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Prof Timothy Cox has guided the Gaucher's Association since its early days in 1991. He works in one of two adult Gaucher's Centres in the UK at Addenbrooke's Hospital, Cambridge. This is a summary of his talk at the Conference in Manchester on 25 April 1999 where he reviewed present, future and past treatments for Gaucher's disease and the problems that patients still have to cope with:
Although enzyme replacement therapy has been successful in treating many of the symptoms of Gaucher's disease, for example increasing blood counts and decreasing the size of the spleen and liver, it has not been completely successful in treating aspects of the disease as it affects the skeleton, even on high doses.
In the case of children, it has helped their bones grow and thicken but in my view its effect on the bone condition of adults is less clear.
Nonetheless, patients receiving enzyme replacement therapy have had a 10-20 fold reduction in the frequency of bone crises (infarctions) - even so two of our patients have had crises shortly after starting therapy.
Death of the Bone
The most common residual bone condition of adults with Gaucher's disease is avascular necrosis in their hips and vertebrae (spine) and some-times in bones close to other joints.
Avascular necrosis means the death of the bone due to deprivation of its blood supply. This is probably caused by obstruction to the fine blood vessels at the growing ends of bone. Evidence of the damage will not appear on an X-ray until several, maybe six weeks, after the bone dies. Doctors unfamiliar with the condition will fail to recog-nise it because despite severe pain, there may be few signs of disease during the early phase of the attack.
Swelling in the Bone
In some individuals with Gaucher's disease, tissue in the bone expands greatly ('Gauchoma'). Sometimes the swelling has an eggshell-like appear-ance on X-ray and the patient can feel a crackling within the bone. As the bone swells, its cortex (outer layer) may thin in response to the Gaucher's tissue adjacent to it and the cortex can erode (osteolysis). This is painful and the bone may fracture on any injury.
Thinning of the Bone
General bone thinning or osteoporosis is where there is loss of bone substance and mineral content which causes the bone to fracture or collapse easily.
Bone remineralisation does occur but the bone is excessively resorbed (taken away). Normally the formation and resorption of bone is almost equally balanced; but when the bone formation/resorption cycles increase, then the bone slowly loses density.
The formation/resorption cycles allow bone to re-model and adapt to changes in patterns of strain brought about by weight bearing. It appears that these cycles are controlled by physical factors (including exercise) as well as hormones and other chemical messengers in the body.
The female sex hormones, especially oestrogens are important here, as are messengers of inflammation, the interleukins. With support from the Gaucher's Association, we recently showed that interleukin 6 is three fold elevated in Gaucher's disease. Interleukin 6 is increased in many inflammatory states and is known to be critical in the control of bone density: mice that lack interleukin 6 do not develop osteoporosis in response to the induction of an artificial menopause.
Osteoporosis occurs with disuse, in smokers and in those who otherwise drink more alcohol than is considered good for them.
There are several bisphosphonate drugs available. Pamidronate is given by infusion once every few weeks or months and there is evidence that this has improved bone lesions (abnormalities) in several children with severe skeletal Gaucher's disease. There is additional anecdotal evidence that pamidronate helps improve bone density and causes a reduction in fracture risk - as this class of drugs does in patients with more typical forms of osteoporosis. Pamidronate is very beneficial in other metabolic bone diseases including Paget's disease (for which it is licensed) and osteogenesis imperfecta in children - a disease causing fragile bones.
Alendronate (Fosamax) and etidronate (Didronel) are bisphosphonate drugs taken orally. They are licensed for the treatment of post-menopausal women with osteoporosis and these drugs have been given to some patients with Gaucher's disease. We know little of these effects in Gaucher's disease, yet.
Bisphosphonates work by inhibiting the resorption (taking away) of bone, thus reducing risk of fracture, increasing bone mineralisation and improving the solidity of bone. There has been no evidence that these drugs reduce the frequency or effects of bone crises. We await the outcome of trials shortly to be carried out in the US on the influence of alendronate (Fosamax) on Gaucher's disease and its many manifestations in the skeleton.
Vitamin D and Calcium help keep bones healthy and may be recommended in patients found to be deficient in these although this is an unusual finding in Gaucher's disease. These agents have a weak but significant protective effect on the skeleton in patients with osteoporosis due to hormonal deficiency (eg after the menopause and in the elderly).
Hormone Replacement Therapy in post-menopausal women should also help increase bone mineral density which is doubly threatened in patients with Gaucher's disease, partly because of hormone changes.
Raloxifene (Evista) is a hormone receptor modulatory agent licensed in 1997. This is an alternative to hormone replacement therapy and decreases the effects of osteoporosis. Its actions resemble those of hormones: fracture risk is decreased in post-menopausal patients with osteo-porosis. An advantage is that there would be no return of mentrual bleeding in women receiving this agent and that the drug has been shown to reduce the risk of breast cancer in women who receive it.
Cathepsin K is an enzyme we have found to be overactive in Gaucher's disease. Previously this enzyme of the osteoclast (the macrophage-like cell which breaks down and eats up bone) has been implicated as a target for drug treatment of osteoporosis because it is essential for the normal bone absorbing (taking away) properties of these cells.
