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Article: Pathogenesis and therapies for infantile neuronal ceroid lipofuscinosis (infantile CLN1 disease).

Hawkins-Salsbury, Jacqueline A / Cooper, Jonathan D / Sands, Mark S

2013 Volume 1832, Issue 11, Page(s) 1906–1909

Abstract: The neuronal ceroid lipofuscinoses (NCL, Batten disease) are a group of inherited neurodegenerative diseases. Infantile neuronal ceroid lipofuscinosis (INCL, infantile Batten disease, or infantile CLN1 disease) is caused by a deficiency in the soluble ... ...

Abstract	The neuronal ceroid lipofuscinoses (NCL, Batten disease) are a group of inherited neurodegenerative diseases. Infantile neuronal ceroid lipofuscinosis (INCL, infantile Batten disease, or infantile CLN1 disease) is caused by a deficiency in the soluble lysosomal enzyme palmitoyl protein thioesterase-1 (PPT1) and has the earliest onset and fastest progression of all the NCLs. Several therapeutic strategies including enzyme replacement, gene therapy, stem cell-mediated therapy, and small molecule drugs have resulted in minimal to modest improvements in the murine model of PPT1-deficiency. However, more recent studies using various combinations of these approaches have shown more promising results; in some instances more than doubling the lifespan of PPT1-deficient mice. These combination therapies that target different pathogenic mechanisms may offer the hope of treating this profoundly neurodegenerative disorder. Similar approaches may be useful when treating other forms of NCL caused by deficiencies in soluble lysosomal proteins. Different therapeutic targets will need to be identified and novel strategies developed in order to effectively treat forms of NCL caused by deficiencies in integral membrane proteins such as juvenile neuronal ceroid lipofuscinosis. Finally, the challenge with all of the NCLs will lie in early diagnosis, improving the efficacy of the treatments, and effectively translating them into the clinic. This article is part of a Special Issue entitled: The Neuronal Ceroid Lipofuscinoses or Batten Disease.
MeSH term(s)	Animals ; Disease Models, Animal ; Humans ; Membrane Proteins/genetics ; Mice ; Mutation/genetics ; Neuronal Ceroid-Lipofuscinoses/genetics ; Neuronal Ceroid-Lipofuscinoses/pathology ; Neuronal Ceroid-Lipofuscinoses/therapy ; Phenotype
Chemical Substances	Membrane Proteins
Language	English
Publishing date	2013-06-06
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	60-7
ISSN	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbadis.2013.05.026
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Article ; Online: Innovations in MD-only physician-scientist training: experiences from the Burroughs Wellcome Fund physician-scientist institutional award initiative.

McElvaine, Allison T / Hawkins-Salsbury, Jacqueline A / Arora, Vineet M / Gladwin, Mark T / Goldenring, James R / Huston, David P / Krakow, Deborah / Rhee, Kyu / Solway, Julian / Steinman, Richard A / Towler, Dwight A / Utz, Paul J / Yokoyama, Wayne M / Simpson, Rolly L / Muglia, Louis J / Permar, Sallie R / Gbadegesin, Rasheed A

The Journal of clinical investigation

2021 Volume 131, Issue 10

MeSH term(s)	Awards and Prizes ; Biomedical Research/education ; Education, Medical, Continuing ; Financial Management ; Humans ; Physicians
Language	English
Publishing date	2021-05-17
Publishing country	United States
Document type	Journal Article
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI149948
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Article ; Online: Combination therapies for lysosomal storage disease: is the whole greater than the sum of its parts?

Hawkins-Salsbury, Jacqueline A / Reddy, Adarsh S / Sands, Mark S

Human molecular genetics

2011 Volume 20, Issue R1, Page(s) R54–60

Abstract: Lysosomal storage diseases (LSDs), as a group, are among the most common inherited diseases affecting children. The primary defect is typically a genetic deficiency of one of the lysosomal enzymes, often causing accumulation of undegraded substrates ... ...

