Neurodegenerative diseases
Alzheimer's Research
Elan’s scientists have been leaders in Alzheimer’s disease research for more than 25 years. Insights gained from our work are an important part of the scientific foundation of the understanding this disease. Throughout the Research community and biotech industry around the world, we are known and respected for our dynamic Alzheimer’s disease platform and our profound commitment to creating new therapeutic options for patients.
Elan’s Scientific Approach
Elan’s scientific approach to Alzheimer’s disease is centered upon its landmark basic research that revealed the fundamental biology that leads to the production and accumulation of a toxic protein, beta amyloid, in the brains of Alzheimer’s disease patients. The process by which this protein is generated, aggregates and is ultimately deposited in the brain as plaque is often referred to as the beta amyloid cascade. The formation of beta amyloid plaques is the hallmark pathology of Alzheimer’s disease.
Beta amyloid forms when a small part of a larger protein called the amyloid precursor protein (APP) is cleaved from the larger protein. This separation happens when enzymes called secretases "clip" or cleave APP. It is becoming increasingly clear that once beta amyloid is produced, it exists in multiple physical forms with distinct functional activities. It is believed that the toxic effects of some of these forms may be involved in the complex cognitive, functional and behavioral deficits characteristic of Alzheimer’s disease.
A growing body of scientific data, discovered by researchers at Elan and other organizations, suggest that modulating the beta amyloid cascade may result in breakthrough treatments for Alzheimer’s disease patients. Elan scientists and others continue to study and advance research in this critical therapeutic area.
Three Approaches to Disrupting the Beta Amyloid Cascade
Our scientists and clinicians have pursued separate therapeutic approaches to disrupting three distinct aspects of the beta amyloid cascade:
- Clearing existing beta amyloid from the brain (JANSSEN Alzheimer Immunotherapy in collaboration with Pfizer, following its acquisition of Wyeth)
- Preventing aggregation of beta amyloid in the brain, in collaboration with Transition Therapeutics
- Preventing production of beta amyloid in the brain with secretase inhibitors
Beta amyloid immunotherapies
Beta amyloid immunotherapy pioneered by our scientists involves the potential treatment of Alzheimer’s disease by inducing or enhancing the body’s immune response in order to clear toxic species of beta amyloid from the brain. In almost a decade of collaboration with Wyeth, our scientists developed a series of therapeutic monoclonal antibodies and active vaccination approaches that may have the ability to reduce or clear beta amyloid from the brain. These new approaches have the potential to alter the underlying cause of the disease by reducing a key pathway associated with it.
Elan and Johnson & Johnson announced on September 17, 2009, that JANSSEN Alzheimer Immunotherapy, a Johnson & Johnson affiliate, had acquired substantially all of Elan’s assets related to the Alzheimer’s Immunotherapy Program (AIP).
The AIP includes multiple compounds being evaluated for slowing the progression of Alzheimer's disease. The lead compound (bapineuzumab), administered intravenously once every three months, is in Phase 3 clinical trials. A subcutaneous formulation, administered once a week, is in Phase 2 trials. In addition, a vaccine for Alzheimer's disease (ACC-001) is also under development.
Beta amyloid aggregation inhibitor
In 2006, Elan entered into an exclusive, worldwide collaboration with Transition for the joint development and commercialization of the small molecule ELND005, which is a beta amyloid anti-aggregation agent that has been granted fast track designation by the FDA. Preclinical data suggest that ELND005 may act through the unique mechanism of preventing and reversing the fibrilisation of beta amyloid (the aggregation of beta amyloid into clumps of insoluble oligomers), thus enhancing clearance of amyloid and preventing plaque deposition. Daily oral treatment with this compound has been shown to prevent cognitive decline in a transgenic mouse model of Alzheimer’s disease, with reduced amyloid plaque load in the brain and increased life span of these animals.
Secretase inhibitors
Beta and gamma secretases are proteases, or enzymes that break down other proteins, that clip APP and result in the formation of beta amyloid. This is significant because if the “clipping” of APP could be prevented, the pathology of Alzheimer’s disease may be changed. We have been at the forefront of research in this area, publishing extensively since 1989, and have developed and are pursuing advanced discovery programs focused on molecule inhibitors of beta and gamma secretases.
