Computer-Based Antibodies to Treat Alzheimer's Disease

A research team from the University of Cambridge has developed antibodies which target the toxic protein deposits in the brain of Alzheimer’s disease patients, thereby stopping the production of these proteins. The antibodies were developed using computer-based methods, targeting the misfolded proteins which are classic of Alzheimer’s. The scientists tested the newly developed antibodies in test tube based experiments and also on nematodes, finding that there was total elimination of the pathogens. The study was published in the journal Science Advances.

Mechanism of Action

The toxic deposits, amyloid beta, that accumulates in patients with Alzheimer’s disease is systematically scanned by the antibodies. These newly developed antibodies target regions on the amyloid beta sequences that prevent these toxic substances from forming aggregates.

Alzheimer’s disease is one of the most common forms of dementia among the elderly and is characterized by problems associated with memory, behavior and thinking. This neurodegenerative disorder is found to affect more than one million people in the UK and nearly 50 million across the world. In India, the number of people with Alzheimer’s disease continues to increase due to its vast population.

The characteristic toxic build-up of plaques affects the brain of the patients with symptoms that include loss of memory, poor language skills, irritability and outbursts of anger. The protein deposits that occur in the brain are naturally occurring proteins that are folded wrongly, leading to aggregation that damages the brain. The two proteins are:

• amyloid-beta
• tau (τ proteins)

The protein aggregation that occurs also leads to small clusters called oligomers which are believed to be damaging to the brain as they are toxic to nerve cells. The exact mechanism that is involved in the development of Alzheimer’s disease remains unknown and scientists have been trying to find a method of preventing the aggregation of these toxic proteins in the brain.

Antibodies have for so long been used to target antigens which are harmful pathogens. The current study utilizes this mechanism of the antibodies to find a method of preventing the toxic protein aggregation in Alzheimer’s disease. Though there are a few antibody-based treatment methods that are currently being trialed in clinical trials for Alzheimer’s disease, there are no antibodies that have been specially developed to treat Alzheimer’s till now.

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The senior author of the paper from The Centre for Misfolding Diseases in Cambridge, Dr. Michele Vendruscolo said that developing the antibody-based therapies was time-consuming and involved a lot of money, but the essence of developing an effective treatment lay in developing cost effective antibodies that would improve the chances of treatment.

Methods of Producing Antibodies

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Currently, there are two main methods of developing antibodies

• Injecting animals: This method of developing antibodies have been in use for longer than 50 years, and it involves the injection of animals with the antigen. This antigen then elicits an immune response from the host, which results in the development of antibodies. These antibodies are extracted and used for therapy.
• Laboratory-based Antibodies: In the laboratory-based method, there are large libraries that are constructed to isolate relevant antibodies.

The co-author of the study, Dr. Pietro Sormanni, said that the technological advancements in computers have been useful in developing and designing antibodies using computers. This postdoctoral researcher further stated that these antibodies have certain advantages over traditional antibodies like:

• Being able to target specific regions on the antigen
• Being stable
• Being soluble
• Being smaller in size

The size of these antibodies is one of the major advantages, as these antibodies are single domain antibodies, which means that the aspect of antibodies that elicit an immune response has been removed. The ability of these antibodies to trigger an immune response has been the major reason behind an inflammatory response following antibody use, preventing them from being used in the treatment of Alzheimer’s disease thus far. However, the newly developed antibodies are now devoid of the ability to trigger an immune response and, therefore, will not be able to lead to an inflammatory reaction.

Since the antibodies are designed using a computer, they are systematically altered to bind to the various regions of the antigen. This would help the scientists define the best method of preventing the aggregation of toxins in Alzheimer’s disease.

Treatment of Alzheimer’s Disease with Drug Therapy

Alzheimer’s disease has been treated with drug therapy that is largely symptom based. The drugs are used to lower the intensity of cognitive decline. The amyloid beta aggregates are known to begin about 20 years before the onset of the disease, therefore, for effective treatment, and to prevent the disease, treatment should begin before the onset of symptoms.

There are two monoclonal antibodies that are currently under clinical trials for use as treatment for Alzheimer’s disease

• Solanezumab these antibodies have shown to be effective against cognitive decline that is found to affect Alzheimer’s disease patients
• Gantenerumab and Crenezumab – These antibody-based treatment methods are aimed at controlling the course of the disease.

The treatment methods involve larger costs and lead to inflammation, which the current computer-based antibodies have been designed to solve. The computer-based antibodies could be used alongside traditional antibodies to help treat Alzheimer’s and to improve the quality of life led by patients with Alzheimer’s disease.

References:

1. What Is Alzheimer’s? - (http://www.alz.org/alzheimers_disease_what_is_alzheimers.asp)
2. Alzheimers in India - (http://www.alzheimerindia.org/alzheimers-in-india/)
3. Novel strategies for Alzheimer’s disease treatment: An overview of anti-amyloid beta monoclonal antibodies - (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5155461/)

Source-Medindia