Biotechnology-driven therapies boost innovative treatments

New research by scientists at Imperial College London showing how drugs stick to a key protein in the bloodstream could help to create drugs that are delivered more effectively to organs in the body.

Their work gives a vital insight into how a large number of drugs are impeded from reaching their targets by the protein human serum albumin (HSA).
HSA is found at high concentrations in blood plasma and its primary function is to transport molecules of fat around the body. The protein also binds tightly to a wide range of different drugs, preventing them from travelling to their destination (Fig.1).
Scientists have produced detailed three-dimensional images showing how HSA binds twelve different drugs including ibuprofen, diazepam and warfarin. This information should help them to modify the structures of drugs to improve their effectiveness.
Stephen Curry, lead researcher on the study from Imperial’s Biophysics Group, said: “This is the first time we have been able to see high resolution images of HSA interacting with different drugs. Working out which features of HSA are responsible for binding drugs may make it possible to change the design of the drugs so they cannot be bound so easily.”

HSA’s ability to bind a variety of drugs often presents a serious problem during the development of new medicines. If a drug binds too tightly to HSA, it can get trapped in the bloodstream, meaning higher doses are needed to ensure that the drug's benefits are felt. Ideally, doses should be as low as possible to reduce the risks of toxicity or other side-effects.

Curry adds: “Usually drug companies want to prevent HSA from limiting the concentration of drug being released into the body. Our new information should help them to design features into new drugs to achieve this. However, sometimes the binding properties of HSA can be useful if you want to create a reservoir of drug that can be released slowly and our results should help here too.”

The structures of the HSA-drug complexes were determined using x-ray crystallography, a complex and delicate procedure whereby small protein crystals are grown after adding each drug to a purified preparation of the protein. Scientists then work out the detailed atomic structure, showing how the drug binds to the protein, by shining x-rays onto the crystal and analysing how these are scattered.

HSA is a particularly difficult protein to crystallise because it is a flexible molecule. This is the first time that scientists have succeeded in completing a survey of the binding modes of a range of drugs, although HSA’s structure has been known for over 10  years.

Genetics of pain disorder

Meanwhile researchers at the Flanders Interuniversity Institute for Biotechnology (VIB) have uncovered a small piece of the molecular puzzle behind neuralgic amyotrophy by identifying defects in the gene responsible for this disorder.

Hereditary neuralgic amyotrophy (HNA) is characterised by repeated attacks of pain in a shoulder, arm, and/or hand, followed by total or partial paralysis of the affected area.

The pain and the loss of movement usually disappear within a couple of weeks, but sometimes recovery can take months or even several years. Many HNA patients also have particular facial features, such as eyes that are somewhat closer together, a fold in the upper eyelid that covers the inside corner of the eye, and sometimes a cleft palate.

HNA is a relatively rare disorder: the disease appears in some 200 families worldwide. There is also a non-hereditary form of HNA, called the Parsonage-Turner Syndrome. The clinical picture of this more frequently occurring form – 2 to 4 cases per 100000 persons – is not distinguishable from that of the heritable form.

The attacks of pain are usually provoked by external factors such as vaccination, infection, operation, and even pregnancy or childbirth. By virtue of their genetic predisposition, carriers of the hereditary form of HNA run greater risk of having an attack. Its re-occurrence, and the fact that the disease is provoked by environmental factors, makes this disorder unique in the group of peripheral nervous system disorders. Therefore, HNA is a genetic model for more frequently occurring disorders such as the Parsonage-Turner Syndrome and neurological disorders such as Guillain-Barré Syndrome.

VIB researchers in Antwerp, under the direction of Vincent Timmerman and Peter De Jonghe, have discovered the genetic defect that underlies HNA. The work was carried out in conjunction with colleagues from the universities of Munster in Germany and Seattle in the USA.

The researchers studied several large families and identified the gene responsible for the disorder. They have now shown that HNA is linked to the long arm of chromosome17, and they have found mutations or alterations in the genetic code of the Septin9 protein in the patients being studied. HNA is the first mono-genetic disorder caused by a defect in a gene of the Septin family.

The researchers do not yet know exactly how Septin 9 functions in the peripheral nervous system or why mutations give rise to HNA. They do know that other members of the Septin family are involved in the cell division that forms the cytoskeleton and in the development of tumours. The fact that mutations in Septin9 prevent cell division from occurring properly can perhaps explain why so many HNA patients also have facial abnormalities.

Today, no effective therapies yet exist to retard or prevent the progress of HNA. The current treatment is merely supportive. The findings of the researchers in Antwerp are a first essential step in the development of a specific treatment. Now that they know the gene involved, scientists can acquire more insight into the molecular processes of this disease, which may ultimately lead to a therapy.

Vaccinating against Alzheimer’s

An innovative vaccination can significantly reduce deposits of the substances in the brain responsible for causing Alzheimer's disease according to results disclosed by Affiris, a company located at the Campus Vienna Biocentre in Austria.

The rapid progress during the pre-clinical development phase has already enabled the Vienna-based company, although having operated only since April 2004, to plan clinical trials for 2006.

Beta-amyloids are pathological fragments of a normal brain protein. They are responsible for the development of Alzheimer’s disease, as they cause the death of brain cells. Amyloid fragments are found in large amounts in the cerebral fluid of Alzheimer patients. Deposits are formed in the brain over the years, thus creating the plaque structures typical of Alzheimer’s disease.

Affiris is reporting that it has succeeded in significantly reducing Alzheimer plaques by at least two-thirds in pre-clinical models by means of an innovative vaccine. Affiris’ vaccine approach has been shown to be highly specific for beta amyloids and not to react with the normal constituent of cerebral cells.”

So the Affiris approach not only avoids an autoimmune disease, but also offers the advantage of targeting simultaneously both the plaques and the soluble beta-amyloid fraction.

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