Neuroprotection of Host Cells by Human Central Nervous System Stem Cells in a Mouse Model of Infantile Neuronal Ceroid Lipofuscinosis

Tamaki, Stanley; Jacobs, Yakop; Dohse, Monika; Capela, Alexandra; Cooper, Jonathan D.; Reitsma, Michael J.; He, Dongping; Tushinski, Robert; Belichenko, Pavel V.; Salehi, Ahmad; Mobley, William C.; Gage, Fred H.; Huhn, Stephen L.; Tsukamoto, Ann; Uchida, Naoshige

doi:10.1016/j.stem.2009.05.022

Cited by 127 publications

(97 citation statements)

References 37 publications

(56 reference statements)

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“…Various experimental therapies have been tested to treat forebrain pathology in Ppt1 −/− mice, including antioxidants (19,20), enzyme replacement therapy (ERT) (21,22), human neuronal stem cells (23), and forebrain-directed gene therapy (12,(24)(25)(26)(27). Of these, adeno-associated virus (AAV) vector-mediated gene transfer has been the most promising (3,28).…”

mentioning

confidence: 99%

Synergistic effects of treating the spinal cord and brain in CLN1 disease

Shyng

Nelvagal

Dearborn

et al. 2017

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

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101

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Infantile neuronal ceroid lipofuscinosis (INCL, or CLN1 disease) is an inherited neurodegenerative storage disorder caused by a deficiency of the lysosomal enzyme palmitoyl protein thioesterase 1 (PPT1). It was widely believed that the pathology associated with INCL was limited to the brain, but we have now found unexpectedly profound pathology in the human INCL spinal cord. Similar pathological changes also occur at every level of the spinal cord of PPT1-deficient (Ppt1 −/− ) mice before the onset of neuropathology in the brain. Various forebrain-directed gene therapy approaches have only had limited success in Ppt1 −/− mice. Targeting the spinal cord via intrathecal administration of an adeno-associated virus (AAV) gene transfer vector significantly prevented pathology and produced significant improvements in life span and motor function in Ppt1 −/− mice. Surprisingly, forebrain-directed gene therapy resulted in essentially no PPT1 activity in the spinal cord, and vice versa. This leads to a reciprocal pattern of histological correction in the respective tissues when comparing intracranial with intrathecal injections. However, the characteristic pathological features of INCL were almost completely absent in both the brain and spinal cord when intracranial and intrathecal injections of the same AAV vector were combined. Targeting both the brain and spinal cord also produced dramatic and synergistic improvements in motor function with an unprecedented increase in life span. These data show that spinal cord pathology significantly contributes to the clinical progression of INCL and can be effectively targeted therapeutically. This has important implications for the delivery of therapies in INCL, and potentially in other similar disorders.infantile Batten disease | adeno-associated virus | spinal cord | brain | combination therapy

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mentioning

confidence: 99%

Synergistic effects of treating the spinal cord and brain in CLN1 disease

Shyng

Nelvagal

Dearborn

et al. 2017

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

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101

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“…Extensive engraftment and migration of the transplanted cells were noted in the CNS that translated into widespread production of therapeutic levels of the lysosomal enzyme palmitoyl protein thioesterase-1, the enzyme deficient in INCL. Treated mice exhibited significantly reduced neuropathology, a delay in the loss of motor coordination, and an extended survival benefit [64]. This demonstration that early intervention with cellular transplants of huCNS-SCs into the brains of INCL patients might allow for the sustained production of therapeutic levels of palmitoyl protein thioesterase-1 and consequent protection of host neurons was the experimental basis for the human clinical studies with banked huCNS-SCs.…”

Section: Cell-mediated Gene Therapymentioning

confidence: 89%

“…In some animal models of LSDs with neurometabolic diseases, such as Sandhoff [62,63] and infantile neuronal ceroid lipofuscinosis [64], immortalized NSCs that had been isolated directly from human CNS or derived secondarily from ESCs, are able to secrete appropriate levels of the deficient enzymes. In contrast, in Niemann Pick A disease, adult mouse-derived NPCs needed to be modified by ex-vivo gene transduction before they were able to secrete therapeutic amounts of acid sphingomyelinase (SMPD1), the deficient enzyme [58].…”

