced that the FDA has granted marketing approval for ELAPRASE, a human enzyme replacement therapy for the treatment of Hunter syndrome, also known as Mucopolysaccharidosis II (MPS II). Hunter syndrome is a rare, life-threatening genetic condition that results from the absence or insufficient levels of the lysosomal enzyme iduronate-2-sulfatase. Without this enzyme, cellular waste products accumulate in tissues and organs, which then begin to malfunction. ELAPRASE
is the first and only treatment approved for people suffering from Hunter
syndrome. The product, which is given as weekly infusions, replaces the
missing enzyme that Hunter syndrome patients fail to produce in sufficient
quantities. Clinical Trial Results A
53-week, randomized, double-blind, placebo-controlled Phase II/III trial
demonstrated that ELAPRASE provides clinically important benefits to Hunter
syndrome patients. The primary efficacy endpoint of the trial was a
composite analysis of changes from baseline in two clinical measures: a
6-minute walk test and percent predicted forced vital capacity. Shire is
pleased to report that this endpoint achieved statistical significance
compared to placebo. After one year of treatment, patients receiving weekly
infusions of ELAPRASE experienced a mean increase in the distance walked in
six minutes of 35 meters compared to patients receiving placebo. Treatment with ELAPRASE was generally well-tolerated by patients in the Phase II/III trial. Adverse reactions were commonly reported in association with infusions, and were generally mild to moderate.
ELAPRASE
is a purified form of the lysosomal enzyme iduronate-2-sulfatase and is
produced by recombinant DNA technology in a human cell line.
Hunter
syndrome (MPS II) is a serious genetic disorder mainly affecting males that
interferes with the body’s ability to break down and recycle waste
substances called mucopolysaccharides, also known as glycosaminoglycans or
GAG. Hunter syndrome is one of several related lysosomal storage diseases. Friedreich's Ataxia Research Alliance Announces Support From NIH RAID Pilot ProgramJuly 14, 2006 – Washington, D.C. – The Friedreich's Ataxia Research Alliance announced today that the National Institutes of Health has accepted the University of Pennsylvania and Edison Pharmaceuticals into the Rapid Access to Interventional Development (RAID) Pilot Program for the development of Edison Pharmaceuticals EPI-A0001 for Friedreich's Ataxia. Under the NIH Roadmap initiative, the RAID Pilot Program has assembled an inter-institute team consisting of the National Institute of Neurological Disorders and Stroke, the National Institute of Child Health and Human Development and the Developmental Therapeutics Program of the National Cancer Institute that will combine resources and expertise to translate EPI-A0001 into the clinic. This NIH RAID project will provide drug development guidance and resources to enable an Investigative New Drug application to be filed with the Food and Drug Administration – the first step in its regulatory submission process. The Orphan Products Division of the Food and Drug Administration recently awarded EPI-A0001, Orphan Designation status for inherited respiratory chain diseases of the mitochondria. "Our acceptance into the NIH RAID Pilot Program heralds the Friedreich's Ataxia Research Alliance (FARA) entering the era of therapeutic development," stated Ron Bartek, President of FARA. "The benefits of the last 8 years of discovery and clinical research funded by FARA are now beginning to be realized. This translational initiative brings us one step closer to the clinical evaluation of EPI-A0001, and evaluating its potential for arresting the damage done by Friedreich's ataxia. Our goal is to develop a therapy that will stop the devastating progression of Friedreich's ataxia in its tracks. We are grateful to all of the NIH institutes and their personnel who have provided invaluable support for this goal since the inception of FARA." Friedreich's ataxia is an inherited disease. It is caused by a defect in the gene encoding for a protein – frataxin – whose function is essential for biological energy production. In the last 5 years, medical and research communities have shown growing interest in Friedreich's ataxia. This attention is based on a renewed interest in the role that mitochondria play in disease, and an emerging body of literature suggesting that Friedreich's ataxia may share a common mechanism with other neurodegenerative diseases and movement disorders, as well as the aging process. Today, there is no effective treatment or cure available for Friedreich's ataxia. It often first becomes noticeable as a balance and coordination problem in children of elementary school age. Further loss of strength and