Targeted Diseases:

• Alzheimer's Disease
• Parkinson's Disease
• Epilepsy
• Huntington's Disease

Alzheimer's Disease

Alzheimer's Disease, a progressive degenerative brain disorder, kills more than 100,000 Americans a year. It is the fourth leading cause of death in the United States.

Described in 1907 by the German neurologist Alois Alzheimer, it afflicts 10 percent of the population of the United States 65 or older, and half of people 85 or more. Their treatment now costs about $100 billion a year. Because the population is aging, the disease will afflict 14 million more Americans annually by 2050 when today's 30-year-olds are moving into their 80s.

At Duke University's Medical Center, Dr. Warren J. Strittmatter and his Deane Laboratories colleagues treat Alzheimer's patients every day. "Most of our patients are remarkably brave," Dr. Strittmatter says. "Their families, too. Alzheimer's is a relentless illness; catastrophic, frightening, draining emotionally and financially."

There is no cure yet; but there is be found is in the work of the Deane Labs, where neuroscientists apply genetic, biochemical and cellular approaches to understanding the pathogenesis of the disease.

That work has already produced promising discoveries. In 1993 these Duke University Medical Center scientists uncovered the strongest evidence yet that a specific gene is linked to an increased risk of Alzheimer's Disease. In a study of Alzheimer's patients, they spotlighted apolipoprotein E —ApoE— a lipoprotein involved in the transport of lipids to cells.

ApoE is important to the neurons of the brain. Every person inherits two genes for ApoE, which have three genetic variants or alleles —ApoE2, ApoE3, and ApoE4. The Duke investigators found ApoE2 delays the onset of Alzheimer's, but that ApoE4 increases susceptibility.

A patient with two ApoE4s is nine times as likely to contract Alzheimer's some people with two copies of ApoE4 show no signs of the disease. The ApoE4 variation is seen in about 15 percent of the population, but is present in 50 percent of patients with late-onset Alzheimer's, and is 300 percent more common in Alzheimer's patients than in healthy people.

Scientists are now sure Alzheimer's is genetically based, and through research they are uncovering other genes implicated in the disorder. Basic research in the Deane Labs is helping to improve the understanding of how ApoE is involved in the mechanisms of this disease.

Through patient-focused laboratory research, Deane Labs scientists are working to develop novel strategies for intracellular delivery of protein therapies- drugs to block the abnormal protein reactions that lead to the expression of these inherited neurological disorders in people. People like Carter.

Patient Profile: Carter

Parkinson's Disease affects more than a million American men and women. A neurodegenerative disorder, it most often afflicts people over 50, but also appears in people in their 30s and 40s.

The disease is progressive. Its symptoms usually worsen with the passage of time. Parkinson's is rarely life-threatening, but always compromises the quality of life.

The disorder is characterized by tremor at rest; rigidity in the arms, legs and neck; difficulty in walking and standing erect; and impaired movement. It may be seen in abnormal facial expression and fine finger movements, and heard in soft, monotone speech.

Originally described in 1817 by the English physician James Parkinson— who called it "Shaking Palsy"— Parkinson's is a malfunction of the central nervous system caused by the an area of the brain called the substantia nigra.

Only in the 1960s were the bio-chemical changes in Parkinson's identified, leading to the first effective medication. Parkinson's reduces the availability of the neurotransmitter dopamine, essential to normal movement. Some success in treating symptoms is found with the drug levodopa, but it does not stop the deterioration of the affected brain cells.

There is no cure yet; but there is hope. A place where hope is to be found is at the Deane Labs. Here neuroscientists apply genetic, biochemical and cellular approaches to understanding the development and progression of the disease.

Deane Labs investigators work to understand how to slow the progression of Parkinson's. The final goal, however, that target the molecular mechanisms of Parkinson's in the neurons themselves. The Deane Labs also are developing novel strategies for delivering medicines to treat the disorder at the level of the cell-therapies to block the abnormal protein reactions that lead to the expression of neurological disorders.

The patient-focused research of the Deane Labs is networked. The Deane Labs are an agile research institution with facilities and resources that can quickly take up promising new lines of discovery. Collaborating with neuroscientists across the nation, the Deane Labs are developing practical therapies, cures, and diagnostic predictions for people. People like Bernie.