Section: Cell-mediated Gene Therapymentioning

confidence: 99%

“…Recently, Tamaki et al [64] also reported studies of transplantation of normal, nontumorogenic, and unmodified fetal human NSCs that had been grown as neurospheres (huCNS-SCs) into the brains of an immunodeficient mouse model of infantile neuronal ceroid lipofuscinosis (INCL). Extensive engraftment and migration of the transplanted cells were noted in the CNS that translated into widespread production of therapeutic levels of the lysosomal enzyme palmitoyl protein thioesterase-1, the enzyme deficient in INCL.…”

Section: Cell-mediated Gene Therapymentioning

confidence: 99%

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Neural Stem Cell Transplantation as a Therapeutic Approach for Treating Lysosomal Storage Diseases

Shihabuddin¹,

Cheng²

2011

Neurotherapeutics

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Treating the central nervous system manifestations of subjects with neuropathic lysosomal storage diseases remains a major technical challenge. This is because of the low efficiency by which lysosomal enzymes in systemic circulation are able to traverse the blood brain barrier into the central nervous system. Intracranial transplantation of neural stems cells genetically modified to overexpress the respective deficient enzymes represents a potential approach to addressing this group of diseases. The unique properties of neural stem cells and progenitor cells, such as their ability to migrate to distal sites, differentiate into various cell types and integrate within the host brain without disrupting normal function, making them particularly attractive therapeutic agents. In addition, neural stem cells are amenable to ex vivo propagation and modification by gene transfer vectors. In this regard, transplanted cells can serve not only as a source of lysosomal enzymes but also as a means to potentially repair the injured brain by replenishing the organ with healthy cells and effecting the release of neuroprotective factors. This review discusses some of the well-characterized neural stem cell types and their possible use in treating neuropathic lysosomal storage diseases such as the Niemann Pick A disease.

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“…Using CNS stem cells, the company is currently developing stem cell products for use in patients with SCI, macular degeneration, and Pelizaeus-Merzbacher disease. In most cases, de novo neurogenesis is not the goal, but rather the treatment of enzyme deficiencies, as well as remyelination, or the modulation of endogenous repair via neoangiogenesis and/or neuroprotection [131][132][133][134] . Moreover, the company has isolated fetal liver progenitor cells and developed a unique co-culture system with endothelial cells in a threedimensional matrix [135] .…”

Section: Cd24mentioning

confidence: 99%

Fetal stem cell transplantation: Past, present, and future

Ishii

Eto

2014

WJSC

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Since 1928, human fetal tissues and stem cells have been used worldwide to treat various conditions. Although the transplantation of the fetal midbrain substantia nigra and dopaminergic neurons in patients suffering from Parkinson's disease is particularly noteworthy, the history of other types of grafts, such as those of the fetal liver, thymus, and pancreas, should be addressed as there are many lessons to be learnt for future stem cell transplantation. This report describes previous practices and complications that led to current clinical trials of isolated fetal stem cells and embryonic stem (ES) cells. Moreover, strategies for transplantation are considered, with a particular focus on donor cells, cell processing, and the therapeutic cell niche, in addition to ethical issues associated with fetal origin. With the advent of autologous induced pluripotent stem cells and ES cells, clinical dependence on fetal transplantation is expected to gradually decline due to lasting ethical controversies, despite landmark achievements.

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Neuroprotection of Host Cells by Human Central Nervous System Stem Cells in a Mouse Model of Infantile Neuronal Ceroid Lipofuscinosis

Cited by 127 publications

References 37 publications

Synergistic effects of treating the spinal cord and brain in CLN1 disease

Synergistic effects of treating the spinal cord and brain in CLN1 disease

Neural Stem Cell Transplantation as a Therapeutic Approach for Treating Lysosomal Storage Diseases

Fetal stem cell transplantation: Past, present, and future

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