Developmental Candidates for Cell-Based Therapies for Parkinson's Disease (PD)

Funding Type:

Early Translational I

Grant Number:

TR1-01267

Funds Committed:

$5,416,003

Disease Focus:

Parkinson's Disease

Collaborative Funder:

Victoria, Australia

Stem Cell Use:

Adult Stem Cell

Status:

Active

Public Abstract:

Parkinson's Disease (PD) is a devastating disorder, stealing vitality from vibrant, productive adults & draining our health care dollars. It is also an excellent model for studying other neurodegenerative conditions. We have discovered that human neural stem cells (hNSCs) may exert a significant beneficial impact in the most authentic, representative, & predictive animal model of actual human PD. Interestingly, we have learned that, while some of the hNSCs differentiate into replacement dopamine (DA) neurons, much of the therapeutic benefit derived from a stem cell action we discovered a called the “Chaperone Effect” – even hNSC-derived cells that do not become DA neurons contributed to the reversal of severe Parkinsonian symptoms by protecting endangered host DA neurons & their connections, restoring equipoise to the host nigrostriatal system, and reducing pathological hallmark of PD. While the ultimate goal may someday be to replace dead DA neurons, the Chaperone Effect represents a more tractable near-term method of using cells to address this serious condition. However, many questions remain in the process of developing these cellular therapeutic candidates. A major question is what is the best (safest, most efficacious) way to generate hNSCs? Directly from the fetal brain? From human embryonic stem cells? From skin cells reprogrammed to act like stem cells? Also, would benefits be even greater if, in addition to harnessing the Chaperone Effect, the number of stem cell-derived DA neurons was also increased? And could choosing the right stem cell type &/or providing the right supportive molecules help achieve this? This study seeks to answer these questions. Importantly, we will do so using the most representative model of human PD, a model that not only mimics all of the human symptomatology but also all the side-effects of treatment; inattention to this latter aspect plagued earlier clinical trials in PD. A successful therapy for PD would not only be of great benefit for the many patients who now suffer from the disease, or who are likely to develop it as they age, but the results will help with other potential disease applications due to greater understanding of stem cell biology (particularly the Chaperone Effect, which represents “low hanging fruit”) as well as their potential complications and side effects.

Statement of Benefit to California:

Not only is Parkinson's Disease (PD) a devastating disease in its own right-- impairing typically vibrant productive adults & draining our health care dollars -- but it is also an excellent model for studying other neurodegenerative diseases. We have discovered that stem cells may actually exert a beneficial impact independent of dopamine neuron replacement. As a result of a multiyear study performed by our team, implanting human neural stem cells (hNSCs) into the most authentic, representative, and predictive animal model of actual human PD, we learned that the cells could reverse severe Parkinsonian symptoms by protecting endangered host dopaminergic (DA) neurons, restoring equipoise to the cytoarchitecture, preserving the host nigrostriatal pathway, and reducing alpha-synuclein aggregations (a pathological hallmark of PD). This action, called the "Chaperone Effect" represents a more tractible near-term method of using cells to address an unmet medical need. However, many questions remain in the process of developing these cellular therapeutic candidates. A major question is what is the best (safest & most efficacious way) to generate hNSCs? Directly from the fetal brain? From human embryonic stem cells? From human induced pluripotent cells? Also, would benefits be even greater if, in addition to harnessing the Chaperone Effect, the number of donor-derived DA neurons was also increased? And could choosing the right stem cell type &/or providing the right supportive molecules help achieve this? This study seeks to answer these questions. Importantly, we will continue to use the most representative model of human PD to do so, a model that not only mimics all of the human symptomatology but also all the side-effects of treatment; inattention to this latter aspect plagued earlier clinical trials in PD. Because of the unique team enlisted, these studies can be done at a fraction of the normal cost, allowing for parsimony in the use of research dollars, clearly a benefit to California taxpayers. Not only might California patients benefit in terms of their well-being, and the economy benefit from productive adults re-entering the work force & aging adults remaining in the work force, but it is likely that new intellectual property will emerge that will provide additional financial benefit to California stakeholders, both citizens & companies.

