News

LRRK2 inhibitors may be key to combating Parkinson’s disease

An enzyme closely associated with genetic forms of Parkinson’s disease appears to play a larger role in its progression than previously thought, say UAB investigators. The new research offers encouraging evidence that drugs to block this enzyme, known as leucine-rich repeat kinase 2 or LRRK2, could slow — or even prevent — Parkinson’s from developing.In the study, published online in the Proceedings of the National Academy of Sciences June 4, UAB researchers eliminated the gene for LRRK2 (pronounced “lark two”) in rats and combined these animals with genetic models of Parkinson’s.

“We found that this offered very good protection from over-expression of a protein — alpha synuclein — that is linked to Parkinson’s disease,” said Andrew West, Ph.D., lead author on the paper and the John A. and Ruth R. Jurenko Endowed Professor in Neurology at UAB.

The genetic model used in the UAB study more closely mimics Parkinson’s disease than do other, more frequently used models, which suggests that inhibiting LRRK2 in humans could help more than those with the less-common genetic forms.

“The pool of Parkinson’s patients who might benefit from LRRK2 drugs may be bigger than we originally thought,” West said.

West’s lab is working closely with Birmingham-based Southern Research Institute through the Alabama Drug Discovery Alliance to rapidly develop LRRK2 inhibitors. He hopes to reach human testing as early as 2015.

Parkinson’s disease affects more than a million Americans. Tremors, stiff muscles and slow movement are the most common symptoms of the disease. These symptoms are caused by a massive loss of cells in the substantia nigra, a brain region that helps control movement. The dying cells are filled with clumps of alpha-synuclein, making it the chief suspect in Parkinson’s disease.

Refining the target

The trouble is that researchers have not found a way to control alpha-synuclein levels directly.

“It’s a normal protein — actually one of the most highly abundant proteins in the brain — so it isn’t easy to figure out how to block its progression into aggregates that spread through the brain,” West said.

That is why Parkinson’s researchers are so excited about LRRK2. In 2006, West demonstrated that all known mutations in LRRK2 increase LRRK2 activity. Other studies showed that LRRK2 is biochemically linked with alpha-synuclein in several ways.

Andrew West’s lab is working closely with Birmingham-based Southern Research Institute through the Alabama Drug Discovery Alliance to rapidly develop LRRK2 inhibitors. He hopes to reach human testing as early as 2015.
Since those discoveries in the rats, the idea has been that developing drugs to reduce LRRK2 activity should provide protection against damage caused by alpha-synuclein, according to West.

Genetic forms of Parkinson’s that have highlighted LRRK2 involvement in disease are widespread in some populations, including those of Ashkenazi Jewish and North African Berber descent, where inherited Parkinson’s accounts for up to 40 percent of cases.

“But it drops dramatically depending on your ethnic background,” West said. “If you’re from a European, Caucasian population, it’s more on the order of 2 to 3 percent. This may be important in initial first-in-man studies in deciding who should first get LRRK2 drugs.”

Advancing to human trials

Any treatment advance would be welcome in Parkinson’s, which West says has not seen a real breakthrough drug since L-dopa was developed 50 years ago.

“Together with Southern Research Institute, we have a very strong drug pipeline, and we hope to be in first-in-man studies as early as next year,” West said. “But while that work is ongoing, we need to ask a bigger question: What happens if you simply remove all LRRK2 activity? Modern approaches allow us to approximate what a perfect drug would do in rats and mice.”

The results, captured in the PNAS paper, emphasize the importance of LRRK2 and the need for further study, which West is pursuing.

“We think LRRK2 is plugging into Parkinson’s disease in more than one way,” West explained. “It is making the disease more likely to happen and making it progress faster when it does happen. So we think knocking out LRRK2 will do the opposite — slow the disease or make it much less likely to develop.”

Even slowing the disease marginally could have a tremendous effect on patients with Parkinson’s disease, West notes. Drugs like L-dopa are effective at controlling symptoms and making life manageable for patients; but they eventually stop working, and side effects inevitably become as burdensome as the disease itself, West says.

LRRK2 inhibitors could greatly extend the useful window for L-dopa treatment.

“Whereas L-dopa may be effective for 10 years currently, if LRRK2 inhibitors slowed disease progression, we could dramatically extend the effectiveness of existing drugs to 20, 30 or 40 years — basically the rest of the patient’s life.”

UAB neurologist edits first textbook on newly defined disease process

Anthony Nicholas, M.D., associate professor in the Department of Neurology at the University of Alabama at Birmingham, is a co-editor of the first textbook on the subject of protein deimination in human health and disease.Deimination is a process by which selected positively charged arginine amino acids are converted to neutral citrulline amino acids by the peptidyl arginine deiminase family of enzymes. The book is a comprehensive look at this rapidly developing field and illustrates the connection between deimination and numerous illnesses, including autoimmune diseases, Alzheimer’s, Parkinson’s, Creutzfeldt-Jakob disease, amyotrophic lateral sclerosis, cancer, periodontitis, glaucoma, spinal cord trauma and peripheral nerve injury.

Authors for each chapter of the book, titled “Protein Deimination in Human Health and Disease,” are international experts from the United States, Canada, Europe and Asia.

