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.

A needs assessment and review of services for people with inherited metabolic diseases in the United Kingdom by Dr Hilary Burton, PHGU Cambridge is available in the short overview (here) or the full version (here) in PDF format – consider this a must read for all those involved with inherited metabolic diseases.

Phenylketonuria (PKU) is a metabolic disorder that is caused by a deficiency of a liver enzyme known as phenylalanine hydroxylase. This enzyme is needed to convert phenylalanine to another amino acid known as tyrosine. When the enzyme is deficient, excessive phenylalanine accumulates in the blood and is toxic to brain tissue and the central nervous system (CNS).

The blood phenylalanine (phe) level has to be maintained between 2 mg/dl to 10 mg/dl (milligram per deciliter) for controlling PKU which means patients need regular and frequent monitoring of blood phenylalanine levels. This is usually tested through blood tests at clinics.

MetGen Inc, in collaboration with Georgia Tech researchers, is developing the first-ever self-monitoring device for PKU patients. The new device works by the patient providing a drop of blood (by the prick of a finger) and placing it on the chemical test strip. The strip is then inserted in the medical device, which calculates the rate of absorption of a specific colour of light by the chemical strip. This rate gives the level of phenylalanine in the blood.

The device is not replacing clinical monitoring of patients diets but does mean that blood tests will not need to be performed as often and means patients will be able to control their phenylalanine levels better at home. The device also memorises tests done by the individual so specialists can be provided with a history of phenylalanine levels.

The device is currently being reviewed by the FDA. In the meantime, manufacturers are being sought for so if the review goes well the product will hopefully be on the market within six months. MetGen plans to use this model to develop similar solutions for other genetic disorders and commercialise the next concept in a 24 months timeframe after the launch of this self-monitoring device for PKU.

BETHESDA, Md., Mon., Aug. 29, 2005 - In a surprising development, a research team led by the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health (NIH), has found that a class of experimental anti-cancer drugs also shows promise in laboratory studies for treating a fatal genetic disorder that causes premature aging.

In a study published Monday in the online edition of the Proceedings of the National Academy of Sciences (PNAS), Brian Capell and his colleagues at NHGRI reported that drugs known as farnesyltransferase inhibitors (FTIs), which are currently being tested in people with myeloid Leukemia, Neurofibromatosis and other conditions, might also provide a potential therapy for children suffering from Hutchinson-Gilford Progeria Syndrome, commonly referred to as Progeria. A related study from Stephen Young, M.D., and colleagues at the University of California at Los Angeles is being published in the same issue of PNAS.

There are currently no treatments for Progeria, which is a genetic disorder estimated to affect one child in 4 million. When they are born, children with Progeria appear normal. But, as they grow older, they experience growth retardation and show dramatically accelerated symptoms of aging - namely hair loss, skin wrinkling and fat loss. Accelerated cardiovascular disease also ensues, typically causing death from heart attack or stroke at about the age of 12.

"Our findings show that FTIs, originally developed for cancer, are capable of reversing the dramatic nuclear structure abnormalities that are the hallmark of cells from children with Progeria. This is a stunning surprise, rather like finding out that the key to your house also works in the ignition of your car," said NHGRI Director Francis S. Collins, M.D., Ph.D., who is the study's senior author.

The new work involved using FTIs to treat skin cells taken from Progeria patients and grown in laboratory conditions. If upcoming studies in a mouse model validate the results of the cell experiments and translate into improvements in the animals' conditions, a clinical trial of FTIs in children with Progeria may begin as early as next spring, researchers said.

Dr. Collins and his colleagues discovered in April 2003 that mutations in the lamin A (LMNA) gene cause Progeria, spurring renewed interest among researchers to study this rare syndrome. Among those were Capell, a New York University medical student participating in the Howard Hughes Medical Institute/NIH (HHMI/NIH) Research Scholars Program. In July 2004, he joined Dr. Collins' lab and immediately set his sights on understanding the molecular basis of Progeria.