coordination in all four extremities usually forces those with the disease into wheelchairs by their teens. It is progressive and can lead to impaired vision, speech and hearing. Friedreich's ataxia is also commonly associated with severe heart disease, spinal abnormalities and diabetes. In the later stages of the disorder, patients are frequently incapacitated with cardiac failure leading to death. Friedreich's ataxia, although in relative terms rare, is the most prevalent inherited ataxia, affecting about 1 in every 50,000 people in the United States. About FARAThe Friedreich's Ataxia Research Alliance (FARA) (www.faresearchalliance.org) is a 501(c)(3), non-profit, charitable organization dedicated to accelerating research leading to treatments and a cure for Friedreich's Ataxia. It was founded by Friedreich?s ataxia-affected families and scientists in 1998. Since then, it has provided almost $7 million in grants to scientists around the world who are pursuing treatments. A follow-up study of Lorenzo's Oil confirms that the Oil is effective in delaying the onset of adrenoleukodystrophy (ALD) in boys without symptoms who started the therapy under the age of six. Dr. Hugo Moser of Kennedy Krieger Institute in Baltimore, Maryland, said the results validate those of his earlier international study. The reliability of the results is enhanced by the fact that the original trial and the follow-up study, which used different statistical methods, led to similar conclusions. A further issue that may be addressed through longer follow-up of patients is whether Lorenzo's Oil has the ability to not only delay but avoid completely the onset of childhood ALD.
Gene Mutations Responsible For Rett Syndrome In Females Present Sporadically in Males International study refutes prior theory that faulty gene leads to in utero death in males (Baltimore, MD) — Gene mutations that are responsible for the majority (seventy to eighty percent) of cases of Rett syndrome (RTT) in females are not always lethal in males prior to birth, refuting previous assumptions, and can occur sporadically in infant males without a family history of the disorder. A study published in the journal Neurology reports four sporadic occurrences of MECP2 gene mutations in infant males with progressive encephalopathy. RTT is an X-linked neurodevelopmental disorder that is caused by mutations in the MECP2 gene and is characterized by stagnation of development followed by regression. In an international collaboration, researchers from the United States and Australia identified and evaluated four non-familial, sporadic occurrences of MECP2 gene mutations. Prior to this study, the majority of reported males with MECP2 mutations had a family history of RTT. Based on the results of this study, MECP2 abnormalities should be evaluated in young infant males who develop progressive encephalopathy including respiratory insufficiency, microcephaly, abnormal muscle tone and various movement disorders, as mutations to the gene may be the source of the infant’s neurological problems. “Boys born to families with a history of Rett syndrome are examined very closely for MECP2 mutations, but beyond these families, physicians usually do not test for mutations to the gene,” said Walter E. Kaufmann, M.D., study author and research scientist at the Kennedy Krieger Institute in Baltimore. “Infant males with progressive encephalopathy may go undiagnosed because the prevailing assumption is that males with these mutations die before they are born. We’ve found that this is not the case, and encourage neonatologists and pediatricians to consider MECP2 as a possible cause of severe neurological abnormalities.” All four newly identified cases exhibited common features, including: moderate or severe early postnatal progressive encephalopathy; unexplained central hypoventilation or respiratory insufficiency; abnormal movements; intractable seizures and abnormal tone. Three of the four cases had definitely pathogenic mutations and the fourth was potentially pathogenic. Acute observations and knowledge of the clinical picture of RTT prompted suspicion of MECP2 mutations in the four newly reported cases. “While the findings of this study represent an important step forward in learning more about MECP2 mutations in infant males, many questions still remain regarding the role of the gene and its contribution to the encephalopathy of Rett syndrome,” said Dr. Gary Goldstein, President and CEO of the Kennedy Krieger Institute. “To help answer these and other questions regarding RTT, Kennedy Krieger has played a leading role in organizing an international consortium of scientists from every major Rett center around the world to conduct clinical studies on the diagnosis and treatment of the disorder.”
