"Good proteins gone bad" is one way to characterize the causes of two dreaded neurodegenerative conditions, Alzheimer's and Creutzfeld-Jakob diseases, both of which ravage cognitive function and ultimately kill their victims. In each case, an aberrant protein is the culprit in the disease pathology. Creutzfeld-Jakob is an infectious disease in which corrupt proteins - prions - infect normal ones and destroy brain tissues. In Alzheimer's, toxic deposits of amyloid protein, among others, form when it interacts with sulfated glycosaminoglycans, or GAGs. This interaction leads to the aggregation of abnormal amyloid proteins and GAGs and the formation of insoluble fibrils, or sheets of neurotoxic amyloid deposits, in the brain.

Another thing that the two diseases have in common is that there are currently no specific diagnostic tests that can pinpoint the pathology at the earliest stages, before symptoms occur and irreversible damage is done. However, Neurochem, based in St. Laurent, Canada, hopes to change with diagnostic and therapeutic agents now in development the prognosis of Alzheimer's patients. Both are based on knowledge of how amyloid proteins function - and malfunction - in the human body, a niche the company occupies in the fight against Alzheimer's disease and other conditions characterized by amyloid plaques.

A deal Neurochem signed this past summer with Nycomed Amersham Imaging, of London could lead within the next two years to the commercial release of the first Alzheimer's diagnostic capable of imaging the amyloid fibrils in the brain - something no one has yet been able to do.

Current diagnostic tests are less than ideal: they measure surrogate markers in the cerebrospinal fluid to measure the levels of two types of amyloids. Genetic tests also exist to identify individuals with familial forms of Alzheimer's who have Alzheimer's-linked mutations in the presenilin gene, and those who have specific variations in the ApoE gene linked to higher risk of developing. Such diagnostics do not measure the deadly amyloid fibrils themselves - the true test for Alzheimer's, which now can only be done post-mortem.

"There is currently no biomarker of Alzheimer's disease for early detection," notes Howard Fillit, director of the Institute for the Study of Aging in New York. Currently, MRI and CAT scan images of hippocampus shrinkage and, later on, global brain shrinkage are used to help diagnose advanced disease. "A number of others are working on methods for early detection, but I believe that Neurochem has the best combinatorial chemistry," says Fillit. Some companies are working with blood and urine markers, but they are not specifically highlighting the amyloid pathology associated with Alzheimer's, says Neurochem president and CEO Louis Lamontagne.

With its small-molecule therapeutic, Alzhemed, advancing to a Phase II clinical trial and an antigen-based vaccine also in development, Neurochem has a good chance of making a large dent in the 8.5-million-patient Alzheimer's world market, even with formidable competition from big pharma and top biotech companies. Both of these are competing to develop drugs that will attack the root cause of Alzheimer's - the development of the neurotoxic amyloid plaques - and not just treat the disease's cognitive symptoms.

What distinguishes Neurochem from other companies working on neurodegenerative diseases is its amyloid protein core technology. Originating at Queen's University in Kingston, Canada, the company's amyloid know-how opens the door to treating a wide array of other, seemingly disparate diseases that in fact are united by their association with abnormal amyloid protein deposition in various organs.

Amyloid Biology in Human Diseases

Abnormal amyloid fibrils are formed by a buildup of proteins that are normally present in the body in a soluble, harmless form but are transformed by the disease process into an insoluble, toxic form, according to Neurochem vice president of R&D Francine Gervais. Depending on the specific amyloid protein involved, amyloid plaques can deposit in different organs in certain chronic inflammatory or autoimmune diseases, including Crohn's disease, inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, familial Mediterranean fever, and type 2 diabetes, as well as in some chronic infections, including tuberculosis, Hansen's disease (leprosy), and osteomyelitis. Whether the amyloidosis is primary, as in multiple myeloma, or secondary, as in Crohn's disease, there are currently no treatments that can target amyloid proteins.

Although the type of amyloid or amyloid precursor protein involved varies with the disease, the processes by which good amyloid proteins turn bad - and the outcome - are similar in all cases, says Gervais. In Alzheimer's and in hemorrhagic stroke caused by cerebral amyloid angiopathy, it is the amyloid beta peptide that is the driver of disease; in rheumatoid arthritis, it is amyloid A; for type 2 diabetes it is IAPP; and in primary amyloidosis of multiple myeloma, it is the immunoglobulin light chain. In each case, says Lamontagne, complex carbohydrates known as proteoglycans and their constituent sulfated glycosaminoglycans, or GAGs, interact with the particular amyloid precursor protein and spur it to form an insoluble amyloid deposit that the body cannot rid itself of.