Our PhD student Mary-Teresa Moran has found cathepsin K in Gaucher's tissue suggesting a possible role in the cortical bone erosions and ?Gauchomas' that affect some patients. We think there may be a place for using one of the new cathepsin K inhibitors for this indication.
OGT 918 - Substrate Deprivation in Gaucher's Disease
A clinical trial is currently underway using a drug N-butyl deoxyno-jirimycin, now called OGT 918, which reduces the formation of glycolipids (a fatty material which in the case of Gaucher's disease is glucocere-broside). In Gaucher's disease, the glycolipids are stored in macrophages which are certain cells in the body that destroy old cells and dead microbes in order to recirculate the chemical building blocks that they contain.
Normally the glucocerebroside is broken up and taken away but in the case of Gaucher's disease excess glucocerebroside is stored. This is because there is not quite enough of the enzyme glucocerebrosidase to get rid of it. Macrophages are found all over the body and originally come from the bone marrow but they are particularly active in the lung, spleen and liver.
Excess glycolipids containing different material are formed in many lysosomal storage diseases including Gaucher's disease, Tay-Sachs disease, Sandhoff's disease and Fabry's disease. In these diseases the glycolipids build up in cell types other than macrophages thereby causing the clinical picture unique to each particular condition.
Developed from natural sugars that occur in mulberry leaves, OGT 918 is a simple compound and has been tested on mice with Tay Sachs disease and Sandhoff's disease in a series of experiments by Fran Platt, Terry Butters and colleagues. The mice have been specifically created by gene targeting to show all the disease manifestations of their human coun-terparts, expressly for studies of this kind. Similar efforts to create a model of Gaucher's disease mice resulted in severe Type 2 disease which rapidly died after birth although now Dr Ed Ginns has after eight years produced a convincing model of Type 1 Gaucher's disease that promises to be very useful for the study of new treatments.
The results showed that the treated Tay Sachs mice, which have a normal life expectancy, had a reduction of storage material in their brains and the Sandhoff mice, that show severe signs of disease, had a prolonged life. This was related to the effect of the sugars on the formation of the glycolipids.
Clinical Trial of OGT 918
The trial with Gaucher's disease patients will show if we can shift the balance so that their residual enzyme can remove the necessary amount of glucocerebroside and improve their clinical outcome by correcting the excess burden of storage material in the macrophage system.
The investigation is being carried out on Type 1 adults although eventually we hope that the drug will be used in Gaucher's patients with neurological disease. The participants have never received enzyme therapy or at least not for three months before starting the drug so that its effects can be fully examined.
The trial is running at four centres: Cambridge, Amsterdam, Prague and Jerusalem and will be completed in December 1999 with the results published as early as possible in early 2000 after data analysis had been completed. The drug is now provided by Oxford GlycoSciences.
Patients take 100mg three times daily by mouth for one year. This is estimated to give sugar concentrations in the non toxic effect range. The drug has been found to be fairly well tolerated by patients although mild stomach upsets have occurred as we know from the use of a very similar compound in a previous trial.
A closely related form of the drug was used earlier in a trial for HIV. A larger dose of 3 grams a day was used on about 100 volunteers but it was not found to be effective for HIV. However it was tolerated and found to be safe in humans - a useful platform to design a trial in Gaucher's disease.
Approval for the clinical trials in each of the participating centres was given by the local Research Ethics Committee and by the Medicines Control Agency in the UK that supervises the proper conduct of trials of this kind.
We also have approval to raise the dose gradually to 300mg three times a day after six months treatment and if the drug proves to be beneficial for an individual on the trial, to apply to use it in the long term for their disease.
By January 1999 a full complement of 28 patients was enrolled. All had given written consent to participate. They are being fully monitored including data on long standing medical status, unwanted effects, how long the drug stays in the blood, its maximum and minimum concentrations, blood parameters and disease activity with measurements of serum chitotriosidase and other kidney and liver tests.
To summarise: this is a trial of what is termed 'substrate deprivation therapy' using OGT 918, the intended aim of which is to reduce the amount of glycolipid material turned over in individual cells, including brain cells, to a minimum so as to reduce the excess that is stored. Its main mode of action in Gaucher's disease will be to reduce the amount of membrane glycolipids on blood cells that are ultimately delivered to the macrophage system, thereby eventually allowing the macrophages to recover from the effects of storage.
Ultimately if proven to be successful and safe in Gaucher's disease, OGT 918 and related imino sugars of this class will be used in the more severe lysosomal storage diseases such as Tay-Sachs and Sandhoff's disease. As explained above, patients with the neurological varieties of Gaucher's disease may also benefit from this novel approach to the glycolipid storage disease.
At present a trial of the drug is underway in Fabry's disease which is a glycolipid disorder of the endothelial cells that line small blood vessels in the kidneys and nerves. The results of the trial of OGT 918 in Gaucher's disease are however expected to lead the way for the clinical application of substrate deprivation to human illness.
Prof Cox listed other treatments which have helped those with Gaucher's disease:
Source: Gaucher's News July 1999
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© Copyright Gaucher's Association 1999