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_{By Henrik Larsen}

Is it possible to develop an entirely new type of medicine that can enable a brain affected by the dementia disease Alzheimer’s to begin repairing itself?

There is in fact evidence to suggest that this may be possible, according to three researchers from the Department of Cellular and Molecular Medicine at the University of Copenhagen (UCPH). With support from the Lundbeck Foundation, they are now setting out to try to demonstrate it.

Their work builds on a series of experiments they have already carried out in the laboratory. In experiments involving human cells, fruit flies and mice, the trio of researchers were able to establish that, by means of a modified molecule, they could stimulate the repair of the type of DNA damage in brain cells that is seen, among other conditions, in Alzheimer’s disease.

“Overall, our work is about identifying and further developing molecules that can reduce existing damage to DNA in brain cells and strengthen the cells’ own repair mechanisms,” explains assistant professor Garik Mkrtchyan, who is leading the project.

“In relation to Alzheimer’s, we are working with a molecule that we have modified, and in our laboratory experiments we were able to show that this molecule had a positive effect. We will now continue this work in an effort to develop an entirely new type of medicine for Alzheimer’s,” says Garik Mkrtchyan, whose speciality is drug development.

His two collaborators on the project are Morten Scheibye-Knudsen, MD, PhD and associate professor, who specialises in DNA damage in connection with ageing, and Daniela Bakula, PhD and assistant professor, who specialises in the molecular biology underlying ageing.

The great hunt for molecules

When the three researchers from the University of Copenhagen speak of developing an “entirely new type” of medicine for Alzheimer’s, this largely relates to how they intend to tackle the disease, explains Morten Scheibye-Knudsen:

“Conventional Alzheimer’s medicines target the accumulation of fragments of the protein beta-amyloid, known as plaque, which builds up in the spaces between nerve cells in the brain as the disease progresses. Our approach is different, however, because instead of targeting plaque directly, we seek to reduce DNA damage and strengthen the brain cells’ own repair mechanisms. The type of Alzheimer’s medicine we are working to develop has not been seen before.”

Before the researchers could begin experimenting in the laboratory, however, they had to embark on a very extensive search to identify medicinal active substances with particular properties, explains Garik Mkrtchyan:

“Using advanced analytical models based on artificial intelligence (AI), we examined approximately 15,000 different molecules and their ability to stimulate DNA repair. It was a very comprehensive analysis, which ultimately led us to identify the molecule that we have further developed by modifying it.”

The molecule in question is well known, but for reasons relating to patent rights the researchers do not wish to disclose its name, or the precise way in which it has been modified, at this stage.

The Lundbeck Foundation, which focuses on supporting brain research, is however familiar with the details behind the research trio’s preliminary results and laboratory experiments. The foundation considers the project so promising that it has just decided to support it with DKK 4.3 million in the form of a Frontier Grant. This research grant will be used by the trio for further development and investigation of the modified molecule, with a view to commercialising their discovery at a later stage.

In the laboratory

Once the three researchers had identified and modified the molecule they wished to work with, they began a series of experiments in the laboratory, all focusing on DNA damage.

DNA damage occurs throughout life in our cells and is the result of various forms of stress, both from external sources and from within our own bodies.

“In reality, there is an enormous number of DNA lesions over the course of a lifetime — up to 100,000 lesions per cell per day! To deal with these, the body has a repair system. But the older we become, the less effectively this system functions,” explains Garik Mkrtchyan.

Some of the experiments conducted in the laboratory examined whether the ‘tailor-made’ molecule could reduce existing DNA damage in cells while at the same time stimulating the cells to begin repairing themselves.

The first series of experiments was carried out in petri dishes using living cells from people suffering from a disease that causes them to age at an extraordinarily rapid rate. When these cell experiments yielded positive results, the researchers moved on to working with fruit flies, and later with mice.

“Fruit flies usually live for around 60 days in the laboratory, and in the latter part of their lives — in their old age, so to speak — they are relatively physically inactive. However, when we gave normal, healthy fruit flies doses of the modified molecule, we observed something interesting: they lived longer than they otherwise would have done, and they also maintained a relatively high level of activity in the final phase of life,” says Garik Mkrtchyan.

In another experiment involving fruit flies, the three researchers were also able to show that the modified molecule enhanced the flies’ ability to repair existing DNA damage in their cells, says Morten Scheibye-Knudsen:

“In this experiment, we worked exclusively with flies that, through genetic manipulation, have a reduced efficiency of their cellular repair system and therefore age more rapidly than normal fruit flies. Here we could see that the fruit flies that received the modified molecule performed significantly better than the control group that did not receive it.”

This was followed by experiments in mice, in which the three researchers used so-called Alzheimer’s mice — a strain of laboratory mice that, through genetic manipulation, have had a dysfunctional memory function ‘built into’ their genetic makeup. This congenital memory defect becomes increasingly pronounced as the mice grow older.

Some of the Alzheimer’s mice were given a dose of the modified molecule in their drinking water from the age of two months. And this had an effect, explains Daniela Bakula:

“By six months of age, when the ‘built-in’ memory impairment really begins to manifest itself, these mice performed markedly better in various tests than the Alzheimer’s mice in the control group that had not received the molecule — almost as well as completely normal mice. This was true both in terms of memory and motor function.”

The path to medicine 

The aim is for the modified molecule eventually to form part of a medicine for Alzheimer’s, a disease for which modern medicine currently has no effective treatment. However, the road to a drug is long.

The three researchers must now carry out a series of further laboratory experiments with the modified molecule before it can be tested in human trials.

These laboratory studies are partly intended to ensure that the substance does not cause cancer, and partly to gain more knowledge about how the molecule actually works. Finally, the mouse experiments must be repeated, this time using a different strain of Alzheimer’s mice, to see whether the same positive results are obtained.

“If no problems arise in connection with these control experiments — and we can therefore proceed with the modified molecule we have developed — it is realistic to test it in the first human trials within approximately two years. If, however, it proves necessary to develop a different modified molecule, the timeline is somewhat longer. In that case, we are probably talking about closer to five years — and in both scenarios it would then take a number of years to reach a final medicinal product. So, this is not something that is just around the corner,” says Morten Scheibye-Knudsen.

Read more about the Lundbeck Foundation Frontier Grant:

Frontier Grants

Frontier Grants facilitate transitions from basic research to attractive prospects for biotech investors