The publisher, Springer Publishing, said “‘Protein Deimination in Human Health and Disease’ is the first publication to compile this knowledge and the growing amount of new information now known about the presence of deiminated proteins in the eye, skin, hair, gums, lungs and nervous system, as well. Chronicling the earliest studies of deimination up to the present, this volume distills what is currently known about citrullination of proteins in the human body and is the first book of its kind on the topic.”

Will I have Alzheimer’s? Personalized dementia risk assessment now available at UAB

Neurologist David Geldmacher, M.D., who leads the University of Alabama at Birmingham memory disorders program, sees a lot of older patients with memory loss, dementia or Alzheimer’s disease.One of the questions frequently asked of him by the caregivers of these patients, often a spouse or the patients’ adult children, is “could this happen to me?”

“It is very common for family members of a patient receiving a diagnosis of Alzheimer’s disease or other form of dementia to wonder about their own risk,” said Geldmacher, the director of the UAB Division of Memory Disorders and Behavioral Neurology.

Geldmacher is launching a new clinical effort — the first of its type in the United States — to prepare a personalized dementia risk assessment for people concerned about their risk for developing memory problems as they age. The assessment will include family history, a detailed memory history for the patient, cognitive testing and a baseline MRI scan. That information can be incorporated into existing risk predictor models that have been validated by research studies to produce an accurate risk assessment.

Patients will get a comprehensive analysis from Geldmacher, including information on nonmodifiable risk factors such as age and family history, as well as strategies for dealing with modifiable risk factors like weight, diet, blood pressure and level of physical activity. He says research in the field has shown that reducing one or more risk factors can have a significant effect on reducing one’s overall chances of developing Alzheimer’s disease.

David Geldmacher is launching a new clinical effort — the first of its type in the United States — to prepare a personalized dementia risk assessment for people concerned about their risk for developing memory problems as they age.
“Our goal is to understand what risk factors are present in each individual and create a plan that best helps them reduce their risk and make appropriate plans for the future,” Geldmacher said.

The assessment is targeted primarily at individuals in their 50s and 60s, and it will provide a 20-year risk prediction. It can also be used for individuals in later life, with a six-year risk prediction.

“For most people, Alzheimer’s disease is an illness you live with, not an illness from which you die,” Geldmacher said. “With a better understanding of individual risk, there are steps that people can take to minimize the risk for serious memory loss.”  

Patients will have two clinical visits with Geldmacher and his staff. The first will be to compile histories and conduct testing. The second will be to review a personalized treatment plan, including how to access resources to help achieve lifestyle changes, and where to find supportive and educational materials. The clinic will also suggest coping strategies that can be employed to ease the burden of dementia on the individual and his or her family. The two-visit assessment is fee-for-service and will cost about $1,000, which includes the MRI scan.

Geldmacher says this risk assessment service appears to be the first in the nation offered in a clinical setting and not as part of a research study.

“It’s really for those who are worried about their cognitive health but do not currently have major memory issues,” he said. “People with active memory or cognitive issues that interfere with everyday activities are best cared for through the services of our existing UAB Memory Disorders Clinic.”

Geldmacher anticipates that the risk assessment clinic will also ultimately serve as a gateway to research projects aimed at finding medications or other treatments designed to lower risk of memory disorders.

Call 205-975-7575 for more information or to make an appointment for a personalized dementia risk assessment.

By: Bob Shephard - UAB Media Relations

Study of blood-thinners to advance personalized medicine

Blood-thinners help prevent and treat strokes, heart attacks and venous clots, but not without the risk of uncontrolled bleeding. Determining who may develop this common complication and the reasons for it is the goal of a UAB study examining the ways varied factors influences individual response to these drugs.UAB, which developed one of the largest, most racially diverse, prospective warfarin-study cohorts in the country, is uniquely qualified to conduct real-time studies of its effects, said Nita Limdi, Pharm.D., Ph.D., associate professor in the Department of Neurology and primary investigator of the new study.

“This enables us to observe bleeding complications to better understand and study the influence of genes, clinical factors and environment,” Limdi said. That capability is valuable in understanding this process and a key element in securing a $3.5 million grant from the National Heart, Lung and Blood Institute, one of the National Institutes of Health.

UAB’s comprehensive genomic approach will assess both common and rare genetic variations to identify novel genetic variants associated with hemorrhage in warfarin (Coumadin), the most commonly used oral anticoagulant, and also dabigatran (Pradaxa).

UAB, which developed one of the largest, most racially diverse, prospective warfarin-study cohorts in the country, is uniquely qualified to conduct real-time studies of its effects.
Limdi says this research is another step toward personalized medicine. The study will begin to develop algorithms, including clinical, genetic and environmental factors, to predict a patient’s risk of hemorrhage. Such tools will enable clinicians to refine patient-specific, risk-benefit assessments and help determine personalized choices for oral anticoagulant therapy.

Limdi, along with colleagues Timothy Beasley, Ph.D., and Nianjun Liu, Ph.D., associate professors in the Department of Biostatistics, and Todd Brown, M.D., assistant professor in the Division of Cardiovascular Disease, are recruiting subjects for the new study. Call 205-996-6009 or email
ayourich@uab.edu
This email address is being protected from spambots. You need JavaScript enabled to view it. 
,
jfuller@uabmc.edu
This email address is being protected from spambots. You need JavaScript enabled to view it. 
or
hraiford@uab.edu
This email address is being protected from spambots. You need JavaScript enabled to view it. 
to inquire.



         

Published in Research & Scholarship