Gamma secretase
Gamma secretase is an unusual multi-protein complex that is required to produce beta amyloid. We have played a critical leadership role characterizing how gamma secretase may affect Alzheimer’s disease pathology. Our finding that functional gamma secretase inhibitors appear to reduce beta amyloid levels in the brain, published in the Journal of Neurochemistry in 2001, was an important step in this area of Alzheimer’s disease research. We continue to progress our gamma secretase discovery program with unique molecules that affect the activity of gamma secretase in a substrate-specific manner.
Beta secretase
Beta secretase, sometimes called BACE (for Beta-site of APP Cleaving Enzyme), is believed to initiate the first step in the formation of beta amyloid, the precursor to plaque development in the brain. Our findings concerning the role beta secretase plays in beta amyloid production, published in Nature in 1999, are considered a landmark discovery. Today, we continue to be at the center of understanding the complexities of beta secretase. Our ongoing drug discovery efforts in this area focus on inhibiting beta secretase and its role in the progression of Alzheimer’s disease pathology.
Small molecule (p75) ligands
In June 2009, Elan formalized its relationship with PharmatrophiX, a biotechnology company focused on the development of small molecule ligands for growth factor receptors relevant to neurological disorders. Elan is working with PharmatrophiX on continued research on all p75 ligands, compounds that mimic the activity of neurotrophins by interacting with neurons that are susceptible to loss in Alzheimer's disease, for neurologic indications.
LM11A-31, which is the lead compound in the PharmatrophiX portfolio, interacts with and potentially protects neurons that are susceptible to loss in Alzheimer's disease. The addition of this compound diversifies our portfolio by adding an orally available therapeutic platform that may attack Alzheimer's disease from a different, and potentially complementary, approach than current investigational molecules in the Elan pipeline.
Parkinson’s Research
Elan has several active early discovery efforts in Parkinson's disease, guided by our expertise in Alzheimer’s disease. Elan scientists are exploring multiple therapeutic strategies to tackle this poorly understood, devastating disease. Specifically, Elan has focused discovery efforts on analysis of human genetics and pathology to find mechanisms to prevent disease progression.
Parkinson’s disease may be a result of misfolded proteins in the brain. Parkinson’s disease is characterized by the accumulation of aggregated alpha-synuclein, or abnormal fibrils and inclusions known as Lewy bodies, in degenerating neurons in specific regions of the brain.
Alpha-synuclein is a protein genetically linked to Parkinson’s disease and a key component in degenerating neurons in brain regions controlling movement. Alterations in alpha-synuclein are believed to play a critical role in Parkinson's disease.
Our scientists have made significant scientific progress in identifying unusual modified forms of alpha-synuclein in human Parkinson’s disease brain tissue. In January 2009, Elan scientists published new research in the Journal of Biological Chemistry about the discovery of a protein that may be involved in the modification of alpha-synuclein. The normal function of alpha-synuclein is unknown, but modified forms accumulate during pathological conditions and form Lewy bodies. Elan scientists are studying the nature of these modifications and, in the recently published paper, reported the identity of a protein that appeared to be a contributor to changes in the alpha-synuclein protein. Elan’s scientists are using experimental models of Parkinson’s disease to conduct tests to determine the involvement of the protein in the formation of Lewy bodies in brain tissue.
Additional Discovery Efforts in Parkinson’s Disease
Our scientists are also studying parkin, a protein found in the brain that, like alpha-synuclein, has been genetically linked to Parkinson’s disease. Parkin may be involved in the elimination of misfolded proteins within neurons, and has demonstrated neuroprotective capabilities in cells. Some familial forms of Parkinson’s disease have been linked to mutations in parkin, with more than 50 percent of early-onset Parkinson’s disease being linked to a loss of parkin protein and function in neurons. We are actively studying the relationship between parkin activity and neurodegeneration. Elan is exploring a number of therapeutic approaches to investigate the Parkinson’s disease process and this research is in the drug discovery stage.