Research News

Welcome to the National Information and Advice Centre for Metabolic Diseases Research News Sheet - Vol 1 No 4.

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.

Volunteers Wanted For New Project Investigate Auditory Processing in Neuronopathic Gaucher Disease.

Pauline Campbell and Professor Chris Harris at the University of Plymouth are undertaking an exciting new project to investigate auditory processing in children and young adults with Neuronopathic Gaucher Disease (NGD).

Auditory processing is when your brain recognizes and interprets the sound around you. An auditory processing disorder (APD) means that something is adversely affecting the processing or interpretation of the information. Recent research shows that many children with learning difficulties have trouble processing and understanding sound even though their hearing is normal. Children with APD often do not recognize subtle differences between sounds in words and these kinds of problems are more likely to occur when they are in a noisy environment or if they are listening to complex information. As a consequence of these primary difficulties, children with APD may have secondary characteristicsof language, reading and spelling disorders, as well as inattentionand distractibility.

The team in Plymouth has developed several new auditory electrophysiological techniques to help identify such auditory deficits. They hope to correlate audiological findings with eye movement studies and other cognitive measures to determine if they can better understand what is happening in children diagnosed with NGD.

As part of this research they are seeking to recruit children and young adults with NGD.

All of the tests are straightforward and non-invasive and are conducted in a child friendly and relaxed environment. Return travel and accommodation expenses will be paid for the participants and their parents/guardians.

If you would like to participate in the study, they would be delighted to hear from you. If you would like to take part but are unable to travel to Plymouth, they may be able to undertake some of the studies at your home. Please contact Pauline Campbell on 01752-233359 or e-mail pauline.campbell@plymouth.ac.uk if you think you may be able to help.

Lorenzo Oil Therapy Trial in Adrenomyeloneuropathy (AMN) – Progress Report

This is a progress report on the Lorenzo Oil Dietary Study for the treatment of Adrenomyelinoneuropathy (AMN) that is now being conducted at the Kennedy Krieger Institute and the General Clinical Research Centre at Johns Hopkins Hospital. This study uses Lorenzo’s Oil, which when combined with a reduction of fat intake lowers, and if done carefully, reduces to normal the levels of very long chain fatty acids in the plasma of patients with Adrenoleukodystrophy (ALD), including those with the Adrenomyelinoneuropathy (AMN) form of the illness. The question is whether lowering of these levels helps patients with AMN.

A preliminary report of Dr. Wolfgang Köhler in Germany suggests that it does. His study involved 45 men with AMN who did not have brain involvement and who were followed for a mean period of 6.7 years (range 2-12.8 years). Severity of AMN was assessed by the AACS (Adult Adrenoleukodystrophy Clinical Scale) a scoring system devised by Drs. Köhler and Sokolowski. The mean progression of AACS in the treated patients who had reduced their VLCFA levels to normal was 1.5 AACS units compared to the estimate of 2.6 units who were untreated. Moreover, 22 of the treated patients remained stable, that is the AACS score did not worsen. This important and exciting result is limited because the study was not controlled: The progression of untreated AMN patients is known to vary a great deal, and in this study the progression prior to oil therapy was based on patients’ historical accounts.

The purpose of the present study is to determine as quickly and accurately as possible whether these preliminary results of the favourable effects of Lorenzo Oil therapy in AMN are sustained.

This study uses gold standard “phase 3” study design. That is, it is placebo controlled. Half of the patients will receive the oil half a frequently used dietary oil that does not contain Lorenzo oil but resembles in appearance and taste, and caloric content. The study is “double blinded” neither the patients or treating personnel know who is receiving the Lorenzo Oil or the placebo. A four year study is planned, even though patients and treatment staff are “blinded” as to treatment category, all the data are reviewed by an “unblinded” highly experienced data and safety committee who will review the effect of the therapy continuously and would call for an end of the study if decisive results are obtained before that time. The study is approved by the FDA and this trial will serve as a key factor in determining whether Lorenzo Oil will become an approved therapy. At present the study is supported financially by the National Institutes of Health, The General Clinical Research Center at John Hopkins Medical Institutions, the Myelin Project and the United Leukodystrophy Foundation.