"What really interested me in this research in the first place were the potential links to aging and atherosclerotic disease," said Capell. Indeed, understanding Progeria at the molecular level may illuminate the general processes involved in normal human aging.

The LMNA gene codes for a protein called lamin A, which constitutes a major component of the scaffold-like network of proteins just inside the cell's nuclear membrane, called the lamina. The gene mutation implicated in Progeria causes a section of 50 amino acids within the lamin A protein to be deleted, resulting in a mutated protein that is called progerin. This protein fails to integrate properly into the lamina, thereby disrupting the nuclear scaffolding and causing gross disfigurement of the nucleus. Cells with progerin have a nucleus with a characteristic "blebbed," or lobular, shape.

To find its way to the lamina, lamin A carries two tags, rather like ZIP codes, that help to direct the protein's travels. One tag at the end of lamin A instructs another protein to modify it through a process called farnesylation. Farnesylation tethers lamin A to the inner nuclear membrane. Once there, a second tag within the protein signals an enzyme to cleave off the terminal portion of the protein, including the farnesyl group, freeing lamin A to integrate properly into the nuclear lamina.

Because progerin carries the farnesylation tag but lacks the second cleavage tag, Capell speculated that progerin was becoming permanently stuck to the inner nuclear membrane. There, he suspected, it enmeshed other scaffolding proteins, preventing their proper integration into the lamina. If progerin's tendency to stick to the inner nuclear membrane is indeed the culprit in nuclear blebbing and the root of the Progeria defect, Capell and his colleagues reasoned that they could prevent these defects by blocking farnesylation of progerin.

The researchers' hunch proved correct. When they changed one amino acid within progerin's farnesylation tag to prevent the addition of a farnesyl group and tested the effect in cells grown in the laboratory, progerin did not anchor itself to the inner nuclear membrane and instead clumped within the nucleus. Moreover, they observed no nuclear blebbing.

The researchers then tried treating the cells carrying progerin with FTIs, which are drugs originally developed to inhibit certain cancer-causing proteins that require farnesylation for function. FTIs are now being tested in phase III clinical trials of patients with myeloid Leukemia.. So far, clinical trials using FTIs have found little toxicity, even when the drug treatment significantly raises levels of unfarnesylated proteins.

After FTI treatment, the progerin-carrying cells showed no blebbing. More importantly, researchers saw the same effect when they used FTIs to treat cells grown from skin biopsies of Progeria patients: Cell blebbing decreased to near normal levels.

In addition to Capell and his colleagues in NHGRI's Genome Technology Branch, researchers from the University of North Carolina at Chapel Hill and the University of Michigan School of Public Health in Ann Arbor took part in the study.

The HHMI/NIH Research Scholars Program gives outstanding medical and dental students the opportunity to conduct biomedical research under the direct mentorship of senior NIH research scientists.

High resolution photos displayed on this page of the Progeria cell changes brought about by FTI and of Megan, 5, are available at: www.genome.gov/10005141.

NHGRI is one of the 27 institutes and centers at NIH, which is an agency of the Department of Health and Human Services. The NHGRI Division of Intramural Research develops and implements technology to understand, diagnose and treat genomic and genetic diseases. Additional information about NHGRI can be found at its Web site: www.genome.gov.

The National Human Genome Research Institute (NGHRI) is sponsoring a 3-year Phase 2 study at the NIH Clinical Centre in America to examine the long term safety and effectiveness of Nitisinone (Orfadin). Nitisinone can be used for treating joint problems in individuals with Alkaptonuria, a disorder where there is a deficiency of an enzyme called homogentisic acid oxidase. This deficiency prevents a compound known as homogentisic acid from being broken down and this leads to a build up of the acid in the body. Homogentisic acid is destructive to connective tissue and bones.

