Research News

Welcome to the National Information and Advice Centre for Metabolic Diseases Research News Sheet - Vol 1 No 3

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.

Scientists at Sangamo Biosciences in California have developed a new technique to permanently rewrite any gene in the human body. The new gene editing technique offers hope for many individuals affected by inherited disorders.

The scientists have used the technique to correct mistakes in the gene that causes X-linked Severe Combined Immune Deficiency (SCID). According to Sangamo, this could be enough to cure some SCID patients. The results appear in the online version of the journal Nature.

The gene editing technique uses the body's ability to repair the broken strands of DNA that the blueprint cells use to produce thousands of proteins. The scientists combined a zinc finger protein molecule, which can identify and bind to a specified gene, with an enzyme that can cut DNA. The protein effectively delivers the enzyme to just in front of the gene that the scientists want to cut out. The scientists supply a DNA template for the cell to copy so it will use their chosen gene to repair the cut DNA strands, rather than a new version of the faulty one.

The gene editing technique can also be used to target and destroy genes. Clinical trials of its ability to stop the HIV virus infecting immune system cells will start in humans next year. The results from the SCID trial highlight the potential for gene correction therapy for diseases caused by a defect of a single gene it also provides the grounds for gene modification without the safety issues that have been associated with conventional gene therapy.

Shwachman Diamond Syndrome (SDS) is a rare inherited bone marrow failure syndrome associated with blood cytopenias (low white cell count, anaemia, thrombocytopenia), pancreatic insufficiency, presenting with diarrhoeas and failure to thrive, short stature, skeletal and dental anomalies There is evidence that the associated haematological abnormalities are persistent and may progress to Acute Leukaemia (AL) or Myelodysplastic Syndrome (MDS-preleukaemia). The gene has been recently identified on chromosome 7 and is named SBDS. Since the discovery of the gene that encodes for the SBDS protein, in 2003, there has been a fervent interest on the effect that this protein exerts on different cell types in the body. There are now laboratories in several countries, including UK, that offer genetic testing for patients with the clinical diagnosis of the syndrome. There are also research laboratories experimenting on various aspects of the gene and its protein. The tantalising question now is, how the SBDS gene and its can affect so many and of different ontogeny systems in the body?

These developments have provoked an intense interest on the possible association between certain gene mutations, and the risk of malignancy. However as this a rare disorder further future research on other aspects of the syndrome would be facilitated by the establishment of a national registry.

I have sought Research Ethics Committee (REC) approval to establish an SDS registry in UK. Meanwhile I have initiated an anonymous survey of haematologists and paediatricians, through the British Society of Haematology and Royal College of Paediatrics and Child Health- RCPCH. The link is

There have been reports on the unusual or incomplete presentations of the syndrome. This is something that, doctors interested and working on the syndrome know very well. There is a crude estimates that a fifth of the patients out there may not have the described classical features. These patients represent a challenge to the clinicians and a high index of suspicion is required to think of the syndrome and request the appropriate investigations.

Regional Clinic: For the regular follow up of patients and a holistic approach to management, regional clinics and managed networks of specialists is the way forward. One such clinic has been set up at Great Ormond Street Hospital and it could serve the population in the southeast. I am planning a similar multidisciplinary clinic in Leicester at the Children’s Hospital, Leicester Royal Infirmary. We have set up the 1^st clinic for spring 2005.

26 April 2005: OXFORD, UK.—Genzyme announced today that it has completed a planned analysis of interim data from its pivotal clinical trial of Myozyme^® (alglucosidase alfa), which is being studied for the treatment of Pompe disease. The interim analysis was included in the trial’s protocol to allow for the potential expedited submission of a biologics license application. It found that the trial has already met one of its key secondary efficacy endpoints and that there is a high probability the study will meet its primary efficacy endpoint upon completion.

“The results are extremely encouraging and confirm our plan to submit a BLA in the middle of this year,” said Richard A. Moscicki, senior vice president and chief medical officer for Genzyme Corp. “This analysis will allow us to seek U.S. approval for Myozyme as quickly as we had expected and to supplement our previously filed European marketing application with data from the pivotal study. We have proceeded with a great sense of urgency throughout the development of Myozyme, given the devastating nature of Pompe disease.”

The pivotal trial, known as AGLU01602, includes 18 patients with infantile-onset Pompe disease. These patients were enrolled in the trial and began receiving Myozyme by 6 months of age. Because of the rapidly progressive and fatal nature of infantile-onset Pompe disease, outcomes for these patients are being compared with a matched historical cohort rather than a placebo cohort.