What does the study mean for the patient who is enrolled? Below is a step-by-step account:

Initial “screening” contact with research nurse (Kim Hollandsworth) Tel: (443) 923-2772 or E-Mail: Hollandsworth@KennedyKrieger.org For general information and determination of eligibility. The study is designed for men and women with proven diagnosis of ALD, 18 years or older who have mild-severe symptoms of AMN but have still remained some capacity to walk (walk 20 yards without the use of canes or a walker), and who do not have evidence of disease-related changes in the brain on the basis of symptoms and MRI. (Alternate programs for patients who do have brain involvement exist in other medical centres and with which we will collaborate and will make referrals).

Two day and admission to the General Clinical Research Centre at Johns Hopkins Hospital for studies at the Kennedy Krieger Institute.

Arrangements for this are made by the study co-ordinator (Willy Foreman) and Kim Hollandsworth. The following happens during this busy two-day stay:

(for more information on the above please contact Climb or the United Leukodystrophy Foundation for the full article)

Costs: The Lorenzo Oil, placebo oil, hospital admission and all tests provided without cost to the patient

Current Status: The trial was initiated on March 7, 2005. Fifty-two patients (32 women and 20 men) are now enrolled and 12 additional patients are scheduled.

Additional: AMN patients from the US or Canada are invited to join this study. For more detailed information please contact Kim Hollandsworth by email Hollandsworth@KennedyKrieger.org or phone (443) 923-2772.

The European Patent Office has notified Zymenex of the decision to grant Zymenex a European Patent on the "Production of rhPBGD". This patent covers the production method for Zymenex lead product Porphozym, for the treatment of Acute Intermittent Porphyria, that is now in the end of clinical phase II and phase III is expected to be initiated mid 2006. This patent has already been granted in Australia and South Africa.

Zymenex has previously been granted a broad world-wide patent on "New therapeutic method for treating patients with acute intermittent porphyria (AIP) and other porphyric diseases" in Europe, United States, Australia and South Africa.

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

Zymenex has developed a number of new products (human 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 marked reduced expected lifetime. Enzyme replacement therapy is a well known treatment method and there are a number of products on the market today.

One is Porphyria (Acute Intermittent Porphyria). The disease is due to a defect in one of the active substances of the human body, an enzyme called PBGD. The enzyme defect impairs the patients’ ability to metabolize certain molecules in the cells. The patients get acute attacks, that are very painful and if untreated can be lethal.

The second focus area is Lysosomal storage diseases (LSD). LSD is a common name for diseases, where the ability of the human body to break down specific molecules in the cells’ lysosomes is reduced or impaired. The disease most often affects children, is lethal and there is no therapy available today.

The patient groups are small and therefore the authorities have established specific programs to encourage the development of new products (”Orphan drugs”). It results in both development and marketing being able to be performed faster and less resource demanding than for pharmaceutical products with a much larger therapeutic area. Furthermore the number of competitors on the market are limited.

Zymenex was established in 1998. The Management in Zymenex consists of a team, with broad experience from leading positions in pharmaceutical companies and with competencies that span from research and development to production and marketing of pharmaceutical products. The company has built up its own portfolio of product candidates and manages the development process based on own competencies, supplemented by outsourcing, where it is strategically relevant. The company has 22 employees today.

For the first time, scientists studying a fatal childhood neurodegenerative disorder, juvenile Batten disease, have identified a defect in transport of the amino acid arginine in cells from affected children. The finding helps researchers understand how the disease develops and may lead to new ways of treating it.

“This is one more step toward understanding the defect in the cells that causes this disease,” says David A. Pearce, Ph.D., of the University of Rochester School of Medicine and Dentistry in New York, who led the study. The study was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) and appears in the December 1, 2005, issue of Human Molecular Genetics.*

Juvenile Batten disease results from mutations in a gene called CLN3. Symptoms of this disorder usually appear between the ages of 5 and 10 and may include seizures, mental impairment, and progressive loss of vision and motor skills. The disease is often fatal by the late teens or twenties. Juvenile Batten disease is the most common of a group of disorders called neuronal ceroid lipofuscinoses, or NCLs. NCLs are characterized by a buildup of pigments called lipofuscins in the body's cells.

