Research News

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.

Pinpointing Cause of Fibrodysplasia Ossificans Progressiva (FOP) Will Accelerate Development of Treatments for FOP and Common Bone Disorders

(Philadelphia, PA) – Researchers at the University of Pennsylvania School of Medicine have located the “skeleton key,” a gene that, when damaged, causes the body’s skeletal muscles and soft connective tissue to undergo a metamorphosis into bone, progressively locking joints in place and rendering movement impossible. Identifying the gene that causes fibrodysplasia ossificans progressiva (FOP), one of the rarest and most disabling genetic conditions known to humans and a condition that imprisons its childhood victims in a “second skeleton,” has been the focus at Penn’s Center for Research in FOP and Related Disorders for the past 15 years. This important discovery is relevant, not only for patients with FOP, but also for those with more common skeletal conditions.

Senior authors Eileen M. Shore, PhD, and Frederick S. Kaplan, MD, both from the Penn Department of Orthopaedic Surgery, and their international consortium of colleagues, report their findings in the April 23 advanced online edition of Nature Genetics. “The discovery of the FOP gene is relevant to every condition that affects the formation of bone and every condition that affects the formation of the skeleton,” says Kaplan.

The discovery of the FOP gene was the result of painstaking work by the Penn scientists and their colleagues in the International FOP Research Consortium over many years. It involved the identification and clinical examination of multigenerational families, often in remote regions of the world; genome-wide linkage analysis; identification of candidate genes; and finally, the DNA sequencing and analysis of those candidate genes. The team found that FOP is caused by a mutation of a gene for a receptor called ACVR1 in the bone morphogenetic protein-signalling pathway.

Kaplan describes FOP as the “Mount Everest” of genetic skeletal disorders. His lifelong ambition, as he puts it “is to conquer the summit of this daunting mountain range and see this emerging knowledge turned into novel therapies that can dramatically improve the life of these children. This is nothing less than a campaign for physical independence and personal freedom for these kids. If the knowledge helps us to see farther to help others that will be great but this work is for and about the children

Zymenex to focus on the Lysosomal Storage Disease, Metachromatic Leukodystrophy (MLD)

Lead project, Metazym, to enter Phase I/II trials H2 2006. Development program in Porphyria discontinued.

Zymenex announced today that it is prioritizing the Company’s Research and Development on the recombinant enzyme, Metazym, for treatment of the Lysosomal Storage Disease, Metachromatic Leukodystrophy (MLD). The Company also announced that it has discontinued clinical development in the area of Acute Intermittent Porphyria.

Metazym is completing pre-clinical testing and is expected to enter Phase I/II clinical trials in the second half of 2006. MLD is a childhood disease in which myelin is broken down. The disease is caused by a deficiency of the ASA enzyme and results in irreversible neurological damage. The disease is fatal and there is no therapy available. Children with MLD are most often diagnosed at three years of age and progress within three to four years to being wheelchair-bound and then bedridden prior to death.

Zymenex has published proof-of-principle data in a disease mouse model (Hum. Mol. Gen., vol. 14, no. 9, May 1, 2005) that document that Metazym breaks down specific molecules, associated to the development of the disease, in brain- and nervous tissue. Zymenex has developed a large-scale production process to manufacture the enzyme and the company has received Orphan Drug Designation for MLD in Europe. The Phase I/II clinical trial is expected to be completed in 2007.

Zymenex will not pursue further development of its Porphozym product in the area of Acute Intermittent Porphyria, a blood related disease. The goal of this program has been to remove a circulating toxic factor PBG (biomarker) from the blood stream and thus relieve acute attacks in patients. In the clinical trials performed to date, the product has been demonstrated to be safe and well tolerated by all patients and has shown the expected effect on the biomarker. However, due to the acute nature of the disease and the patient variability observed, an evaluation of the results from a recent phase IIb study indicates insufficient evidence to correlate a reduction in the biomarker PBG with a desired clinical effect. Although a positive effect cannot be ruled out, Zymenex has decided, that it is not commercially and financially viable to develop the product further in house. Zymenex will be open to partnering the porphyria product, but will now focus exclusively on the validated concept of Enzyme Replacement Therapy for Lysosomal Storage Diseases.