Patient Profile: Bernie

Epilepsy

Epilepsy afflicts 2.6 million Americans; 40 million to 50 million people worldwide. About one person in every hundred has some form of the brain disorder. It strikes individuals of all ages and races in all walks of life.

In its milder forms, epilepsy may cause episodic confusion. At its worst, there are sudden and recurrent motor seizures. Many epileptics hide their affliction for fear they will be denied social, educational, athletic and employment opportunities. It is the third-most commonly concealed illness.

There are more than 40 kinds of epilepsy. Among the causes are cerebral hemorrhage, head trauma, infections of the brain, prenatal injury, and genetic predisposition. Each triggers what amount to electrical storms in some or all of the brain. When the entire brain is involved, the seizures are generalized.

Drug therapy commonly produces side effects. In 40 percent of cases, the medication doesn't work. In the other symptoms, not the cause. Under treatment, some patients become seizure-free long term, but the disorder is chronic, and the risk of premature death is two or three times that of the general population.

In nearly a third of the cases, the patient inherits a susceptibility to epilepsy. Multiple genes are involved. Suspect are gene sequences that appear to overlap from one form of inherited epilepsy to another.

In a study of juvenile myoclonic epilepsy—among the most prominent of the severe forms of epilepsy —a Deane Labs investigator is isolating those gene sequences. He's taking a "brute force" approach, comparing DNA samples from a huge pool of epilepsy patients and looking for patterns that distinguish them from the rest of the population. As he finds them, he narrows the genetic possibilities that figure in the most severe cases of inherited epilepsy.

He hopes his discoveries will lead for the disease. The breeding of an experimental mouse—a mouse bio-engineered to isolate suspect gene sequences —could permit scientists to better target the testing of compounds for therapeutic use.

Then, he thinks, might come the development of a drug to interfere with the proteins those genes produce —"a magic-bullet drug that will solve the problem." Like most leaders in neuroscience research, he needs more personnel and more equipment to gather DNA and data to screen large numbers of gene samples.

The patient-focused research of the Deane Labs is networked. In a sense, the Deane Labs are virtual, with research facilities and resources that can quickly take up promising new lines of discovery. Collaborating with neuroscientists across the nation, the Deane Labs are working on developing practical therapies for people. People like Lynn.

Patient Profile: Lynn

Huntington's Disease

Huntington's Disease may be the best understood of the genetic neurologic disorders.

Initially described by Long Island physician George Huntington in 1872, Huntington's is an inherited illness that causes progressive, selective neural cell death. About 30,000 Americans have Huntington's, and 150,000 children of Huntington's patients stand a 50-50 chance of inheriting the mutated gene that is its cause. It affects men and women of all races.

Huntington's usually begins at mid-life with depression, mood swings, forgetfulness, clumsiness, twitching and lack of coordination. Decreased short-term memory follows. Spasmodic movement becomes more pronounced. Emotional and cognitive symptoms grow acute, and movement of the head, trunk and limbs becomes ceaseless. There is difficulty walking, speaking, or swallowing. Huntington's is always fatal, usually within 17 years of onset.

Scientists mapped the Huntington's Disease gene to chromosome 4 in 1983, and cloned it ten years later. They discovered that Huntington's is associated with increases in the length of an otherwise normal sequence of DNA in the gene needed for assembly of huntingin protein.

In most people, a three-element string of DNA code—a triplet — repeats itself as many as 30 times. Huntington's patients have strings of 50, 60, 100, or more. Similar patterns are seen in Kennedy's Disease and in Fragile X Syndrome, the most common form of inherited mental retardation.

In 1996, the Deane Labs' Dr. Warren Strittmatter and co-investigators discovered the abnormal protein in Huntington's interferes with the function of an enzyme critical for supplying cells with energy, for DNA repair, and for building the internal scaffolding of nerve cells. They determined that the abnormal proteins in Huntington's bind in clumps to the framework of nerve cell neurofilaments. They are exploring ways of keeping them from clumping abnormally.

Deane Labs' studies of how the mutated protein abnormally interacts with other proteins could lead to the identification of treatment targets. Deane Labs' patient-focused investigations may produce an understanding of how to block the triplet repeat interaction in target cells through practical protein therapies as a strategy for slowing progression of Huntington's and similar disorders.

Patient Profile: Woody