NEWYORK, NY — The Michael J. Fox Foundation for Parkinson’s Research has awarded total funding of $2.6 million under its Progressive, Predictive Animal Models initiative to seven research groups working to develop progressive, predictive mammalian models of Parkinson’s disease. The dearth of validated models of this kind is a primary roadblock to the development of neuroprotective and neurorestorative treatments to prevent, slow or stop the progression of Parkinson’s disease — something no current treatment has been proven to do.
“Drug development for PD has historically centered on symptomatic therapies, due in part to useful models showing the effects of dopamine replacement on motor symptoms,” said Deborah W. Brooks, the Foundation’s president and CEO. “While relieving symptoms remains a priority, our greater hope is to facilitate development of disease-modifying therapies that can truly transform patients’ lives. With Progressive, Predictive Animal Models we aim to accelerate such treatments by driving the validated, reproducible models that can help make neuroprotective therapies possible.”
Reflecting the urgency of the need for models to advance disease-modifying therapies, the Animal Models initiative includes the Foundation’s first-ever contractual work-sharing stipulation: Awardees must make any new model resulting from their work under this initiative available to the Parkinson’s research community at large within six months of project completion.
Projects funded include the development or modification of models of several known genetic and environmental factors in PD onset and etiology. Chenjian Li, PhD, of Weill Medical College of Cornell University aims to create the first mammalian models of PD that reproduce the cardinal PD pathology of dopaminergic neuronal death in the substantia nigra. Dr. Li will use bacterial artificial chromosome (BAC) technology to create a transgenic rat overexpressing the human genes LRRK2 and alpha-synuclein, both of which play a role in Parkinson’s disease. BAC technology, of which Dr. Li was an original inventor, enables large amounts of human DNA to be introduced into an animal model via a vector and then overexpressed, allowing researchers to observe the effects of the human DNA in the animal system. Once the rats have been generated, Dr. Li’s group will put the animals through a standard battery of motor behavior and neurochemical tests to determine whether they exhibit the progressive nigral neuronal death seen in Parkinson’s patients.
The animal model proposed by Robert Nussbaum, MD, of the University of California, San Francisco, School of Medicine could potentially offer researchers a way to study early disease development. Dr. Nussbaum will breed different lines of mice expressing the normal or mutated forms of human alpha-synuclein in the absence of the mouse’s own alpha-synuclein gene. The resulting mice will be followed for two years to see if those with a double-dose of mutated alpha-synuclein develop any of the abnormalities seen in PD. Studies will include testing the mice for how well they walk and move, examining their brains for loss of relevant nerve cells and for the abnormal alpha-synuclein clumping seen in PD patients, and measuring levels of dopamine and related chemicals in their brains. If the mice develop PD, researchers will be able to use the model to study early changes associated with the disease and to test novel interventions to reverse, slow down or halt progression.
The following is a complete list of researchers who were awarded grants under the Animal Models initiative:
Ted Dawson, MD, PhD
Johns Hopkins University School of Medicine
Generation of Transgenic Mice with Selective and Progressive Loss of Nigrostriatal Dopaminergic Neurons
Chenjian Li, PhD
WeillMedicalCollege of CornellUniversity
Rat Transgenic Models for Autosomal Dominant PD via BAC Technology
Robert Nussbaum, MD
University of California, San FranciscoSchool of Medicine
P1 Artificial Chromosome Transgenic Mice as Models for Progressive Parkinson’s Disease
Lars Olson, PhD
Karolinska Institutet (Sweden)
The PD Mouse: A Progressive Model of Parkinson’s Disease with Key Pathology and Behavior Caused by Targeting Mitochondrial Function in Dopamine Neurons
Jie Shen, PhD
Brigham and Women’s Hospital, HarvardMedicalSchool
LRRK2 and PD Genetic Mouse Models
Malu Tansey, PhD
University of Texas Southwestern MedicalCenter at Dallas
Inflammation Stimuli as ‘Second-hit’ Triggers for Development of Progressive Nigral Degeneration
Demetrios Vassilatis, PhD
Foundation for Biomedical Research of the Academy of Athens
Two-Hit Mouse Models for Parkinson’s Disease