To be eligible for the study, patients must be between 30 and 80 years of age and symptoms must have affected the hip, but have at least one remaining hip joint. Individuals are randomly assigned to one of two groups: one group takes their regular medicines plus a 2-mg Nitisinone capsule daily; the other group takes only their regular medicines. Patients taking Nitisinone have blood tests 2 weeks and 6 weeks after starting treatment to measure liver function.

Before starting therapy, all patients are admitted to the Clinical Centre for 4-5 days to undergo a number of clinical tests such as blood tests and x-rays. All patients, whether or not they receive Nitisinone, return to the Clinical Centre for a 2-3 day follow-up admission every 4 months for a history and physical examination, blood tests, and two 24-hour urine collections.

Every 12 months (12, 24 and 36 months after starting the study), patients also have repeat bone x-rays, spiral CT, kidney ultrasound, echocardiogram, and electrocardiogram. An MRI of the brain is done at the end of the study. Sixteen months after the end of the study enrolment period, the treated and non-treated groups are evaluated. If Nitisinone has delayed the progression of joint disease in the treated group, the study continues and all patients receive the drug for the remainder of the study. If not, the study continues for another 20 months, at which time the study ends and the evaluation process is repeated.

Patients who develop symptoms such as corneal crystals, pain, or severe liver or nervous system toxicity may be taken off the study.

Anti-social behaviour in children with Attention Deficit Hyperactivity Disorder (ADHD) may be associated with a variant gene involved in brain signalling, British researchers report.

This variant of the “catechol O-methyltransferase” (COMT) gene may also increase the susceptibility to the effects of lower birth weight the study said.

Researchers at Cardiff University in Wales looked for the COMT variant in 240 children, ages 5 to 14, with ADHD who were at high risk for early onset anti-social behaviour.

The study found a significant association between the COMT variant and anti-social behaviour and between birth weight and anti-social behaviour.

The researchers also concluded that interaction between this COMT variant could be associated with anti-social behaviour.

“Early onset anti-social behaviour in a high risk clinical group was predicted by a specific COMT gene variant previously linked with prefrontal cortical (brain) function and birth weight”, the study authors concluded.

The findings appear in the November issue of the journal Archives of General Psychiatry.

Giving cholesterol-lowering statin drugs to kidney transplant recipients may reduce their increased risk of heart attack and other cardiovascular events, a Norwegian study found.

“As patients continue to live longer after kidney transplantation, there is an increased need to prevent some of the long-term complications that can develop. One major risk is premature cardiovascular disease, related to high cholesterol levels after transplantation”, study leader Dr. Hallvard Holdaas of National Hospital in Oslo, said in a prepared statement.

The study included more than 2,100 kidney transplant recipients divided into two groups. One group received the cholesterol-lowering drug fluvastatin for up to eight years, while the other group received a placebo. All the patients in the study had good long-term functioning of their transplanted kidney.

In the group taking fluvastatin, the average level of so-called “bad” low-density lipoprotein (LDL) cholesterol decreased from 159 milligrams per decilitre (mg/dl) to 98 mg/dl. These patients also achieved a 21 percent reduction in their risk of heart attack and other major cardiovascular events, while their combined risk of death from cardiac causes decreased by 29 percent, compared to patients taking the placebo.

Both groups had a similar overall risk of death from all causes and similar rates of long-term survival of the transplanted kidney.

The study was presented Nov. 11 at the American Society of Nephrology annual meeting, in Philadelphia.

Two studies led by researchers at The University of Auckland's Faculty of Medical and Health Sciences have pioneered new, more effective treatment for two forms of Paget's disease - a chronic and often painful bone disease.

The results of the studies, one led by Professor Ian Reid, who heads the University's Bone Research Group, and the other by his colleague, Professor Tim Cundy have been published in separate articles in the latest edition of the prestigious New England Journal of Medicine.

Professor Reid led an international study which confirmed a new treatment for Paget's disease, giving a more rapid, effective and longer-lasting result than existing medication.

