Disease Team Therapy Planning I
Parkinson’s disease is one the most frequent neurodegenerative disorders affecting a progressively larger population worldwide. The exact initial pathophysiology leading to a profound cellular dysfunction of dopamine secreting neurons in the midbrain and cellular accumulation of metabolic byproducts leading to death remains unknown. The early stages respond usually well to medical management, consisting mainly of oral ingestion of precursors of dopamine, or dopamine receptors agonists or metabolite antagonists. But the progression of the disease is irreversible and lead to more advanced stages with debilitating motor and non-motor symptomatology. Chronic medical therapy causes secondary complications, sometimes worse than the disease itself. Surgical procedures such as the implantation of chronic stimulators within different targets can lead to symptomatic improvement in the motor functions. This improvement is usually transient but may benefit some patients for several years. Other symptoms progress however with increasing oral intake of dopaminergic medication and stimulation parameters. Parkinson’s disease is a relatively confined pathological disorder within the basal ganglia, at least initially. Cellular replacement therapy (CRT) appears applicable to this disorder and has been investigated at the basic and clinical level for several years. Most of the studies assumed a simple deficit of focal dopaminergic discharge, and used a classic animal. Our current translational effort gives us a unique position in CRT. It is based on the selective isolation, expansion and differentiation of autologous adult neural stem cells with epigenetic factors, replicating certain steps of human neurogenesis by inducing a shift in the expression pattern of homeobox genes in vitro. Unlike embryonic stem cells, adult neural stem cells have a committed path to the formation of tissue from the central nervous system, and the unique autologous approach makes this therapy immune-compatible with minimal infectious risks. Our objectives in this proposal aims at achieving the planning for the following activities to be funded under Part II: a)To create a CIRM Parkinson’s Disease Therapy Team linking academic scientists, animal model experts, clinical trials experts, and regulatory specialists to prepare a new IND filing with the FDA. b)To establish a cGMP manufacturing facility and complete Production, Storage and Process Controls for clinical grade Target Product validation. c)To complete parallel IND enabling animals studies with new animal models of PD. d)To lay the foundation for a Phase I/II prospective randomized control surgical trial to be completed within 4 years of funding.
Statement of Benefit to California:
This proposal meets several goals from the CIRM 2009 syllabus on its mission and roles within the State of California. [REDACTED], will establish its animal studies in [REDACTED] and establish a cGMP facility within the state as well. The clinical trial will be conducted in [REDACTED]. It will be one of the first clinical study using autologous adult neural stem cells for advanced Parkinson's disease. A multidisciplinary team of clinicians and scientists will be fully committed for the duration of the funding to seek a potential revolutionary treatment for Parkinson's disease. Our group will develop collaborative networks with world renowned experts in the field of neurodegenerative disorders and those scientists already funded by CIRM and working both at the basic and preclinical levels. Experts in clinical surgical trials, statisticians, ethicists, neurologists will oversee the proposed Phase II trial once approved by the FDA.
EXECUTIVE SUMMARY Project Synopsis The goal of this project is to file an IND and complete a Phase I/II trial for a cell therapy for Parkinson's disease (PD). The proposed therapy is transplantation of a post mitotic neuronal cell population including dopaminergic (DA) neurons derived from autologous adult neural stem cells (hNSCs). The hNSCs will be isolated from samples taken from patients with advanced Parkinson’s disease while undergoing deep brain stimulation surgery. During the planning award period, the applicant proposes to: a) create a multi-disciplinary team, b) develop plans to establish a cGMP manufacturing facility and produce autologous product under cGMP, c) develop plans to complete IND enabling animals studies with new animal models of PD, and d) develop plans for a Phase I/II prospective randomized control surgical trial to be completed within 4 years of funding. Significance and Impact − If successful, transplantation of stem cell-derived DA-producing cells could be very significant for the treatment of PD. The intended patient population is a significant population with a very high unmet medical need. − Reviewers considered the potential for impact of this proposed project to be low because the absence of key data and the premature nature of this proposal made it unlikely that the goals of the project would be achieved. Project Rationale and Feasibility − Reviewers agreed that the rationale for dopaminergic cell replacement therapy in PD is strong but is tempered by clinical experience during the past decades (some instances of patient benefit, 2 controlled trials which did not meet primary endpoint and development of dyskinesias in some treated patients). Although the reviewers believe that our understanding has evolved such that there is rationale for new clinical studies of transplantation of a DA cell product, they all agreed that a well characterized, consistent dopaminergic neuronal population that had been adequately tested preclinically would be crucial before moving into the clinic. − Reviewers found the present proposal to be extremely premature, with a poor chance of achieving the proposed goals of the project in the allotted time. − The amount, quality and reliability of the preclinical data presented in this application were inadequate and fell well short of what would be required to take this project forward at this time. − A key issue for cell therapy for PD is the nature and consistency of the proposed cell population for transplantation. An autologous cell source has far greater issues of variability than an “off-the shelf” product. Before embarking on the clinical program outlined in the application, reviewers believed that there should be solid data showing that autologous adult NSCs can be reliably harvested from PD patients, expanded in culture, and reliably differentiated to a product that has a consistent composition of dopaminergic and non-dopaminergic cells. Moreover, they should demonstrate that the derived cells engraft and survive long term in a relevant animal model of disease and are functionally effective. This data is not shown in the proposal and achieving it is highly unlikely in the time allotted by the applicant. − Reviewers agreed that treatment of a single human subject (5 year follow-up) does not show a path towards more general use. − Despite the potential of this autologous approach to circumvent some of the problems associated with allogeneic graft transplantation (i.e. immune rejection), there is little or no evidence to suggest that the product cells would be less likely to evoke dyskinesias, as suggested but not demonstrated in the application. Principal Investigator (PI) and Planning Leader − The PI, who will also be the Planning Leader, is a neurosurgeon with an interest in neural transplantation. − It is not clear that the PI has the relevant translational research experience that will be necessary to see this project through to completion. − The proposed team suggested in the application is rather limited and does not appear to cover all the major areas that would be important.