Dopamine Cell Transplantation for Parkinson's Disease: The Importance of Controlled Clinical Trials

Freed, Curt R.; Zhou, Wenbo; Breeze, Robert E.

doi:10.1007/s13311-011-0082-9

Cited by 56 publications

(31 citation statements)

References 71 publications

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“…Transplantation strategies, particularly ectopic transplantation of DA neurons into the striatum, has long been pursued as a therapeutic strategy for PD (Freed et al, 2011). Recently, optogenetic control of DA neural transplants, and optogenetic control of striatal neurons surrounding DA neuronal transplants, was used to demonstrate proof-of-concept examination of host-graft synaptic interactions that regulate activity in transplanted neurons (Tonnesen et al, 2011).…”

Section: Optogenetics and Dreadds In Current And Emerging Therapeumentioning

confidence: 99%

New tricks for old dogmas: Optogenetic and designer receptor insights for Parkinson's disease

Vazey

Aston‐Jones

2013

Brain Research

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Optogenetics and novel designer receptors have revolutionized the way neuroscientists can interrogate neural circuits. These new tools are being rapidly applied to many facets of neuroscience including the study of Parkinson's disease circuitry and therapies. This review highlights how optogenetics and designer receptors can be applied in the study of Parkinsonian dysfunction to understand the mechanisms behind motor and non-motor symptoms. We discuss how these tools have recently advanced our understanding of basal ganglia function and outline how they can be applied in future to refine existing treatments and generate novel therapeutic strategies for Parkinson's disease.

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Section: Optogenetics and Dreadds In Current And Emerging Therapeumentioning

confidence: 99%

New tricks for old dogmas: Optogenetic and designer receptor insights for Parkinson's disease

Vazey

Aston‐Jones

2013

Brain Research

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“…Prior to the advent of pluripotent stem cells, clinicians attempted to treat PD by transplanting cells derived from a variety of heterologous tissue sources into the striatum (Bjorklund and Kordower, 2013). Fetal ventral mesencephalon tissue demonstrated the most success in preclinical studies in rodents, but ultimately failed to significantly reduce parkinsonism in double-blind clinical trials (Freed et al, 2001(Freed et al, , 2011Olanow et al, 2003). There are at least three factors potentially culpable for the failure of previous human clinical trials of cell-based transplantation therapy for PD: 1.)…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, questions still remain as to the safety and efficacy of cell-based therapies for PD. Clinical trials have not yet been attempted in humans (Freed et al, 2011), but the inconsistent results of animal studies conducted to date exemplify the need for further, more informative NHP preclinical studies to optimize the safety and efficacy of cell-based therapies for PD.…”

Section: Introductionmentioning

confidence: 99%

Advantages of nonhuman primates as preclinical models for evaluating stem cell-based therapies for Parkinson's disease

Grow¹,

McCarrey²,

Navara³

2016

Stem Cell Research

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The derivation of dopaminergic neurons from induced pluripotent stem cells brings new hope for a patient-specific, stem cell-based replacement therapy to treat Parkinson's disease (PD) and related neurodegenerative diseases; and this novel cell-based approach has already proven effective in animal models. However, there are several aspects of this procedure that have yet to be optimized to the extent required for translation to an optimal cell-based transplantation protocol in humans. These challenges include pinpointing the optimal graft location, appropriately scaling up the graft volume, and minimizing the risk of chronic immune rejection, among others. To advance this procedure to the clinic, it is imperative that a model that accurately and fully recapitulates characteristics most pertinent to a cell-based transplantation to the human brain is used to optimize key technical aspects of the procedure. Nonhuman primates mimic humans in multiple ways including similarities in genomics, neuroanatomy, neurophysiology, immunogenetics, and age-related changes in immune function. These characteristics are critical to the establishment of a relevant model in which to conduct preclinical studies to optimize the efficacy and safety of cell-based therapeutic approaches to the treatment of PD. Here we review previous studies in rodent models, and emphasize additional advantages afforded by nonhuman primate models in general, and the baboon model in particular, for preclinical optimization of cell-based therapeutic approaches to the treatment of PD and other neurodegenerative diseases. We outline current unresolved challenges to the successful application of stem cell therapies in humans and propose that the baboon model in particular affords a number of traits that render it most useful for preclinical studies designed to overcome these challenges.

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“…[1–4]. These preclinical studies have been translated into clinical trials for a multitude of conditions including Parkinson’s disease (PD) [5–7], Huntington’s disease [8–12], and stroke [13–15]. However, human patient studies have produced mixed therapeutic results.…”

Section: Introductionmentioning

confidence: 99%

Radially Branched Deployment for More Efficient Cell Transplantation at the Scale of the Human Brain

Silvestrini

Yin

Coppes

et al. 2013

Stereotact Funct Neurosurg

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Background: In preclinical studies, cell transplantation into the brain has shown great promise for the treatment of a wide range of neurological diseases. However, the use of a straight cannula and syringe for cell delivery to the human brain does not approximate cell distribution achieved in animal studies. This technical deficiency may limit the successful clinical translation of cell transplantation. Objective: To develop a stereotactic device that effectively distributes viable cells to the human brain. Our primary aims were to (1) minimize the number of transcortical penetrations required for transplantation, (2) reduce variability in cell dosing and (3) increase cell survival. Methods: We developed a modular cannula system capable of radially branched deployment (RBD) of a cell delivery catheter at variable angles from the longitudinal device axis. We also developed an integrated catheter-plunger system, eliminating the need for a separate syringe delivery mechanism. The RBD prototype was evaluated in vitro and in vivo with subcortical injections into the swine brain. Performance was compared to a 20G straight cannula with dual side ports, a device used in current clinical trials. Results: RBD enabled therapeutic delivery in a precise ‘tree-like’ pattern branched from a single initial trajectory, thereby facilitating delivery to a volumetrically large target region. RBD could transplant materials in a radial pattern up to 2.0 cm from the initial penetration tract. The novel integrated catheter-plunger system facilitated manual delivery of small and precise volumes of injection (1.36 ± 0.13 µl per cm of plunger travel). Both dilute and highly concentrated neural precursor cell populations tolerated transit through the device with high viability and unaffected developmental potential. While reflux of infusate along the penetration tract was problematic with the use of the 20G cannula, RBD was resistant to this source of cell dose variability in agarose. RBD enabled radial injections to the swine brain when used with a modern clinical stereotactic system. Conclusions: By increasing the total delivery volume through a single transcortical penetration in agarose models, RBD strategy may provide a new approach for cell transplantation to the human brain. Incorporation of RBD or selected aspects of its design into future clinical trials may increase the likelihood of successful translation of cell-based therapy to the human patient.

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Dopamine Cell Transplantation for Parkinson's Disease: The Importance of Controlled Clinical Trials

Cited by 56 publications

References 71 publications

New tricks for old dogmas: Optogenetic and designer receptor insights for Parkinson's disease

New tricks for old dogmas: Optogenetic and designer receptor insights for Parkinson's disease

Advantages of nonhuman primates as preclinical models for evaluating stem cell-based therapies for Parkinson's disease

Radially Branched Deployment for More Efficient Cell Transplantation at the Scale of the Human Brain

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