The researchers studied blood cells from children with juvenile Batten disease and compared them to cells from children without the disease. They looked specifically at lysosomes, tiny sacs within the cell that contain enzymes to help to break down substances so that their components can be recycled. The lipofuscin in Batten disease accumulates within these structures.

Cells from children with the disease were unable to transport arginine across the lysosomal cell membranes as efficiently as normal cells, the researchers found. The total amount of arginine was also abnormally low in cells from affected children. Previous studies have shown that yeast cells without the yeast version of the CLN3 gene have a defect in arginine transport, but this is the first study to find a similar defect in human cells.

Blocking the function of the CLN3 gene in normal cells inhibited the transport of arginine, and tranferring normal CLN3 to Batten disease cells using gene therapy techniques restored arginine transport to normal levels, the researchers found. This showed that the arginine transport defect was caused by the gene mutation.

The researchers have not yet determined exactly how the arginine transport defect is linked to the symptoms of the disease, they say. However, arginine is one of the building blocks for protein, and maintaining a certain level of arginine may be necessary for normal cell function. Arginine also is critical for the production of nitric oxide, a molecule that is important for cell function and immune response. Nitric oxide serves as a neurotransmitter, or nerve-signaling chemical, in the nervous system. Studies have shown that either too much or too little nitric oxide in animals can increase their susceptibility to seizures. Therefore the cellular arginine deficiency may explain why children with juvenile Batten disease tend to develop epilepsy.

The researchers also found evidence that arginine deficiency may be linked to the altered pH found in cells of people with juvenile Batten disease. However, it is not yet clear whether the arginine transport defect triggers the pH abnormality, or vice versa, Dr. Pearce says.

While the results of this study provide important clues about how juvenile Batten disease causes neurodegeneration, parents of affected children should not start supplementing their children with arginine, Dr. Pearce cautions. The arginine deficiency may be the body's way of compensating for some other, yet-undetermined problem, he says. Therefore arginine supplementation could easily cause more harm than good.

The researchers are now looking at the effects of altered arginine transport in a mouse model for Batten disease in order to learn how this defect affects different cell types in the brain. They also are planning other studies to determine how CLN3 mutations lead to the arginine transport defect and how this defect affects cells. "This is our first marker for understanding what's wrong with the lysosome. It gives us something to really get our teeth into," says Dr. Pearce.

The NINDS is a component of the National Institutes of Health (NIH) within the Department of Health and Human Services and is the nation’s primary supporter of biomedical research on the brain and nervous system. The NIH is comprised of 27 Institutes and Centers. It is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research, and investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

*Ramirez-Montealegre D, Pearce DA. “Defective lysosomal arginine transport in juvenile Batten disease.” Human Molecular Genetics, December 1, 2005, Vol. 14. No. 23, pp. 3759-3773.

Shire announces status of ongoing FDA review of NDA for DAYTRANA^TMfor the treatment of ADHD

Philadelphia, PA, US and Basingstoke, UK – March 10, 2006 -- Shire plc (LSE: SHP, NASDAQ: SHPGY, TSX: SHQ) announced today that the U.S. Food and Drug Administration (FDA) has confirmed that Shire’s resubmission for DAYTRANA in response to information that the FDA requested in its December 23, 2005 approvable letter for DAYTRANA’s New Drug Application is being treated as a Class I resubmission. The review period for Class I resubmissions is 60 days, and since Shire’s resubmission was made on February 9, 2006, the anticipated FDA action date is April 9, 2006.

DAYTRANA (methylphenidate transdermal system (MTS)) is an investigational transdermal patch formulation for methylphenidate designed for once-daily use to treat attention deficit hyperactivity disorder (ADHD) in children aged 6 to 12 years. Shire is planning to launch DAYTRANA, if approved, during the first half of 2006.

For further information on Shire, please visit the Company’s website: www.shire.com.

