Safety and Tolerability Assessment of Intrastriatal Neural Allografts in Five Patients with Huntington's Disease

Bachoud‐Lévi, Anne‐Catherine; Bourdet, Catherine; Brugières, Pierre; Nguyen, J. P.; Grandmougin, Thierry; Haddad, Bassam; Jeny, R.; Bartolomeo, Paolo; Boissé, MF; Barba, G. Dalla; Degos, JD; Ergis, Anne-Marie; Lefaucheur, J.-P.; Lisovoski, F.; Pailhous, Edwige; Rémy, Philippe; Palfi, Stéphane; Defer, G.; Césaro, P.; Hantraye, Philippe; Peschanski, Marc

doi:10.1006/exnr.1999.7239

Cited by 144 publications

(88 citation statements)

References 35 publications

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“…For these reasons, we believe that neurons, differentiated from parthenogenetic stem cells, may provide an important source of therapeutic treatments. Clinical transplantation of specific fetal neurons has shown promise in the treatment of Parkinson's disease (29) and Huntington's disease (30), but obtaining such cells from animals or human fetal brain remains problematic. Neurons derived in vitro from a renewable source, such as CNS precursors (31), ES cells (32,33), or stem cells of parthenogenetic origin, could alleviate some of the ethical and technical concerns of human cell therapy.…”

Section: Discussionmentioning

confidence: 99%

Nonhuman primate parthenogenetic stem cells

Vrana

Hipp

Goss

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

176

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Parthenogenesis is the biological phenomenon by which embryonic development is initiated without male contribution. Whereas parthenogenesis is a common mode of reproduction in lower organisms, the mammalian parthenote fails to produce a successful pregnancy. We herein describe in vitro parthenogenetic development of monkey (Macaca fascicularis) eggs to the blastocyst stage, and their use to create a pluripotent line of stem cells. These monkey stem cells (Cyno-1 cells) are positive for telomerase activity and are immunoreactive for alkaline phosphatase, octamer-binding transcription factor 4 (Oct-4), stage-specific embryonic antigen 4 (SSEA-4), tumor rejection antigen 1-60 (TRA 1-60), and tumor rejection antigen 1-81 (TRA 1-81) (traditional markers of human embryonic stem cells). They have a normal chromosome karyotype (40 + 2) and can be maintained in vitro in an undifferentiated state for extended periods of time. Cyno-1 cells can be differentiated in vitro into dopaminergic and serotonergic neurons, contractile cardiomyocyte-like cells, smooth muscle, ciliated epithelia, and adipocytes. When Cyno-1 cells were injected into severe combined immunodeficient mice, teratomas with derivatives from all three embryonic germ layers were obtained. When grown on fibronectin/laminin-coated plates and in neural progenitor medium, Cyno-1 cells assume a neural precursor phenotype (immunoreactive for nestin). However, these cells remain proliferative and express no functional ion channels. When transferred to differentiation conditions, the nestin-positive precursors assume neuronal and epithelial morphologies. Over time, these cells acquire electrophysiological characteristics of functional neurons (appearance of tetrodotoxin-sensitive, voltage-dependent sodium channels). These results suggest that stem cells derived from the parthenogenetically activated nonhuman primate egg provide a potential source for autologous cell therapy in the female and bypass the need for creating a competent embryo

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Section: Discussionmentioning

confidence: 99%

Nonhuman primate parthenogenetic stem cells

Vrana

Hipp

Goss

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

176

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“…[107][108][109] In one study, five patients with genetically confirmed HD, with minimal cognitive impairment, underwent unilateral (nondominant hemisphere) fetal cell graft implantation, mostly precommissurally in putamen and caudate. 110 Postsurgical complications included transient confusion, face and upper limb paresis, and slight postural instability. Postoperative magnetic resonance imaging did not detect any complications.…”

