NEW RESEARCH EXPLORES POTENTIAL IMMUNE THERAPIES TO PROTECT AGAINST ALZHEIMER'S, OTHER DISEASES
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NEW RESEARCH EXPLORES POTENTIAL IMMUNE THERAPIES TO PROTECT AGAINST ALZHEIMER'S, OTHER DISEASES
ATLANTA, October 16, 2006 - A new group pf vaccine techniques may soon result in effective ways to prevent several neurological disorders. These developments include:
- A novel method of gene transfer to protect against symptoms of Alzheimer's disease (AD),
- An antibody that appears to reduce the accumulation of plaques associated with AD,
- A new approach to slow the progression of a disorder similar to "mad cow" disease,
- An oral vaccination that may prevent infection, and
- Novel immune strategies to protect neurons from injury and death in a mouse model of Parkinson's disease.
"Overall, these novel strategies may have potential to progress to immunotherapies for human neurodegenerative diseases," saysHoward Federoff, MD, PhD, at the University of Rochester. He will lead a symposium on potential new immunotherapies against such diseases at Neuroscience 2006 in Atlanta. He has ownership interests in several private companies, including MedGenesis and AmpliVex, LLC.
Research by William Bowers, at the University of Rochester supports a gene transfer vehicle based upon the virus that causes cold sores that can be used to generate investigator-controlled immune responses against a protein deposit found in the brains of individuals stricken with AD. Bowers also has an ownership interest in AmpliVex, LLC.
One of the central disease features of AD is the excessive accumulation of amyloid beta peptide. Among its disease-promoting properties, amyloid beta induces inflammation, a state that persists throughout the course of the disease. Because efforts to ease the inflammation once AD has been diagnosed have proven unsuccessful, says Bowers, research is looking at stopping the effects before they get started.
Previous observations showed that amyloid beta-directed vaccination of a mouse model of AD could prevent the disease. Viral vectors exploit the evolutionary achievements of viruses to propagate, package, and transfer genetic material from cell to cell and organism to organism. Via genetic modification of mammalian viruses, it is possible to specifically target gene expression in desired cellular populations.
Bowers' laboratory uses the herpes simplex virus-based vector to express amyloid beta along with different cytokines to generate varying responses to the disease-causing protein in mouse models of AD. This vector does not express any herpes genes that typically would cause cold sores in infected individuals, says Bowers, because it has been stripped of these genes and only serves as a vehicle to deliver a desired genetic payload.
"We are in the midst of repeating our experiments and are performing various behavioral tests on vaccinated mice to determine if any of the vaccines result in improvement of memory functioning," says Bowers.
Subsequent research will focus on evaluating animal models of AD where brain inflammation is present, says Bowers. "Adhering to such a … deliberate process may eventually herald the arrival of a truly new therapeutic for AD."
Other research focusing on AD and the amyloid beta protein has led researchers to find anti-amyloid antibody fragments that appear to reduce amyloid beta accumulation.
One of the challenges to developing better amyloid beta vaccines is that amyloid beta is a normal protein produced in the body, says Yona Levites, PhD, at the Mayo Clinic in Jacksonville, Fla. Any vaccine that uses amyloid beta to stimulate an anti-amyloid beta immune response could induce a harmful autoimmune response.
Levites has explored a novel approach to amyloid beta immunotherapy based on the notion that the amyloid beta aggregates are pathogenic agents. "Rather than targeting amyloid beta, we are trying to target amyloid beta amyloid," Levites says. "In order to accomplish this, we have developed novel methods to rapidly deliver a fragment of the antibody to the brains of mice and evaluate the effects of that antibody fragment on amyloid beta deposition."
To prove that this methodology is effective, Levites and colleagues showed that they can reduce amyloid beta deposition by viral mediated delivery of anti-amyloid beta antibody fragments. They then set out to isolate antibody fragments that bind amyloid beta amyloid, but not amyloid beta.
Levites screened an antibody fragment (scFv) library for antibodies that bind amyloids derived from peptides that have no sequence homology to amyloid beta. "This enabled us to isolate multiple antibody fragments that bind various amyloids," Levites says. "These antibody fragments also recognize amyloid beta amyloid. Thus, they recognize the overall structure of amyloid and not the sequence of the protein that forms the aggregate."
When expressed in the brain of mice that deposit amyloid beta, several of these anti-amyloid antibody fragments appear to reduce amyloid beta accumulation.
"These data suggest that it may be possible to target amyloid beta amyloid, which is not a normal structure in the body," says Levites. "Using this technology we hope to be able to identify antibody fragment that recognize additional forms of amyloid beta that accumulate in the body."
Their lab is working on an active vaccination paradigm designed to induce an anti-amyloid response. "Collectively, these studies may provide essential insights into the roles that various amyloid beta aggregates play in the disease and could lead to novel AD therapeutics."