Progress Report:

Year 1

Parkinson's Disease (PD) is a devastating disorder, stealing vitality from vibrant, productive adults & draining our health care dollars. It is also an excellent model for studying other neurodegenerative conditions. We have discovered that human neural stem cells (hNSCs) may exert a significant beneficial impact in the most authentic, representative, & predictive animal model of actual human PD (the adult African/St. Kitts Green Monkeys exposed systemically to the neurotoxin MPTP). Interestingly, we have learned that, while some of the hNSCs differentiate into replacement dopamine (DA) neurons, much of the therapeutic benefit derived from a stem cell action we discovered called the “Chaperone Effect” – even hNSC-derived cells that do not become DA neurons contributed to the reversal of severe Parkinsonian symptoms by protecting endangered host DA neurons & their connections, restoring equipoise to the host nigrostriatal system, and reducing pathological hallmark of PD. While the ultimate goal may someday be to replace dead DA neurons, the Chaperone Effect represents a more tractable near-term method of using cells to address this serious condition. However, many questions remain in the process of developing these cellular therapeutic candidates. A major question is what is the best (safest, most efficacious) way to generate hNSCs? Directly from the fetal brain? From human embryonic stem cells? From skin cells reprogrammed to act like stem cells? Also, would benefits be even greater if, in addition to harnessing the Chaperone Effect, the number of stem cell-derived DA neurons was also increased? And could choosing the right stem cell type &/or providing the right supportive molecules help achieve this? This international study – which involves scientists from California, Madrid, Melbourne -- has been seeking to answer these questions. Importantly, we have been doing so using the most representative model of human PD, a model that not only mimics all of the human symptomatology but also all the side-effects of treatment; inattention to this latter aspect plagued earlier clinical trials in PD. A successful therapy for PD would not only be of great benefit for the many patients who now suffer from the disease, or who are likely to develop it as they age, but the results will help with other potential disease applications due to greater understanding of stem cell biology (particularly the Chaperone Effect, which represents “low hanging fruit”) as well as their potential complications and side effects. To date, we have transplanted nearly 40 Parkinsonian non-human primates (NHPs) with a range of the different stem cell types described above. We have been able to generate neurons from some of these stem cells that appear to have the characteristics of the desired A9-type midbrain dopaminergic neuron lost in PD. Following transplantation, some of these stem cell derivatives appear to survive, integrate, & behave like dopaminergic neurons. Preliminary behavioral analysis of some engrafted NHPs offers encouraging results, suggesting an improvement in the Parkinsonism score in some of the animals. These NHPs will need to be followed for 1 year to insure that improvement continues & that no adverse events intervene. Over the next year, more stem cell candidates will be tested as we further optimize their preparation & differentiation.

Year 2

We have made substantial progress in what will amount to the largest and most comprehensive head-to-head behavioral analysis of stem cell transplanted MPTP-NHPs to date and have identified cell types that show dramatic improvement in this model. Compared to the improvement observed with undifferentiated fetal CNS-derived hNSCs (the stem cell type in used Redmond et al, PNAS, 2007), 3 human stem cell candidates have shown a larger improvement in PS. Summary of Achievements for this reporting period • Comprehensive Behavioral data collection of 84 monkeys comprising over 10,000 observation data points • Statistical analysis of Behavioral data collected to date identifies striking and statistically significant improvements in PS for several stem cell types. (Accordingly, NO-GO (or near NO-GO) cell types have been identified via comparison of levels of improvement or no improvement) [Figure 1] • DNA samples collected in order to pursue the first ever complete genome sequencing of the Vervet in collaboration with the Washington University Genome Center • Biochemistry sample processing and data collection of a 2nd large batch of samples completed.