The consortium, called ‘RettSearch,’ will provide a forum
for scientists to combine research efforts and share results from around the
world. With only 15 cases of MECP2 mutations in infant males currently
identified worldwide, researchers’ observations are limited. Through the
‘RettSearch’ network, which is being coordinated by Dr. Kaufmann, scientists
from Kennedy Krieger and other member institutions hope to identify
additional cases and conduct multi-center trials with both males and females
with MECP2 mutations and RTT.
Rett Syndrome (RTT) is a neurological disorder often
misdiagnosed as autism, cerebral palsy or non-specified developmental delay
caused by a defective regulatory MECP2 gene found on the X chromosome. The
disorder is seen almost exclusively in females. Unlike females, who have two
X-chromosomes, males have an X and a Y chromosome. Because males lack a
"backup" copy of the X chromosome that can compensate for a defective one,
mutations in MECP2 are often lethal to the male fetus. This is why RTT is
found overwhelmingly in females. RTT occurs in a variety of racial and
ethnic groups worldwide and is now known to occur in 1:10,000 to 1:23,000
female births, but incidence may be far greater as new genetic evidence is
discovered. Internationally recognized for improving the lives of children and adolescents with disorders and injuries of the brain and spinal cord, the Kennedy Krieger Institute in Baltimore, MD serves more than 12,000 individuals each year through inpatient and outpatient clinics, home and community services and school-based programs. Kennedy Krieger provides a wide range of services for children with developmental concerns mild to severe, and is home to a team of investigators who are contributing to the understanding of how disorders develop while pioneering new interventions and earlier diagnosis. For more information on Kennedy Krieger Institute, visit www.kennedykrieger.org. Approval granted for Harvard Stem Cell Institute researchers to attempt creation of disease-specific embryonic stem cell lines After more than two years of intensive ethical and scientific review, Harvard Stem Cell Institute (HSCI) researchers at Harvard and Children's Hospital Boston have been cleared to begin experiments using Somatic Cell Nuclear Transfer (SCNT) to create disease-specific stem cell lines in an effort to develop treatments for a wide range of now-incurable conditions afflicting tens of millions of people. As far as is known, this decision marks the beginning of the first noncommercial effort in the United States to use human embryonic stem cells in a series of experiments whose principle has already been proven in animals. The work is being entirely supported with private funds because of the federal restrictions on human embryonic stem cell work. If successful, it will mark a major step forward in the effort to use stem cells to treat chronic diseases. The work will be conducted by two groups headed by HSCI senior investigators: Douglas Melton, co-director of the Harvard Stem Cell Institute and Thomas Dudley Cabot Professor of Natural Science in Harvard's Faculty of Arts and Sciences (FAS), and HSCI principal faculty member Assistant Professor Kevin Eggan, of the FAS Department of Molecular and Cellular Biology; and Harvard Medical School Associate Professor George Daley of Children's Hospital Boston, who has already begun some of his experiments. Melton's work will focus on diabetes; Eggan will initially work with Melton on diabetes, and then plans to focus on neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) - better known as Lou Gehrig's disease. Daley's group will focus on blood disorders. Daley was one of the principal scientists who in 2002 demonstrated in a mouse model the feasibility of using SCNT to treat immune deficiency. Harvard University Provost Steven E. Hyman said during a June 6 telephone press conference that the work has been the subject of "more than two years of thoughtful, intensive review by as many as eight different Institutional Review Boards and Stem Cell oversight committees at five different institutions," including Harvard, Children's Hospital, Partners Health Care, Brigham and Women's Hospital, Boston IVF, and Columbia University. Harvard University President Lawrence H. Summers called the approvals "a seminal event in the University's effort to advance this tremendously promising area of science and fulfill that promise as quickly as possible for the countless patients suffering from diabetes, Parkinson's disease, heart disease, cancers, and a host of other illnesses. "While we understand and respect the sincerely held beliefs of those who oppose this research, we are equally sincere in our belief that the life-and-death medical needs of countless suffering children and adults justifies moving forward with this research," Summers said, referring to the controversy over embryonic stem cell work. The Harvard Stem Cell Institute, co-directed by Melton, a Howard Hughes Medical Institute investigator, and David Scadden, a professor of medicine at Harvard Medical School and director of the Center of Regenerative Medicine at Massachusetts General Hospital, is a unique collaborative effort that includes 99 principal investigators and hundreds of additional scientists in laboratories at Harvard University and at many of Harvard's affiliated hospitals. The institute is dedicated to advancing all forms of stem cell science from laboratory bench to patient bedside as quickly as possible. Somatic Cell Nuclear Transfer involves removing nuclei, which contain the cellular DNA (genes) from egg cells, and replacing them with the nuclei of donor cells. The resulting cell is subject to a chemical, or electrical, charge that triggers cell division and the creation of an embryo genetically identical to the donor of the nuclei. In the HSCI experiments, aimed at understanding diseases, the nuclei will be taken from skin cells donated by patients suffering from diabetes, blood diseases, and neurodegenerative diseases. Further information is available at http://www.news.harvard.edu/gazette/daily/2006/06/06-stemcell.html