Howard Federoff, MD, PhD, at the University of Rochester Medical Center, is using a new approach to slow the progression of a prion disease similar to "mad cow" disease. Prion diseases are a group of fatal, neurodegenerative diseases that includes scrapie and bovine spongiform encephalopathy (BSE) in animals and Creutzfeld-Jacob disease (CJD) in humans. Scrapie is the prototypical prion disease, known to occur in sheep since the 18th century.
BSE, also known as mad cow disease, has only been described in recent decades and is widely believed to have arisen from the feeding of processed, scrapie-infected sheep to cattle. Through a similar mechanism of transmission, BSE was conveyed to humans, creating variant CJD (vCJD).
In a mouse model, Federoff and his collaborators have shown for the first time that brain delivery of a vector harboring an antibody gene that recognizes the offending molecule, known as PrPc, is able to greatly reduce clinical signs and extend the life of animals infected with the disease. "These studies suggest that it may be possible to develop a type of preventative vaccine and also to treat preexisting disease," says Federoff, who is extending the current work in these areas. "The current work also raises the possibility of treating other species, including cows and humans who may be at risk or be afflicted by a similar disease."
Further research into prion diseases has uncovered a mucosal vaccination that may prevent prion infection in animals and, potentially, humans.
In all cases of prion diseases, or prionoses, the causative agent is a protein, called PrP, that is normally present in the membranes of cells of the immune system and neurons. The normal PrP, PrPC, gets converted by still unknown mechanisms into a toxic and infectious form, PrPSc. Although both forms of the protein are identical in terms of their amino acid sequence, their external shape or structure differs greatly. The shape of the normal PrPC allows it to remain soluble and be digested by the body.
The abnormal PrPSc, however, adopts a shape that makes it very insoluble and resistant to degradation. The persistence of PrPSc and its toxicity, sooner or later, destroy the architecture of the brain, producing localized or widespread damage. This damage has a diverse range of neurological manifestations that lead to the death of the animal or the human being affected.
In recent years, major outbreaks of prion diseases linked to oral exposure of the prion agent have occurred in animal and human populations. None of the prion diseases currently has an effective treatment.
In wild animals, vaccination approaches have been shown to slightly prolong the incubation period of prion infection. However, the systems used were hampered by either tolerance to PrP or potential toxicity, says Fernando Goni, PhD, at New York University's School of Medicine.
Because infection of the prions typically occurs via the gut, Goni and his research team developed an oral vaccination system that elicits an immune response in the intestines, eventually preventing entry.
"The PrP was delivered in an innocuous bacterial carrier, and we were able to successfully produce antibodies in the gut against the protein in question," says Goni. Subsequent experiments demonstrated that between 30 and 40 percent of the animals were protected against an oral challenge with the infectious prion.
"Our data suggest that that mucosal vaccination may be a useful method for overcoming tolerance to PrP and preventing prion infection among animal and potentially human populations at risk from oral exposure to prion infection," he says.
Also, the researchers have used a similar strategy to obtain a mild immune response against the fibrillar plaques deposited in the brain, one of the hallmarks of AD. "In an animal model of Alzheimer's disease," says Goni, "preliminary results showed that plaques were efficiently removed in mucosal vaccinated animals."
Other researchers are using novel immune strategies to protect neurons from injury and death in a mouse model of PD. In the model, a toxin kills neurons and induces inflammatory cells analogous to those affected in PD patients, says Lee Mosley, PhD, at the University of Nebraska Medical Center.
Mosley's research uses T lymphocytes, a subset of white blood cells, from mice immunized with glatiramer acetate, a protein polymer used in the treatment of multiple sclerosis. The lymphocytes were shown to quell the inflammatory responses and inhibit subsequent neuron death in toxin-treated mice.
"Toxin-treated mice were completely protected from neuronal death by a specific population of activated T lymphocytes (Tregs), a population also shown to be protective in several models of inflammatory autoimmune diseases," says Mosley.
Neuroinflammation in areas where neurons are injured or dying is thought to play a key role in the extent or progression of disease in several neurodegenerative disorders, such as PD, AD, amyotrophic lateral sclerosis (Lou Gehrig's disease), and stroke, as well as neurodegeneration associated with chronic infectious diseases such as HIV-1.
"In the absence of curative therapies for most neurodegenerative disorders," says Mosley, "we devised therapeutic strategies, which target specific T lymphocyte subsets by vaccination or activation, to inhibit the neuroinflammatory component in neurodegenerative disorders and protect susceptible neurons.
"Implementing successful therapeutic strategies that reduce neuroinflammation and increase neuron survival could profoundly affect disease progression and outcomes in patients suffering from neurodegenerative disorders," he says.