Section: Fetal Cell Transplantationmentioning

confidence: 99%

Symptomatic Treatment of Huntington Disease

2008

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Summary: Huntington disease (HD) is a progressive heredoneurodegenerative disease manifested by chorea and other hyperkinetic (dystonia, myoclonus, tics) and hypokinetic (parkinsonism) movement disorders. In addition, a variety of psychiatric and behavioral symptoms, along with cognitive decline, contribute significantly to the patient's disability. Because there are no effective neuroprotective therapies that delay the progression of the disease, symptomatic treatment remains the cornerstone of medical management. Several classes of medications have been used to ameliorate the various symptoms of HD, including typical and atypical neuroleptics, dopamine depleters, antidepressants, antiglutamatergic drugs, GABA agonists, antiepileptic medications, acetylcholinesterase inhibitors, and botulinum toxin. Recently, surgical approaches including pallidotomy, deep brain stimulation, and fetal cell transplants have been used for the symptomatic treatment of HD. The selected therapy must be customized to the needs of each patient, minimizing the potential adverse effects. The primary aim of this article is to review the role of the different therapies, both available and investigational, for the treatment of the motor, psychiatric, behavioral, and cognitive symptoms of HD, and to examine their impact on the patient's functionality and quality of life.

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“…Although full recovery has not been observed following fetal allografts in the striatum of humans with HD, some suggestions of delayed disease progression indicate positive functional outcomes. 12,13 The contribution of these grafts to functional recovery is enhanced by the fact that implanted cells, lacking the disease-causing gene, do not themselves appear vulnerable to neurodegenerative processes, 56,83 an effect that is also seen in transplants in patients with PD. 86,87,126 All clinical trials to date have been focused on the transplantation of fetal-derived cells into the diseased striatum.…”

Section: Transplantation Of Fetal-derived Cells As Exogenous Cell Thementioning

confidence: 99%

“…23 As in PD, 97,142 the safety of allografts of fetal striatal neural tissue has been demonstrated in HD. 12,72,85,133 Similar to its successful use in cell therapy for PD, 87 hibernation medium used to store harvested cells for up to 8 days has allowed the collection of adequate amounts of tissue and the flexibility to prepare tissue at sites and times other than the site and time of transplantation surgery. 74,76 The use of tissue previously stored in hibernating medium has had no major adverse effects on subsequent transplantation performed according to this validated protocol.…”

Section: Transplantation Of Fetal-derived Cells As Exogenous Cell Thementioning

confidence: 99%

“…86,87,126 The success of allografts of fetal-derived striatal tissue in patients with HD hinges on motor and cognitive improvements following transplantation. [12][13][14][15]85,103,125 Improvements on the Unified Huntington's Disease Rating Scale motor score have been reported as early as 1 month after unilateral grafting of fetal-derived striatal tissue 12 and have stabilized between 6 months 85 and 2 years 13 after transplantation. Patients assessed up to 6 years after bilateral transplantation have demonstrated that immediate improvements in motor scores (between 6 months and 2 years) may not persist long term.…”

Section: Transplantation Of Fetal-derived Cells As Exogenous Cell Thementioning

confidence: 99%

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Cell therapy in Huntington disease

Clelland

Barker²,

Watts³

2008

FOC

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✓ Huntington disease (HD), caused by polyglutamate expansions in the huntingtin protein, is a progressive neurodegenerative disease resulting in cognitive and motor impairments and death. Neuronal dysfunction and degeneration contribute to progressive physiological, motor, cognitive, and emotional disturbances characteristic of HD. A major impetus for research into the treatment of HD has centered on cell therapy strategies to protect vulnerable neuronal cell populations or to replace dysfunctional or dying cells. The work underlying 3 approaches to HD cell therapy includes the potential for self-repair through the manipulation of endogenous stem cells and/or neurogenesis, the use of fetal or stem cell transplantation as a cell replacement strategy, and the administration of neurotrophic factors to protect susceptible neuronal populations. These approaches have shown some promising results in animal models of HD. Although striatal transplantation of fetal-derived cells has undergone clinical assessment since the 1990s, many cell therapy strategies have yet to be applied in the clinic environment. A more thorough understanding of the pathophysiologies underlying HD as well as the response of both endogenous and exogenous cells to the degenerating brain will inform their merit as potential therapeutic agents and enhance the framework by which the success of such strategies are determined.

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Safety and Tolerability Assessment of Intrastriatal Neural Allografts in Five Patients with Huntington's Disease

Cited by 144 publications

References 35 publications

Nonhuman primate parthenogenetic stem cells

Nonhuman primate parthenogenetic stem cells

Symptomatic Treatment of Huntington Disease

Cell therapy in Huntington disease

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