DAYTRANA is a Schedule II controlled substance. DAYTRANA was generally well tolerated in clinical studies. As with other products containing methylphenidate (the active ingredient in DAYTRANA), common side effects reported in children who received DAYTRANA were decreased appetite, insomnia, nausea, vomiting, weight loss, tic, and affect lability (mood swings). DAYTRANA should not be used by children with allergies to methylphenidate or other ingredients in DAYTRANA. The patch should be applied daily to clean, dry skin, which is free of any cuts or irritation. Avoid applying external heat to the patch. Skin irritation may occur. Methylphenidate should not be taken by children with significant anxiety, tension, or agitation; glaucoma; tics; Tourette’s syndrome, or family history of Tourette’s syndrome; or current/recent use of MAO inhibitors (a type of antidepressant). Abuse of methylphenidate may lead to dependence. Tell your healthcare professional if your child has had problems with alcohol or drugs or has had depression, abnormal thoughts/behaviors, visual disturbances, seizures, high blood pressure, or heart conditions.

About ADHD

ADHD affects approximately 7.8 percent of all school-age children, more than 4 million in the United States. ADHD is considered the most commonly diagnosed psychiatric disorder in children and adolescents. ADHD is a neurological brain disorder that manifests as a persistent pattern of inattention and/or hyperactivity-impulsivity that is more frequent and severe than is typically observed in individuals at a comparable age and maturity. If untreated, ADHD can acutely affect a child’s life, leading to problems with family members, friends, sports, after-school activities and academics.

"SAFE HARBOR" STATEMENT UNDER THE PRIVATE SECURITIES LITIGATION REFORM ACT OF 1995

Statements included herein that are not historical facts are forwarding-looking statements. Such forward-looking statements involve a number of risks and uncertainties and are subject to change at any time. In the event such risks or uncertainties materialize, Shire plc's results could be materially affected. The risks and uncertainties include, but are not limited to: risks associated with the inherent uncertainty of pharmaceutical research, product development, manufacturing and commercialization; the impact of competitive products, including, but not limited to, the impact of those on Shire plc's Attention Deficit and Hyperactivity Disorder ("ADHD") franchise; patents, including but not limited to, legal challenges relating to Shire plc's ADHD franchise; government regulation and approval, including but not limited to the expected product approval dates of DAYTRANA^TM(MTS) (ADHD), SPD503 (ADHD), SPD465 (ADHD), MESAVANCE^TM(SPD476) (ulcerative colitis), ELAPRASE^TM(I2S) (Hunter syndrome) and NRP104 (ADHD), including its scheduling classification by the Drug Enforcement Administration in the United States; Shire plc's ability to benefit from the acquisition of Transkaryotic Therapies Inc.; Shire plc's ability to secure new products for commercialization and/or development; and other risks and uncertainties detailed from time to time in Shire plc's and its predecessor registrant Shire Pharmaceuticals Group plc's filings with the US Securities and Exchange Commission, including Shire plc's Annual Report on Form 10-K for the year ended December 31, 2005.

Amicus Therapeutics AT2101 Granted Orphan Drug Designation for the Treatment of Gaucher Disease

Cranbury, NJ, February 15, 2006 – Amicus Therapeutics, a biopharmaceutical company developing small molecule, orally-active pharmacological chaperones for the treatment of human genetic diseases, today announced that AT2101 has received orphan drug designation from the U.S. Food and Drug Administration. AT2101 is an experimental, oral therapy for the treatment of Gaucher disease, a lysosomal storage disorder resulting from an enzyme deficiency that can cause damage to the liver, spleen, bone marrow and in some cases, the central nervous system. Gaucher disease affects approximately 10,000 people in the developed world. Orphan drug designation provides extended marketing rights and other incentives to support and encourage development of drugs that affect fewer than 200,000 people annually in the United States.

AT2101 acts as a pharmacological chaperone that binds to glucocerebrosidase (GCase), the enzyme involved in Gaucher disease. In most Gaucher patients, the GCase deficiency is caused by a missense mutation, which results in the misfolding and degradation of the protein. As a pharmacological chaperone, AT2101 binds specifically to the misfolded protein, which in turn restores proper structure, trafficking and biological activity.

AT2101 is expected to enter clinical studies in the first half of this year.

Amicus’ lead compound Amigal™ (migalastat hydrochloride) is a pharmacological chaperone in Phase ll clinical trials for Fabry disease, and the company has a growing pipeline of other products for a range of genetic diseases. www.amicustherapeutics.com

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