The brain is the control center for most of the functions throughout the body; it is also where we experience the physical world around us and perceive our inner psychological and emotional selves. It is where thought, love and dreams are conjured up and where memory is embedded.
But with ever-increasing longevity we must now watch increasing numbers of our aging friends and relatives suffer the frustrations and humiliations as neurodegenerative diseases erode the most basic, the most human of brain functions. Sometimes the damage is so great that basic cognitive faculties are lost and even the uniqueness of the individual seems to fade away. Such is the decline associated with Alzheimer’s disease. And sometimes those once strong and sturdy are bent low with trembling gait and slurred speech as they succumb to Parkinson’s disease.
At the Hebrew University, cutting-edge research has already given some sufferers of these diseases some of the first medical interventions available to help control and alleviate the symptoms of these diseases. Now ground-breaking research is pointing the way to new understanding and novel therapies.
The brains of patients who suffer from advanced Alzheimer’s disease are wasted and shrunken. Under the microscope it becomes clear that large numbers of neurons die and are coated with a protein-like substance known as amyloid plaques. Within the cells a tangle of proteins can be seen.
One approach is to investigate these tangles and plaques but Professor Marta Weinstock-Rosin, incumbent of the Dr. Leon and Dr. Mina Deutsch Chair in Psychopharmacology at the HU School of Pharmacy, sees the problem differently. “If we are going to produce a drug that can impact on and slow the progress of Alzheimer’s then we must be able to replicate its earliest stages,” she says. Careful experiments using an animal model that mimics the early symptoms of Alzheimer’s provide her with the testing ground for a new generation of drugs to treat the disease.
Weinstock-Rosin certainly has the credentials for success. It was her research over 20 years ago that produced RA7, now sold worldwide under the trade name Exelon – one of the first Alzheimer’s medications. Unique among drugs used to treat Alzheimer’s, Exelon targets only specific parts of the brain and doesn’t have a deleterious effect on other parts of the body.
Marketed by the Swiss Pharmaceutical company Novartis, Exelon has already helped hundreds of thousands of patients and has an annual sales turnover in excess of $350 million. In June 2006 Exelon received further FDA approval for treating mild-to-moderate dementia associated with Parkinson’s disease.
Although Exelon can do much to improve the quality of life for about one-third of all Alzheimer’s patients by slowing the progress of the disease and improving memory skills, it only remains effective for a few years.
Weinstock-Rosin’s latest research focuses on a novel drug called ladostigil and which combines Exelon with Rasagiline, a Parkinson’s disease treatment developed by Professor Moussa Youdim of the Technion-Israel Institute of Technology.
Following a chance conversation between them in 1994, Weinstock and Youdim realized that by combining their expertise and amalgamating the active components of their respective drugs, they might produce a more powerful new drug for combating and controlling the progress of Alzheimer’s. Their research has been funded by Israel’s leading drug company, Teva Pharmaceuticals.
Using an animal model to test the drug, some of the earliest stages of Alzheimer’s disease have been elucidated and insights have also been provided into the workings of the normal brain.
The brain comprises two chief types of cells – neurons and glia. Neurons are responsible for all the mental processes of understanding; the glia provide the support and protection essential for normal neuron function. The glia consist of different types of cells including astrocytes which reach out with long fibrous structures and cling to neurons, supplying them with nutrition and oxygen. There are also microglia which act as the brain’s local immune response, devouring intruders such as viruses or bacteria that might disturb the healthy function of the brain.
The brain, even a sleeping brain, requires a great deal of energy which is provided through metabolism of glucose in the astrocytes. Unfortunately, this metabolic process produces highly reactive “free radicals” and as we get older the brain fails to produce enough of the enzymes needed to neutralize them. Instead these oxidative free radicals rampage through the brain, attaching themselves to cell membranes and various proteins.
Recognizing these free radicals as dangerous intruders, the microglia spring into action and a full-blown immune response is initiated with special chemicals called cytokines released. The cytokines attack the astrocytes and glucose can no longer be metabolized. The energy supply to the brain is thus decreased, the neurons can no longer function properly, and memory begins to fail. Alzheimer’s has claimed another victim.