The Zymenex pipeline also includes Lamazym, for the treatment of the lysosomal disease Alpha-Mannosidosis. This disease is due to a deficiency of the Laman enzyme, affects approximately 500 patients world wide and the project is in late pre-clinical development. The disease is lethal and there is no therapy available today. Zymenex has over the last three years collaborated with a number of European scientific groups under a EU grant “Euraman” to develop this enzyme and has, together with this scientific group, published proof-of-principle data (Hum. Mol. Gen., vol. 13, no. 18, July 21, 2004). Zymenex and its scientific collaborators recently received a new EU grant “Hueman” of € 3.2 million, under the 6th framework, to continue developing Lamazym. Lamazym has received Orphan Drug Designation in both Europe and the US.

The focus on Metazym and Lamazym means that Zymenex will adapt a project oriented organization. The present Senior Management group will be reduced from four to one, with Jens Fogh continuing as President and CEO. The company headquarters and Development team will continue to be in Hillerød and the Research team in Stockholm.

The present investors BankInvest and the Vækstfonden have recently injected new financing, totalling € 7 million.

About Zymenex

Zymenex develops pharmaceutical products to treat rare, serious, genetic diseases, for which there is no treatment available today.

Zymenex has developed several human recombinant enzymes that can be used for therapy within specific disease areas. The products are expected to be able to help patients, who today have serious handicaps, reduced quality of life and a markedly reduced life expectancy. Enzyme replacement therapy is a well-known treatment method and there are a number of products on the market today that validates the company concept.

The company’s Research and Development focuses on Lysosomal Storage Diseases, which is a common name for human diseases, where the ability of the human body to break down specific molecules in the lysosomes in the cells is reduced or impaired. The diseases most often affect children, they are lethal and there is no therapy available today.

Companies like Genzyme, Shire and Biomarin have developed a number of similar enzyme replacement therapies for some of the other Lysosomal Storage Diseases. These diseases fall in the category of Orphan Drugs, affect small patient populations, are life threatening and require chronic life-long treatment. Several products like CerezymeTM for Gaucher disease (total estimated patient population 6000), FabrazymeTM and ReplagalTM for Fabry disease (total estimated patient population 5000) and AldurazymeTM for MPS-1 (total estimated patient population 3000) are already on the market, and a number of additional products are in the pipelines of the companies. According to company annual reports for 2005, sales for the two largest drugs Cerezyme and Fabrazyme, exceeded USD 900 million and USD 300 million respectively.

The authorities actively encourage the development of new pharmaceutical products to treat rare diseases under the Orphan Drug acts. All of Zymenex activities are today focused within the orphan area where development and marketing are expected to be faster and less resource demanding than for ordinary pharmaceuticals. Furthermore there are no competitors on the market today for Zymenex’ two products.

Zymenex was established in 1998. The organization has broad experience from positions in other pharmaceutical companies and competencies spanning from research and development to production and marketing of pharmaceutical products. The company has built its portfolio of product candidates and manages the development process based on own competencies, supplemented by outsourcing.

Edison Pharmaceuticals Announces FDA Grants EPI-A0001 Orphan Drug Designation for Inherited Mitochondrial Respiratory Chain Diseases

Edison's EPI-A0001 gains FDA orphan designation status

April 4, 2006 – SAN JOSE, California, USA – Edison Pharmaceuticals, Inc. announced today that the U.S. Food and Drug Administration (FDA) has granted orphan drug designation to EPI-A0001 for treatment of inherited mitochondrial respiratory chain diseases. These mitochondrial diseases today affect an estimated 60,000 individuals.

The Orphan Drug Act, passed in 1982, provides incentives for companies to pursue treatments for diseases affecting fewer than 200,000 individuals in the United States. Such designation provides an accelerated review and a seven-year period of exclusivity upon FDA approval.

The FDA granted orphan drug designation to Edison's EPI-A0001 based on review of the application, which included pre-clinical data demonstrating a favourable efficacy and safety profile. Current data is consistent with EPI-A0001 targeting electron shuttling and energy production- two processes that are impaired by genetic defects in the (mitochondrial) respiratory chain.

The respiratory chain is located within the inner mitochondrial membrane and is comprised of numerous proteins encoded for by both the nuclear and mitochondrial genome. Genetic errors in the synthesis of these proteins results in a variety of clinical conditions that have disruptions in energy production as a common biochemical feature. These diseases frequently affect skeletal and cardiac muscle, as well as the nervous system, and thus are often classified as mitochondrial encephalomyopathies. They are highly debilitating, and life shortening. Edison is partnered with leading academic centres and foundations to develop first-in-class therapeutics for the treatment of these diseases.