The study’s primary endpoint is the proportion of patients treated with Myozyme who are alive and free of invasive ventilator support at 18 months of age, compared with the proportion of patients who were alive at 18 months of age in the historical cohort (2 percent). Results for the primary endpoint will be known this summer, when patients will have completed 52 weeks of treatment.

By 12 months of age, 89 percent of patients treated with Myozyme (16 of 18) were alive and free of invasive ventilator support compared with 17 percent of patients who were alive at 12 months of age in the historical cohort. This result meets a secondary efficacy endpoint and indicates the trial will very likely meet its primary endpoint.

All patients treated with Myozyme showed a reversal in cardiomyopathy, a condition in which the heart muscle becomes enlarged and heart function is impaired. This reversal was measured by decreases in left ventricular mass index from baseline.

72 percent of patients treated with Myozyme demonstrated gains in motor development as measured by the Alberta Infant Motor Scale.

All patients evaluated demonstrated gains in cognitive, language and personal/social skills from baseline.

83 percent of patients developed antibodies to Myozyme and 44 percent experienced infusion associated reactions.

Genzyme will submit data from study AGLU01602 to the European Medicines Agency, which is reviewing a marketing authorization application (MAA) for Myozyme filed in December 2004. The agency’s Committee for Human Medicinal Products is expected to make a decision on the application later this year. The MAA contains data from other studies, including AGLU01702, which enrolled patients with infantile-onset Pompe disease who were older than those in AGLU01602 and whose disease was more advanced.

Genzyme is pursuing approval for Myozyme’s use as a long-term enzyme replacement therapy for all patients with a confirmed diagnosis of Pompe disease, defined as acid alpha-glucosidase deficiency. There is currently no approved treatment for the disease. More than 100 patients are now receiving Myozyme in clinical studies, through Genzyme’s expanded access program, or through pre-approval mechanisms sponsored by governments in several European countries. The Myozyme program is Genzyme’s largest research and development initiative.

This press release contains forward-looking statements, including statements about clinical trial results, regulatory plans and expected timelines for Myozyme, including the completion of the AGLU-01602 trial and the timing thereof, the submission of a BLA to the FDA and the timing thereof, and the expected timing of a decision from the Committee for Human Medicinal Products on Genzyme’s MAA. These statements are subject to risks and uncertainties that could cause actual results to differ materially from those projected in these forward-looking statements. These risks and uncertainties include, among others: the actual timing and content of submissions to and decisions made by the US and EU regulatory authorities regarding marketing authorization applications for Myozyme; the actual timing and final results of the Myozyme clinical trials; and the risks and uncertainties described in reports filed by Genzyme with the Securities and Exchange Commission. Please see the disclosure under the heading "Factors Affecting Future Operating Results" in the Management's Discussion and Analysis of Financial Condition and Results of Operations section of Genzyme's Annual Report on Form 10-K for the year ended December 31, 2004 for a more complete discussion of these and other risks. Genzyme cautions investors not to place substantial reliance on the forward-looking statements contained in this press release. These statements speak only as of the date of this press release, and Genzyme undertakes no obligation to update or revise the statements.

On 7 Mar 02, Oxford GlycoSciences (OGS) announced that they would be conducting a clinical trial of their glucosylceramide synthase inhibitor miglustat (previously referred to as OGT 918) in Niemann-Pick Type C disease (NPC). This drug which is now licensed to treat some Gaucher Disease patients is hoped to be effective in NPC due to its action to slow down the production of certain lipids that otherwise build up in the cells of patients and also through its ability to cross into the brain, which is vital to treat NPC.

Actelion Pharmaceuticals took over the marketing of miglustat in 2003 and since June 2004 is also fully responsible for the clinical trials and future development as well as marketing of this drug in lysosomal storage disorders worldwide.

The study is being conducted at 2 clinics specialising in the care of patients with NPC at Royal Manchester Children’s Hospital in the UK and Columbia Presbyterian Medical Centre in the US. Fifteen patients will be enrolled at each centre onto the adult trial (aged 12 and over).

The Paediatric trial will seek to enroll six patients at each centre (under 12 years).

The study is designed to assess the safety and efficacy of miglustat for the treatment of NPC, which is not without difficulties in a disease which can have a very different course of progression across individual patients.

In order to do this, the adult trial employs a no treatment control arm whereby one-third of patients enrolled will be randomly assigned to NOT receive the trial therapy for one year (but still receiving standard care) whilst the remaining two thirds receive miglustat. A comparison will be made at 1 year to see if there is a difference between the groups. All patients who have completed the first 12 month period: (which include the treated and the non treated group) will then also be offered treatment for the second year of the study.