Inflammation produces a large circulating pool of amyloid precursor proteins, which are synthesized in the liver in response to cytokines produced during the inflammation process. Amyloid-enhancing factor, produced after persistent inflammation, can serve as the focus for the initiation of fibril formation. Basement membrane proteins, including heparan sulfate proteoglycan, laminin, and collagen type IV, are also deposited. Heparan sulfate influences amyloid precursor protein to form a beta-sheet structure, the characteristic protein-folding pattern of amyloids.

A Trojan Horse Approach

The key to Neurochem's approach to treating amyloid-based disorders is the use of small molecules that interfere with amyloid protein interactions, preventing them from becoming fibrils in the first place by acting as decoys. The company has designed synthetic GAG-like proteins that compete with natural GAGs, preventing the precursor protein from binding to them and interfering with the formation and deposition of deadly amyloid tangles.

For its Alzheimer's diagnostic test, Neurochem is using a related compound - generated using the same mimetic approach - that can pass through the blood-brain barrier and bind to the abnormal fibrils. The compound will be radiolabeled to enable the abnormal masses to be visualized.

Neurochem is using the same biochemical Trojan horse approach with other compounds it is testing in people with type 2 diabetes that disrupt the formation of amylin. IAPP and amylin are involved in diabetes type 2, AL (amyloid L) or immunoglobulin light chain is involved in multiple myeloma (cancer) and idiopathic amyloidosis of primary amyloidosis; AA or amyloid A is involved in rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, and familial Mediterranean fever; amyloid beta or AB is involved in cerebrovascular amyloidosis, which causes hemorrhagic stroke; and AB or amyloid beta is also involved in Alzheimer's disease. Cerebril, another drug, is advancing to Phase II testing for the previously untreatable condition cerebral amyloid angiopathy (CAA), the only major type of stroke disorder for which there are neither preventive nor acute treatments. In CAA, progressive invasion of the vascular wall by amyloid fibrils leads to small strokes and hemorrhages. Although generally one such hemorrhage is not fatal, they recur and cause high morbidity and mortality. Such strokes are seen in about one-quarter of all Alzheimer's patients.

Fibrillex, which has orphan drug designation for secondary amyloidosis, has advanced to a pivotal phase II/III clinical trial for testing to prevent kidney damage. It will also be tested in patients suffering from diseases including rheumatoid arthritis, Crohn's disease, and familial Mediterranean fever. For type 2 diabetes, four potential compounds have been identified and are being tested in preclinical models of diabetes. Neurochem expects to begin testing a lead candidate in 2002.

In Alzheimer's disease, controversy still rages concerning the exact pathobiology: are amyloid fibrils the cause or the effect (the "tombstones" of the disease, as Lamontagne puts it)? Some scientists believe that the tau protein is more important in the disease process than the amyloid, whereas others believe that the inflammation seen surrounding the fibrils is the main cause of damage and that this inflammation might result from beta amyloid deposition. This camp is testing anti-inflammatory drugs like the cyclooxygenase 2 (COX-2) inhibitor Celebrex (celecoxib) to treat Alzheimer's.

GlaxoSmithKline's director of genetics, Allen Roses, is the main proponent of the ApoE link. Meanwhile, Bristol-Myers Squibb, Merck, Elan, and Eli Lilly are pursuing inhibitors of beta- and gamma-secretase. These enzymes are proteases, or molecular scissors, that are involved in the formation of the amyloid proteins. Some scientists, however, believe that because the secretases are found throughout the body, they do not make an attractive target, as blocking them could lead to major side effects because of the nonspecific impact. Like Neurochem, Elan has its own peptide-based vaccine in development.

Only in the past two years or so, says Lamontagne, have some scientists come around to Neurochem's way of thinking - that amyloid is an essential part of the disease process in Alzheimer's, not just a result of the disease. Still fewer have recognized that amyloid in the brain is related to amyloid deposits elsewhere in the body in a range of disparate diseases involving inflammation that affect the kidney, spleen, and liver as well as the brain. Neurochem's bet is that amyloid protein - and methods to prevent its transformation into toxic deposits - is the key to Alzheimer's and many other diseases. If testing proves the company right, it will help alleviate the suffering of millions of Alzheimer's patients and their families as well as advancing science toward cures for other amyloid-related conditions.