About Edison Pharmaceuticals

Edison Pharmaceuticals, Inc. is focused on the development of drugs to treat energy impairment diseases, also referred to as mitochondrial diseases. The company is advancing into clinical development EPI-A0001 for the treatment of inherited mitochondrial diseases predominately affecting children. Edison's technology platform consists of a specialized knowledge in redox medicinal chemistry, which the company believes is essential to drugging key targets contained within mitochondria. Edison will leverage clinical and laboratory data obtained in rare, or orphan, diseases to pursue other conditions that share common mechanisms. The company has obtained substantial non-dilutive peer-reviewed grant support to advance both its pre-clinical and clinical initiatives from foundations including the Muscular Dystrophy Association, Friedreich's Ataxia Research Alliance, and Seek A Miracle.

Contact

FRIDAY, May 18 (HealthDay News) -- Mayo Clinic researchers say they've spotted two cardiac genes that could be linked to sudden infant death syndrome (SIDS).

The findings increase the possibility that genetic defects of the heart may cause up to 15 percent of SIDS cases.

The team examined tissue from 135 infants, average age 3 months, who died of SIDS, and found evidence to implicate caveolin-3 (CAV3) and cardiac ryanodine receptor (RyR2) as SIDS-susceptibility genes. Of the 135 infants in the study, all by two had mutations in either CAV3 or RyR2.

SIDS -- the sudden, unexplained death of an infant under 1 year old -- is estimated to cause 2,500 infant deaths each year.

"Combined with our previous discoveries, we now estimate that defects in genes that provide the blueprints for the critical controllers of the heart's electrical system might have played a key role in more than 300 of those tragedies," principal investigator Dr. Michael J. Ackerman, director of Mayo Clinic's Long QT Syndrome Clinic and Sudden Death Genomics Laboratory in Rochester, Minn., said in a prepared statement. "We are continuing to expose the causes of SIDS. So far, we have now added six genes to the SIDS most-wanted list," Ackerman said.

The findings were to be presented today at the Heart Rhythm Society's annual scientific sessions, in Boston. "Although so much of SIDS remains unexplained, these findings that point to the heart for 10 percent to 15 percent of SIDS provide one place to search for a possible explanation," Ackerman said.

"For families that have lost an infant to SIDS, it would be reasonable for parents to talk with their physician to make sure there is no family history of other unexplained deaths, unexplained fainting episodes, unexplained seizures that might provide clues and prevent more deaths," Ackerman added.

Gene therapy experts say they have found a way to persuade cells to repair themselves.

Instead of replacing a faulty gene, the new approach harnesses the cells' own correctional mechanisms.

German researchers showed a drug could influence the way a gene behaved in patients with a debilitating genetic condition.

Details of the research are being presented to the European Society of Human Genetics conference in Amsterdam. The research focused on spinal muscular atrophy (SMA), a relatively common inherited disease, and the leading cause of death in infants, affecting about one in every 6,000 newborns.

Due to degeneration of the motor neurons in the spinal cord patients develop muscle weakness and atrophy of the legs, arms and trunk.

In patients with SMA the survival motor neuron gene (SMN1) is deleted, but they all carry a copy gene (SMN2). However, this only produces about 10% of the correct protein which is insufficient to prevent the diseases.

The severity of the SMA is influenced by the number of SMN2 genes, which normally vary between one and four - the more copies there are the better the patient fares.

The researchers, from the Institute of Genetics at the University of Cologne investigated a drug called valproate, which is already used to treat epilepsy.

Lab tests had shown it could increase levels of the SMN protein by up to four times. Valproate was also found to raise SMN levels in brain tissue.

The team first treated 10 parents of children with SMA with valproate for four months. It was found that using the drug significantly increased SMN levels in blood.

Following this, 20 SMA patients were treated with valproate. Seven showed increased SMN2 levels in their blood.

However, it remains unclear whether SMN expression in blood reflects SMN expression in motor neurons, and would therefore have an effect on muscle strength.

But the researchers said they hoped their findings could have significant benefits in the future. Professor Brunhilde Wirth said: "The long-term outcome could be both improved therapy to enable a better quality of life for SMA patients, and also the introduction of neonatal screening so that therapy could be started before the first symptoms appear."

"This work shows that it may be possible to influence the behaviour of genes with drugs. This is not a cure for SMA, but it's a small step along the road that may lead to an effective treatment. It is exciting to discover that a drug that is used to treat epilepsy may also be helpful in a completely different condition."