Cincinnati Children's Moves Up to Second in Nation In NIH Funding Among Pediatric InstitutionsCincinnati Children's Hospital Medical Center now ranks second in the nation among all pediatric medical centers in research funding from the National Institutes of Health (NIH). For federal fiscal year 2005, Cincinnati Children's received $83.1 million in NIH grants. Cincinnati Children's also ranks 70th among more than 3,400 pediatric and adult institutions nationally. "Cincinnati Children's leadership position in pediatric research means that we also will be leaders in clinical innovation," says Thomas Boat MD, chairman of pediatrics at the University of Cincinnati College of Medicine and director of the Cincinnati Children's Research Foundation. "Ultimately, the result of research is better health for children -- not only in our community but throughout the world." Among the reasons Dr. Boat cites for Cincinnati Children's lofty research rank are:
In addition to proving better health for children, research funding enhances the economic impact on Cincinnati and the state of Ohio through higher levels of employment and new biomedical company formation. For example, technologies owned by Cincinnati Children's in this fiscal year will form the basis of three start-up companies, all of them located in Cincinnati. The Cincinnati Children's Research Foundation was founded in 1931. Its scientists have been responsible for such breakthrough discoveries as the Sabin oral polio vaccine, the first practical heart-lung machine that made open heart surgery possible, and the discovery of key ingredients of the surfactant preparation used throughout the world to save the lives of thousands of premature infants each year. More recently, Cincinnati Children's researchers were responsible for the discovery and testing of a vaccine that prevents rotavirus infection, which kills half a million children throughout the world each year. The vaccine, now known as Rotarix and licensed to GSK, was discovered and tested by David Bernstein MD, director of Infectious Diseases at Cincinnati Children's, and Richard Ward PhD, a scientist in infectious diseases. Rotarix has been licensed in the EU, 15 Latin American Countries and 29 other countries around the world. Cincinnati Children's is currently constructing a new research facility that will provide the lab and office space needed to expand the research programs and recruit new clinical faculty. The research building will be designed to foster collaboration among various scientific disciplines. Groups will be clustered geographically by broad, overlapping interests and themes rather than by academic department or division. For example, researchers from the divisions of immunology and molecular immunology will share space with scientists from hematology/oncology, allergy, rheumatology and other divisions who study the immune system or whose diseases have an important immune component. In the past, divisions and departments would reside in self-contained "silos." When the building is completed in 2007, Cincinnati Children's will have 937,000 square feet of research space. It is believed that Cincinnati Children's will have more research space when the new building opens than any other pediatric medical center in the nation. Cincinnati Children's is a 475-bed institution devoted to bringing the world the joy of healthier kids. Cincinnati Children's is dedicated to transforming the way health care is delivered by providing care that is timely, efficient, effective, family-centred, equitable and safe. Cincinnati Children's ranks third nationally among all pediatric centers in research grants from the National Institutes of Health. It is a teaching affiliate of the University of Cincinnati College of Medicine. The Cincinnati Children's vision is to be the leader in improving child health. Contact InformationJim Feuer, 513-636-4656, jim.feuer@cchmc.org
Penn Researchers Discover “Remote Control” for Expression of Human Growth Hormone Gene Mistakes in Expression Implied in Growth Disorders (Philadelphia, PA) - Researchers at the University of Pennsylvania School of Medicine recently discovered a novel mechanism that works over an extensive genomic distance and controls the expression of human growth hormone (hGH) in the pituitary gland. This mechanism involves a newly discovered set of “non-coding RNAs” expressed in the vicinity of the hGH gene. By examining the relationship between these non-coding RNAs and the hGH gene, researchers hope to understand how these remote regions impact hGH gene expression and dysfunction. Such insight may aid researchers in the development of therapeutics for growth hormone defects and lead to a greater understanding of the causes of other genetic disorders. The human
genome is comprised of both non-coding DNA and coding regions, or genes.
