Researchers to prepare "gene tonic" for the extinguishing brain of Alzheimer's patients

San Diego 08 January 2000American brain researchers at the Department of Neurosciences from the University of California in San Diego (UCSD) are now setting up an experiment to treat patients suffering from Alzheimer's disease with a novel, revolutionary gene therapy. In a couple of months, genetically manipulated skin cells will be implanted into the brain of the first one of eight selected patients with a mild form of Alzheimer's, the most well-known cause of old age dementia. The skin cell referred to as fibroblast, can be modified in the laboratory to secrete the human albumen known as the Nerve Growth Factor (NGF). Initially, the UCSD team will have to check whether this NGF therapy does not involve any dangerous risks for the patient. In a later stage, it will be possible to investigate if the treatment is able to slow down and preferably even stop the decline of the patient's memory and other cognitive functions.


Dr. Mark H. Tuszynski will be leading the experiment. In October last year, the United States Food and Drug Administration (FDA) has granted permission to perform the clinical test. Shortly afterwards, the Recombinant DNA Advisory Committee, which is providing the US government with advice on experiments with gene therapy, stated its agreement as well. A nearly ten-year period of animal experiments has preceded the use of gene technology to restore brain functions within Alzheimer's patients. Dr. Mark Tuszynski has done several tests on rats and monkeys. In September 1999, he and his colleague, Dr. Fred Gage, published a final report on an experiment in which the brain of old rhesus monkeys was injected with human NGF. As a result, certain brain cells which normally tend to decay both in number and size as the apes grow older, now restored almost fully thanks to the NGF therapy.

The restored cells constituted the neurons in a central part of the brain, the so-called basal cholinergic kernels, which play a crucial role in higher brain functions, such as learning, memory, and concentration. As a matter of fact, they manage the information stream in the higher parts of the brain. Also in elderly humans with Alzheimer's disease, this type of neurons located in the basal cholinergic kernels, has been affected. The logical thought behind the animal experiment is that a similar NGF injection might delay and even stop the patient's mental decline. Already some seven years ago, a Swedish team of researchers has directly introduced NGF into the brain ventricles of three Alzheimer's patients. This particular method was chosen because the Nerve Growth Factor cannot be transported to the brain via the blood. The blood-brain barrier prevents the albumen to reach the brain.

The Swedish clinical test was no success. Two NGF-treated patients suffered from neuralgia through the whole body and from loss of weight, while it was impossible to confirm whether the therapy had improved the brain functions in the third patient. The neuralgia and loss of weight seem to be caused by the fact that NGF not only has a crucial impact on the neurons in the basal cholinergic area but equally has an influence on other parts of the brain, like the centres which regulate the appetite and the peripheral nerve system. As a result, several researchers have tried other ways to administer NGF to the brain. Animals have been injected with NGF-producing cells, which first had been encapsulated in a polymere. Other techniques consist in coupling NGF to antibodies reacting against the transferrine-receptor, in order to pass the blood-brain barrier. These methods however were never tried on humans.

Gene therapy is about to change all that. Dr. Tuszynski and his colleagues will take skin cells from the bodies of the eight selected Alzheimer's patients. In the laboratory, the cells will be treated with a virus to introduce the gene which is responsible for the production of the NGF albumen. The genetically manipulated skin cells then will be placed into the patient's basal cholinergic area via a thin syringe. The great advantage in comparison with the Swedish experiment is that the NGF-administering is performed locally to prevent the NGF from spreading through the brain and the spinal cord. Dr. Tuszynski wants to implant the NGF-producing skin cells at five or ten locations within the brain. Possible complications of the procedure consist in the potential risk of brain haemorrhage, the occurring of a brain tumour and the chances at chronic pain and loss of weight.

Taking into account these risks, Dr. Tuszynski decided to select patients to participate in the experiment, who were diagnosed with Alzheimer's disease no longer than two years ago. The test persons indeed will have to be able to communicate in a normal way and to understand the risks the clinical test involves. Whether the experiment will be successful for humans still remains uncertain in view of the fact that Alzheimer's does not occur in animals. In this regard, Professor Dr. Dick Swaab, who is working at the Dutch Institute for Brain Research in Amsterdam, observes that the neurons of Alzheimer's patients have become far less sensitive to NGF since the spots to contain the NGF on these neurons have substantially reduced in number. Therefore, Dr. Swaab's team is trying to develop novel methods to restore the receptors for NGF within these neurons. More news on gene therapy is to be found in this very issue in the VMW article Cold sore virus possibly could help treat Parkinson's disease. We have used de Volkskrant as the major source of data for this article.

Leslie Versweyveld

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