Professor Robin Lovell-Badge, head of genetics at the Medical Research Council's National Institute for Medical Research, said it was crucial to obtain detailed basic understanding of specific genes, and the nature of the defects responsible for genetic disease before the knowledge was applied to treating patients.

He added: "It is still too early to say whether or how well these particular approaches will work in the clinic. But the preliminary results are encouraging and the knowledge gained will hopefully generate yet further tricks to bypass the unlucky set of cards that some people are dealt."

Effective from April 24, 2006, Ucyclyd has consolidated the European distribution of its Ammonaps (sodium phenylbutyrate) product with Swedish Orphan International AB. Previously, the distribution of this product in Europe was split between Swedish Orphan and Orphan Europe, with each of them handling different European countries. Ucyclyd Pharmaceuticals hopes that this consolidation will lead to a simpler and more effective service to European patients.

All European orders for Ammonaps should now be sent to Swedish Orphan International.

If you have any questions about the ordering process, please contact Mr Jan Karlsson of Swedish Orphan by telephone at 46 8 412 98 00 or by email at jan.karlsson@swedishorphan.com.

BBC News, Prague: - A new embryo test offers couples at risk of serious genetic diseases a greater chance of having an unaffected baby through IVF, UK scientists say.

The test looks at the whole DNA of a cell rather than focusing on a specific mutation in one gene, making it quicker to identify diseases in embryos.

The team will tell a Prague fertility conference five couples are expecting healthy babies after the test, and IVF.

However, some campaigners have questioned the morality of such screening tests, as they inevitably lead to the destruction of some embryos.

Simone Aspis, from the British Council of Disabled People, said: "Who is going to make the decision about who should and should not live? We believe all babies have an equal right to life."

The new "DNA fingerprint" test of a cell can spot from a genetic signature that a condition, such as cystic fibrosis, is present, the scientists behind it say.

The team, from the genetics unit at London's Guy's Hospital, have developed a method called pre-implantation genetic haplotyping (PGH), which they expect to offer to over 100 families a year.

PGH involves testing parents and any existing children or relations carrying or with a genetic condition, to identify the faulty units of chromosomal DNA.

Using this information, it is possible to take a cell from the embryo, treat it in the lab to create more copies of its genetic material and then look for markers that show an embryo carries two copies of these faulty units, or haplotypes.

The technique has been used to test for Duchenne Muscular Dystrophy (DMD). It primarily affects boys, who inherit the disease through their mothers.

Families with a history of the condition are currently offered embryo sex testing and no male embryos are implanted, as it is not possible to tell if they have the condition - even though they have a 50/50 chance of being affected.

But with the new test, doctors are able to see if an embryo carries the tell-tale DMD haplotypes seen in its parents, meaning more embryos can be selected for use.

The test also allows detection of any of the genetic mutations which can cause cystic fibrosis.

Like DMD, it is a recessive disease, and means both copies of chromosome 7 must carry a fault for a child to have the disease - but PGD can spot only the most common of the hundreds of faults.

The team have also helped a woman affected by hydatidiform mole - a condition where pregnancy leads to a potentially fatal tumour forming instead of a foetus.

Professor Peter Braude, the fertility specialist who helped develop the test, said: "It doesn't matter what the genetic fault is.

"We can know the same chromosome that has affected a family member, and know the embryo is also affected."

Alison Lockwood, a nurse who is part of the genetics unit team, said the bottom line for couples who came to see her was the wish for a healthy baby. "Until now, you really had to know the name of the mutation to do a direct test. Now that doesn't matter. With sex linked disease, you would currently have to take away probably 50% of embryos because they are male.

However she said the new test would not lead to a flood of people wanting to take advantage of the science. "Of the patients currently referred for PGD, only a third end up going through a cycle.

"These are, generally, couples who can get pregnant without having to undergo fertility treatment, and when they get to know what it involves, many do not go ahead."

Dr Mark Hamilton, chairman of the British Fertility Society, said: "Any technique which has the potential to reduce the risk of serious, debilitating and potentially life-threatening disease has to be greeted with some enthusiasm.

"We are always striving to maximise the chance that fertility treatment will be successful. But not transferring because we are absolutely confident they are affected by a condition, rather than because we suspect they are, is preferable and much less wasteful."

But Josephine Quintavalle, of Comment on Reproductive Ethics, warned against further extensions of screening.

She said: "I am horrified to think of these people sitting in judgment on these embryos and saying who should live and who should die."

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