Professor Cundy's research focused on Juvenile Paget's disease, a rare genetic bone disease with some similarities to adult Paget's. Having earlier been involved in the identification of the genetic cause of the disease, he used an experimental new treatment that substantially relieved bone pain, improved bone density and reversed the metabolic abnormalities of the disease in two patients.

Paget's disease is the second most prevalent bone disease after osteoporosis and affects up to five percent of the older population in New Zealand. It is caused by a malfunction of the body's regular bone building process and results in bone pain, skeletal deformity, bone fractures, deafness and neurological complications. Generally onset is in people over the age of 40.

Juvenile Paget's disease, although very rare is very debilitating. It usually presents in infancy or childhood and results in progressive deformity, growth retardation and deafness.

"Paget's is very painful, affects mobility and can greatly affect the quality of life for sufferers, which is why new treatments are so worthwhile," Professor Reid says.

Professor Reid's international study pioneered the use of zoledronic acid, and showed that a single injection gave a rapid and long-lasting improvement in bone health.

"The new treatment quickly gives sufferers a much improved quality of life, and has a much lower rate of relapse than the conventional treatment."

A further benefit is that it is much easier on the patients - the conventional treatment with tablets requires patients to take daily oral medication in a strict daily regimen for up to six months.

The study involved nearly 360 patients from 10 countries around the world, including 15 from New Zealand.

Based on the results of the study, the new drug under the brand name, Aclasta, was licensed for treatment of Paget's disease in the European Union in April this year, Canada in June and is currently under regulatory review in the United States.

It has not yet been made available in New Zealand for Paget's disease.

Professor Cundy's patients were a brother and sister, who had been wheel-chair bound with Juvenile Paget's since they were 15. He used an experimental new treatment giving them recombinant osteoprotergerin, the protein that is lacking in sufferers and deficiency of which causes the condition.

"While the disease in these patients was too advanced for any treatment to correct deformity, it made enough of an improvement in their bones, and reduction in bone pain for us to believe it could be very useful in halting progress of the disease in infants and children."

American Society of Haematology Genetics (ASH-G) 27^th October. Promising results from a trial into a potential treatment for patients with Niemann Pick Type C (NP-C) were released today. The 12-month data presented at the ASH-G congress showed positive trends or stabilisation on the treatment, miglustat, in a range of neurological symptoms associated with the disease. It is the first study of a potential treatment to show such changes and has been called a watershed for those with NP-C.

NP-C is a fatal, degenerative, genetic condition primarily affecting children and teenagers. It is relentlessly progressive and most patients die within five to ten years of diagnosis. Neurological deterioration is a key feature of the disease, and some of the symptoms can be likened to the dementia seen in Alzheimer’s. It is difficult to diagnose and there is currently no treatment option for this condition.

Toni Mathieson of the Niemann-Pick Disease Group, added, “This trial is a watershed for everyone affected by NP-C - it is not only helping us to learn more about how this dreadful disease works but also raises the prospect of a treatment that has the potential to offer real benefits to patients for whom currently the outlook is bleak. ”

The study is being carried out at both The Royal Manchester Children’s Hospital, Salford and Columbia University (US) and is ongoing for a further 12 months. The results confirm that miglustat is crossing the blood brain barrier and accessing the brain and also suggest that there may be a restoration of function in neurons that have been altered by the disease process. Helena Prady, trials co-ordinator at the Royal Manchester Children’s Hospital commented ‘"These results are encouraging and I look forward to seeing the outcome of the 24month results. I am pleased that trends of improvement have been shown from 12 months treatment of miglustat in adult and juvenile patients with Niemann Pick C.”

The results also showed improvements in terms of patient and carer quality of life, an important factor to consider in the treatment of degenerative conditions. The importance of these trials was summed up by Helena Prady who went on to add, “Obviously the families of patients with Niemann Pick type C, have waited a long time for the trial and subsequently the 12 month analysis and I feel that they will be reassured by the safety reports and encouraged by the improvements reported although none reached formal clinical significance."

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