All patients enrolled onto the Paediatric trial will receive the trial therapy from the outset.

The adult study started in spring 2002 and the paediatric trial commenced in autumn 2003

The saccadic eye movement velocity changes, which are one of the characteristics of this disease, have been chosen as the primary measurement of response for the trial. These are being measured by Professor Chris Harris at Plymouth University where they have the specialist expertise and equipment required to do this properly. In addition a lot of other things are being followed by the research teams such as: neurological assessments, swallowing assessments, nerve conduction and neuropsychological testing as well as checking on safety of this medication.

The recruitment for the Adult (over 12 year old) arm of the trial was closed at both centres on 30th June 2004, just one patient short of our target number of 30 adult patients. Due to the time it took to get everyone started plus the time it takes to get all the data together, all patients currently taking part in the trial who have reached month 24 will be given the option to continue the provision of treatment on an extended use study. This will continue for one year and then be reviewed depending on the results seen.

The final adult patient will complete the main study (Months 0-12) this summer and then start into the extension study (Months 12-24). This will now enable the centres to collect all of the Month 12 visit data. We hope initial results from the first 12 months might be available at the end of the year. It is difficult to know at this stage if we can expect positive results from just 12 months treatment in this very variable disease but we very much hope that the at least the signs will be good since there is no other current treatment option for families with this devastating disease.

Doctors from The Bayor College of Medicine in Houston, Texas have received £25,000 from the Propionic Acidaemia Foundation (PAF) to continue studying a possible gene therapy for those affected by Propionic Acidaemia.

The research study focuses on a gene therapy that uses adenoviral vectors that deliver the propionyl CoA carboxylase alpha gene (PCCA) specifically to the liver without infecting the other cell types in the body. The PCCA codes the PCCA enzyme. This enzyme is required for the correct breakdown of amino acids that are needed for growth and development during infancy. The PCCA enzyme is also required for breaking down cholesterol, some fatty acids and other substances that are needed for metabolic processes. The vectors will be tested throughout the year for their ability to manage persistent expression of the PCCA enzyme in the liver of PCCA-deficient mice and for their ability to extend the lifespan of the mice.

19th January 2005: The Human Fertilisation and Embryology Authority (HFEA) has announced a new policy to streamline the approval of applications for pre-implantation genetic diagnosis (PGD) embryo screening.

Under the new guidelines, if a clinic, with proven expertise in performing embryo biopsies, applies for a license to carry out screening for a particular condition, which is already being carried out successfully in another clinic - such as screening for sickle cell anaemia, cystic fibrosis and Duchenne’s muscular dystrophy - the HFEA will approve the application without having to go through the full HFEA license committee process, providing the same technique and methods are used.

“Our approach to regulating clinical techniques is that we should be cautious and thoroughly consider treatments on a case-by-case basis while techniques are still relatively new and unproven. Once a technique is established with a proven track record of effectiveness and safety then we will adopt a much more proportionate ‘lighter touch’ approach.

“PGD is now an established technique for screening embryos which has been carried out under HFEA scrutiny for several years and we have assessed all the relevant evidence gathered over this time.

“We have decided that whilst PGD is a specialised procedure, which can only be carried out by a qualified embryo biopsy practitioner, it should be straightforward for those clinics with a proven track record in the appropriate techniques to be able to carry out screening for any of the conditions currently approved.

“This will streamline the system, cutting down on bureaucracy and speeding up the approval process which will benefit both the patients who benefit from this treatment and the clinicians treating them”.

However, a number of less common specialised applications of PGD will still require thorough consideration by an HFEA license committee on a case by case basis. These include:

Designated Centres to Provide Service for Patients with Lysosomal Storage Disorders

For a period of two years, from April 2005 to March 2007, six centres have been nationally designated and funded, to provide a service for patients with lysosomal storage disorders (LSDs). The service will include diagnostic, assessment and treatment services. This means that the cost of drug treatments, including enzyme replacement therapies (ERTs), will be funded on a national basis through the designated centres.

National designation and funding will ensure that services to diagnose, assess and treat patients with LSDs will be concentrated in a small number of centres to allow the clinical teams to develop and maintain expertise in the management of these rare diseases. However, much of the care of patients with LSDs will still remain locally provided and funded, for example, bone marrow transplantation services for patients with Hurler's syndrome.

N.B. The national service for Gaucher's disease, previously designated by NSCAG, is included in this service definition.

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