Having developed a rat model that replicates these early features of the disease, Weinstock-Rosin has been able to test the drug ladostigil. The results are impressive: the drug is able to combat the initial stages which lead to degeneration. It plays a key role in restoring normal metabolic processes in the brain’s support system – the astrocytes return to their normal status, neuron function is restored, and memory skills return.
Now nearing completion of clinical trials Phase II, ladostigil has so far been proven a safe drug. The experiments with animal models demonstrate that the drug can not only slow the loss of cognitive function in Alzheimer’s and Parkinson’s diseases but also help alleviate symptoms of major depression. Weinstock-Rosin is convinced that these three debilitating forms of attack on normal brain function have common elements.
Diseases like Alzheimer’s and Parkinson’s do not have a single, simple cause. In an organ as complex as the brain many processes seem to lead to neurodegeneration.
It has become clear through the research of Professor Hermona Soreq, Dean of the Faculty of Science and a member of the Department of Biological Chemistry in the Alexander Silberman Institute of Life Sciences and the University’s multidisciplinary Eric Roland Center for Neurodegenerative Diseases, that stress, both psychological and chemical, has an impact on the progress of neurodegenerative diseases and even affects neuromuscular and blood cell diseases.
Soreq has pioneered the development of new techniques to explore the underlying processes which produce damage and she has successfully identified the mechanism whereby anxiety and stress exacerbate neurological diseases such as Alzheimer’s. She is now progressing with the development of highly innovative treatment.
Soreq is driven by a two-fold quest. “By improving our understanding of the diseased brain, we can develop better ways to prevent and treat,” she says. “However, if we study the changes that take place in a system pushed to the extreme, then we also learn how it functions normally – this is a basic research goal.”
In the brain a large family of neurotransmitters moves between neurons. These chemicals form the web of communication between neurons which is the very essence of normal brain function. The normal brain produces a large family of neurotransmitters. They are secreted by one brain cell, move across to another, latch on to a receptor and thereby stimulate processes within the second cell. Cascades of neurotransmitters create a whole web of communication between different cells in the brain.
In Alzheimer’s disease this network is disrupted. The amount of an essential neurotransmitter, acetylcholine, drastically declines; the connection between brain cells is broken, and memory and other brain functions eroded.
The disappearance of this neurotransmitter under stress has been shown by Soreq to be due to the stress-induced overproduction of acetylcholinesterase (AChE). This enzyme actively destroys too much acetylcholine, leaving the brain lacking a neurochemical essential for its normal cognitive, emotional and psychological functioning.
To prevent the progress of Alzheimer’s disease it is necessary to prevent this excess elimination of acetylcholine. While existing drugs inactivate the destructive enzyme AChE, Soreq and her team have taken a highly original approach. They have designed a drug which prevents AChE from even being produced by the brain.
AChE, like all enzymes, is manufactured by instructions contained in the genetic code on a stretch of DNA in the nucleus of a cell. It took Prof. Soreq’s team five years to identify the actual gene responsible for the manufacture of this particular enzyme. This pioneering work involved developing completely new research tools to carry out these technically innovative procedures.
Having identified the gene, the scientists made an inverse copy of it. This mirror image of the gene could then lock onto the original stretch of the gene, rather like two pieces of a jigsaw fitting together perfectly. The new DNA-based drug clips on to the exposed gene, making it a sealed unit and creating an unfamiliar package in the cell. The cell immediately identifies it as an unwelcome intruder and destroys it, just as if it were an invading virus.
This protective drug, know as Monarsen (for Prof. Soreq’s nickname “Mona”) has been developed through the start-up biopharmaceutical company, Ester Neuroscience. It is already being administered to a group of patients as part of Phase II clinical trials under the approval of the US Food and Drug Administration (FDA), which has designated it as an ‘orphan drug’ for the treatment of the rare muscle-wasting autoimmune disease myasthenia gravis.
Monarsen will soon be poised to enter final Phase III clinical trials. If the drug continues to prove its efficacy, it will receive the essential FDA approval that permits it to enter the pharmacopoeia available to the prescribing physician. “The development of a new drug costs well over $500 million; most of the investment goes into this last phase,” says Soreq, who is optimistic that Ester Neuroscience will find a strategic partner for this potentially powerful new weapon against the misery and debilitation caused by Alzheimer’s and other inflammatory diseases such as myasthenia gravis.
(Reprinted with permission from Scopus Magazine – to read an unabridged version of the article, click here)