Transplantation of Fetal Substantia Nigra and Adrenal Medulla to the Caudate Nucleus in Two Patients with Parkinson's Disease

Madrazo, Ignacio; Leon, David A.; Torres, Claudia MartÃ­nez; Mc, Aguilera; Varela, G.; Álvarez, Fausto; Fraga, Aline Padilha de; Drucker-Colı́n, René; Ostrosky, Feggy; Skurovich, M

doi:10.1056/nejm198801073180115

Cited by 211 publications

(13 citation statements)

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“…However, after refining the technique, subsequent clinical studies showed significant clinical improvements following implantation of fetal DA neurons into the brains of young PD patients (Freed et al, 2001). Unfortunately, this approach resulted in high morbidity and mortality rate in elderly patients (Madrazo et al, 1988b;Goetz et al, 1989;Brundin et al, 2010). However, postmortem studies showed a sustained survival of the transplanted cells (Barrow, 2015;Björklund and Lindvall, 2017).…”

Section: Nigral Cell Transplantationmentioning

confidence: 99%

Strategies for the Treatment of Parkinson’s Disease: Beyond Dopamine

Iarkov

Barreto

Grizzell

et al. 2020

Front. Aging Neurosci.

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Parkinson's disease (PD) is the second-leading cause of dementia and is characterized by a progressive loss of dopaminergic neurons in the substantia nigra alongside the presence of intraneuronal α-synuclein-positive inclusions. Therapies to date have been directed to the restoration of the dopaminergic system, and the prevention of dopaminergic neuronal cell death in the midbrain. This review discusses the physiological mechanisms involved in PD as well as new and prospective therapies for the disease. The current data suggest that prevention or early treatment of PD may be the most effective therapeutic strategy. New advances in the understanding of the underlying mechanisms of PD predict the development of more personalized and integral therapies in the years to come. Thus, the development of more reliable biomarkers at asymptomatic stages of the disease, and the use of genetic profiling of patients will surely permit a more effective treatment of PD.

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Section: Nigral Cell Transplantationmentioning

confidence: 99%

Strategies for the Treatment of Parkinson’s Disease: Beyond Dopamine

Iarkov

Barreto

Grizzell

et al. 2020

Front. Aging Neurosci.

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“…Clinical studies on neural grafting started in the late 1980s, when dopaminergic neurons derived from the human embryonic brain were transplanted into the striatum of patients with PD (Lindvall et al, 1989; Madrazo et al, 1988). Recently, a new body of evidence has emerged showing host-to-graft propagation of LB and α-syn pathology in long term transplants (Hansen et al, 2011; Li et al, 2008), due to the transmission of aberrant α-syn aggregates from the surrounding tissues (Desplats et al, 2009).…”

Section: α-Synuclein Propagation As Immunotherapeutic Target: Reacmentioning

confidence: 99%

Immunotherapy for neurodegenerative diseases: Focus on α-synucleinopathies

Valera

Masliah

2013

Pharmacology & Therapeutics

119

100

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Immunotherapy is currently being intensively explored as much-needed disease-modifying treatment for neurodegenerative diseases. While Alzheimer’s disease (AD) has been the focus of numerous immunotherapeutic studies, less attention has been paid to Parkinson’s disease (PD) and other neurodegenerative disorders. The reason for this difference is that the amyloid beta (Aβ) protein in AD is a secreted molecule that circulates in blood and is readably recognized by antibodies. In contrast, α-synuclein (α-syn), tau, huntingtin and other proteins involved in neurodegenerative diseases have been considered to be exclusively of intracellular nature. However, the recent discovery that toxic oligomeric versions of α-syn and tau accumulate in the membrane and can be excreted to the extracellular environment has provided a rationale for the development of immunotherapeutic approaches for PD, dementia with Lewy bodies, frontotemporal dementia, and other neurodegenerative disorders characterized by the abnormal accumulation of these proteins. Active immunization, passive immunization, and T cell-mediated cellular immunotherapeutic approaches have been developed targeting Aβ, α-syn and tau. Most advanced studies, including results from phase III clinical trials for passive immunization in AD, have been recently reported. Results suggest that immunotherapy might be a promising therapeutic approach for neurodegenerative diseases that progress with the accumulation and propagation of toxic protein aggregates. In this manuscript we provide an overview on immunotherapeutic advances for neurodegenerative disorders, with special emphasis on α-synucleinopathies.

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“…Neural transplantation of fetal dopaminergic neurons was tested as an experimental clinical therapy for PD (Borlongan, 2000; Borlongan et al, 1999; Freeman et al, 1995; Kordower et al, 1995; Lindvall et al, 1988, 1992; Madrazo et al, 1988). However, the logistical issues, associated with procuring large supply of fetal cells, overshadow its therapeutic benefit (Borlongan and Sanberg, 2002; Freed, 2002).…”

Section: Cell Therapy For Neurological Disordersmentioning

confidence: 99%

Recent preclinical evidence advancing cell therapy for Alzheimer's disease

Borlongan

2012

Experimental Neurology

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Alzheimer's disease (AD) causes brain degeneration, primarily depleting cholinergic cells, and leading to cognitive and learning dysfunction. Logically, to augment the cholinergic cell loss, a viable treatment for AD has been via drugs boosting brain acetylcholine production. However, this is not a curative measure. To this end, nerve growth factor (NGF) has been examined as a possible preventative treatment against cholinergic neuronal death while enhancing memory capabilities; however, NGF brain bioavailability is challenging as it does not cross the blood–brain barrier. Investigations into stem cell- and gene-based therapy have been explored in order to enhance NGF potency in the brain. Along this line of research, a genetically modified cell line, called HB1.F3 transfected with the cholinergic acetyltransferase or HB1.F3.ChAT cells, has shown safety and efficacy profiles in AD models. This stem cell transplant therapy for AD is an extension of the neural stem cells' use in other neurological treatments, such as Parkinson's disease and stroke, and recently extended to cancer. The HB1 parent cell and its associated cell lines have been used as a vehicle to deliver genes of interest in various neurological models, and are highly effective as they can differentiate into neurons and glial cells. A focus of this mini-review is the recent demonstration that the transplantation of HB1.F3.ChAT cells in an AD animal model increases cognitive function coinciding with upregulation of acetylcholine levels in the cerebrospinal fluid. In addition, there is a large dispersion throughout the brain of the transplanted stem cells which is important to repair the widespread cholinergic cell loss in AD. Some translational caveats that need to be satisfied prior to initiating clinical trials of HB1.F3.ChAT cells in AD include regulating the host immune response and the possible tumorigenesis arising from the transplantation of this genetically modified cell line. Further studies are warranted to test the safety and effectiveness of these cells in AD transgenic animal models. This review highlights the recent progress of stem cell therapy in AD, not only emphasizing the significant basic science strides made in this field, but also providing caution on remaining translational issues necessary to advance this novel treatment to the clinic.

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Transplantation of Fetal Substantia Nigra and Adrenal Medulla to the Caudate Nucleus in Two Patients with Parkinson's Disease

Cited by 211 publications

References 1 publication

Strategies for the Treatment of Parkinson’s Disease: Beyond Dopamine

Strategies for the Treatment of Parkinson’s Disease: Beyond Dopamine

Immunotherapy for neurodegenerative diseases: Focus on α-synucleinopathies

Recent preclinical evidence advancing cell therapy for Alzheimer's disease

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