Optimizing critical cell transplantation parameters and neurosurgical strategies for the treatment of Parkinson's disease
New Faculty Physician Scientist
$3 045 003
Over 500,000 people in the United States are afflicted with Parkinson’s disease (PD), a neurodegenerative disorder characterized by the death of (DA) dopaminergic neurons in specific regions of the brain. Patients with PD suffer from a disheartening loss of independence due to symptoms such as tremor, slowed movements, stiffness, and difficulty walking. 1-2% of people over the age of 60 will be diagnosed with PD, and the current medical and surgical treatments provide only temporary, symptomatic relief. Since we have not yet been able to address the underlying loss of DA neurons, the disabling symptoms eventually return. DA neuron transplantation has great promise as a PD therapy, and stem cell research has made it possible to produce sufficient quantities of DA neurons. To successfully use DA neurons for the treatment of PD, the neurosurgical transplantation techniques must be safe, efficient, and carefully studied. We have recently innovated a new device for cell transplantation that utilizes the most sophisticated and modern image-guided methods available. Here, we propose moving this work forward to develop DA neuron dosing parameters and surgical strategies that allow us to “tailor” the transplant to individual patient needs. We will also investigate how to best integrate DA neuron transplantation with other current PD therapies. Our work may also benefit the treatment of a wide range of diseases including Alzheimer’s, Huntington’s, multiple sclerosis, and stroke.
Statement of Benefit to California:
Parkinson's disease (PD) is the second most common neurodegenerative disease, and there is currently no cure. Between 1-2% of California citizens over the age of 60 suffer from this disabling disease. The annual national cost of PD has been estimated to be $10.8 billion, creating a tremendous burden on both the national and California state economies. The citizens of California have invested generously into stem cell research for the treatment of human disorders including Parkinson’s disease. In order to successfully convert laboratory research into human therapies, there are certain “practical” hurdles that must be overcome. Our studies of basic cell transplantation parameters, neurosurgical approaches, and clinical trial designs will be crucial for the future treatment of Parkinson’s disease. Furthermore, our work will develop general clinical-surgical principles and methodologies that may benefit the development of cell therapies for Alzheimer’s disease and other important neurological disorders that afflict Californians.
Dopaminergic (DA) neuron transplantation is a potential disease modifying therapy for the treatment of Parkinson’s disease (PD). There are important obstacles that need to be overcome in order to successfully use DA neurons for the treatment of PD. The proposed research aims to address a number of these issues, specifically the ones related to the physical process of transplanting DA neurons for PD. The present study will attempt to overcome these hurdles by further development and optimization of a neurosurgical device that has been designed and fabricated by the team to provide consistent cell delivery to large brain targets. The aims of the current proposal are intended to optimize the use of this device for the particular nuances of DA neuron replacement in PD. The Specific Aims are: 1) To optimize key transplantation parameters for human embryonic stem cell (hESC)-derived DA neuron delivery to larger brain targets in a large animal model of PD; 2) To develop a surgical workflow that enables transplantation tailored to individual PD patient anatomical and pathological variation; and 3) To test transplantation in the context of modern, complementary PD therapies, by evaluating the feasibility of cell transplantation before or after deep brain stimulation (DBS) surgery in a large animal model of PD. Research Plan - The proposed work will likely provide incremental benefit rather than overcoming barriers to finding a cure for PD. - The applicant suggests that the details of neurosurgical delivery represent a major roadblock to translation of hESC DA cells. While there is room for improvement in this area, reviewers did not agree that this is a major unmet need. Rather, the major block to progress in translating hESC DA cells to the clinic is the robust demonstration that such cells can differentiate appropriately and can produce functional improvements equal to, or better than, primary fetal cells. -The applicant highlights variable quality and quantity of deposits of DA neurons as a major cause of side effects in PD transplants, but fails to consider other possibilities such as the presence of serotonergic neurons. - All literature used to support the need to improve homogeneity of cell delivery is based on transplantation of primary ventral mesencephalic (VM) tissue and yet the proposed experiments are on hESC-derived DA neurons. These two sources are very different and the survival and function of hESC-derived DA neurons is not demonstrated in the application. Reviewers suggested that comparisons using primary VM tissue be included in the experimental design. - The applicant proposes to explore the simultaneous implantation of deep brain stimulators (DBS) and cells. While the possibility of comparing DBS and transplantation may be attractive as a strategy for avoiding sham operations, no biological rationale is given for simultaneous implants and the reasons for doing this are not adequately explained. Indeed, there is no consideration as to whether patients suitable for DBS would also be suitable for cell implantation and vice versa. - Other groups have designed similar delivery devices, including one currently being used in the clinic for transplantation in PD. The applicant does not discuss these devices, so it is difficult to assess whether the proposed device has novel features. Principal Investigator - The PI is a neurosurgeon with clinical duties and plans to devote 30% of his/her time to this program. The PI has a track record in the fields of PD transplantation and stem cell biology. - The PI has a respectable publication record with some high profile publications. - The mentoring plan is also essentially a continuation of ongoing interactions, and mentors will contribute expertise more as collaborators than as mentors per se. Institutional Commitment - The candidate appears to have excellent institutional support. Responsiveness - The work proposed is relevant to the RFA, as it addresses techniques and tools that are required to carry out cell therapy for PD in a clinically relevant manner. However, some reviewers were of the opinion that the proposed work is better suited for a Tools & Technologies competition than the present New Faculty grant mechanism.