While researchers once believed that only genes were transcribed into
messenger RNA (mRNA), investigators have recently discovered that non-coding
DNA is copied into mRNA as well. Unlike coding mRNAs, which are translated
into functional proteins and peptides, the function of most non-coding RNAs
is unclear. Although non-coding RNAs fail to produce functional proteins,
researchers believe that in some cases these RNAs may control gene
expression.
Synthesized by the pituitary gland, human growth hormone activates growth
and cell reproduction. In addition to serving as a major contributor to
height growth during childhood,
hGH plays a role in strengthening bones and
increasing muscle mass throughout life. While mutations to the
hGH gene
often lead to abnormal growth in children and adults, these mutations have
provided researchers with key clues regarding the genomic areas that appear
to control expression of the hGH
gene. In order
to determine whether the CD79b
RNA in the pituitary gland served a function, Ho inserted a segment of human
DNA that included hGH,
the hGH
locus control region, and CD79b
into a group of mice. As a result, the transgenic mice expressed high levels
of human growth hormone in the pituitary as well as mouse growth hormone. To
test whether the transcription of the locus control region and
CD79b played
a significant role in hGH
expression in transgenic mice, Ho then inserted a special piece of DNA into
the locus control region. This DNA insertion specifically blocked the
copying of the CD79b
gene into RNA in the pituitary. This blockade led to the five-fold
repression of hGH
gene expression. These findings confirm that the
CD79b
non-coding DNA actively contributes to
hGH
expression. The relationship between
CD79b, the
hGH
locus control region, and the
hGH gene may aid researchers in the
development of treatments for patients suffering from
hGH
deficiency. In the future, Cooke, Liebhaber, and Ho will continue to search for how transcription contributes to long-range activation of hGH gene expression through the development of new transgenic mouse models and the biochemical analysis of the hGH locus. “By understanding how non-coding DNA functions at the human growth hormone locus, researchers may be able to identify similar situations at other genetic loci,” says Liebhaber. “With every step forward in understanding how genes are expressed, we increase our awareness of how naturally occurring and acquired mutations interfere with this process,” adds Cooke. “Our research sets the groundwork for advances in diagnosis and eventual treatment of genetic diseases.” These studies were funded by the National Institutes of Health. PENN Medicine is a $2.9 billion enterprise dedicated to the related missions of medical education, biomedical research, and high-quality patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System. Penn's School of Medicine is ranked #2 in the nation for receipt of NIH research funds; and ranked #3 in the nation in U.S. News & World Report's most recent ranking of top research-oriented medical schools. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine. The University of Pennsylvania Health System includes three hospitals, all of which have received numerous national patient-care honors [Hospital of the University of Pennsylvania; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center]; a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home care and hospice. Climb provides the above third-party links as a convenience and makes no assurances and/or warranties, implied or otherwise, and is not responsible for the information you receive from the linked sites or any supporting information related to the subject. The inclusion of any link does not imply endorsement of Climb or the sites or the information contained therein. Climb is not responsible for the contents of any linked site or any link contained in a linked site or any changes or updates to such sites. This newsletter is provided for information only.
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