Abstract	Lysosomal storage diseases (LSDs), as a group, are among the most common inherited diseases affecting children. The primary defect is typically a genetic deficiency of one of the lysosomal enzymes, often causing accumulation of undegraded substrates within the lysosome. This accumulation causes numerous secondary effects that contribute to the disease phenotype. Viral-mediated gene therapy (GT) can supply a persistent source of the deficient enzyme. However, with some notable exceptions, GT has been only modestly successful as a single approach. Recently, various therapies have been combined in order to more effectively target the diverse pathogenic mechanisms at work in LSDs. One strategy that has shown promise involves providing a persistent source of the deficient enzyme (GT, stem cell transplantation) while targeting a secondary consequence of disease with a more transient approach (substrate reduction, anti-inflammatories, pharmacological mimetic, etc.). This general strategy has resulted in both additive and synergistic effects. Interestingly, some therapeutic approaches by themselves provide essentially no clinical benefit but contribute greatly to the overall efficacy when used in combination with other treatments. Unfortunately, no therapeutic combination is universally effective. This adds to the difficulty in predicting and identifying combinations that will be most effective for individual LSDs. A better understanding of both pathogenic and therapeutic mechanisms is necessary in order to identify potentially successful combinations. While a single treatment would be ideal, the complex nature of these diseases may unavoidably limit the efficacy of single therapies. In order to more successfully treat LSDs, a shift in focus towards a combination therapy may be necessary.
MeSH term(s)	Animals ; Combined Modality Therapy/methods ; Genetic Therapy/methods ; Genetic Therapy/trends ; Genetic Vectors/administration & dosage ; Humans ; Lysosomal Storage Diseases/genetics ; Lysosomal Storage Diseases/therapy ; Phenotype
Language	English
Publishing date	2011-03-19
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddr112
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Article ; Online: Oxidative stress as a therapeutic target in globoid cell leukodystrophy.

Hawkins-Salsbury, Jacqueline A / Qin, Elizabeth Y / Reddy, Adarsh S / Vogler, Carole A / Sands, Mark S

Experimental neurology

2012 Volume 237, Issue 2, Page(s) 444–452

Abstract: Globoid cell leukodystrophy (GLD, Krabbe Disease) is a lysosomal storage disease, resulting from the genetic deficiency of galactosylceramidase (GALC). This disease is marked by accumulation of the cytotoxic lipid psychosine (Psy). Psychosine is known to ...

Abstract	Globoid cell leukodystrophy (GLD, Krabbe Disease) is a lysosomal storage disease, resulting from the genetic deficiency of galactosylceramidase (GALC). This disease is marked by accumulation of the cytotoxic lipid psychosine (Psy). Psychosine is known to induce oxidative stress in cultured cells, and this stress can be ameliorated through co-treatment with the antioxidant N-acetyl cysteine (NAC). Oxidative stress has also been observed in vivo in the mouse model of GLD, the Twitcher mouse (Twi). We hypothesized that treating oxidative stress with NAC; either alone or in combination with bone marrow transplant (BMT) would improve the course of disease. All breeding cages were maintained on water containing NAC. Once born, the pups received IP boluses of NAC three times per week, and were maintained on NAC-containing water. A separate cohort of animals received the same regimen of NAC in addition to a BMT on post-natal days 2-3. Although NAC lowers the level of oxidized proteins in the brains of Twi mice, and dramatically improves immunohistochemical markers of disease, neither treatment results in any clinical improvements in the Twi mouse. Our data suggest that oxidative stress may be sufficiently down-stream in the pathogenic cascade initiated by Psy accumulation as to be difficult or impossible to treat with standard pharmacologic agents. It is possible that NAC may synergize with other therapies or combinations of therapies. A better understanding of the initiating effects of Psy toxicity and oxidative damage may uncover treatable therapeutic targets.
MeSH term(s)	Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Bone Marrow Transplantation ; Disease Models, Animal ; Immunohistochemistry ; Leukodystrophy, Globoid Cell/drug therapy ; Leukodystrophy, Globoid Cell/surgery ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Oxidative Stress/drug effects
Chemical Substances	Antioxidants ; Acetylcysteine (WYQ7N0BPYC)
Language	English
Publishing date	2012-07-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	207148-4
ISSN	1090-2430 ; 0014-4886
ISSN (online)	1090-2430
ISSN	0014-4886
DOI	10.1016/j.expneurol.2012.07.013
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Article ; Online: Psychosine, the cytotoxic sphingolipid that accumulates in globoid cell leukodystrophy, alters membrane architecture.

Hawkins-Salsbury, Jacqueline A / Parameswar, Archana R / Jiang, Xuntian / Schlesinger, Paul H / Bongarzone, Ernesto / Ory, Daniel S / Demchenko, Alexei V / Sands, Mark S

Journal of lipid research

2013 Volume 54, Issue 12, Page(s) 3303–3311

Abstract: Globoid cell leukodystrophy (GLD) is a neurological disease caused by deficiency of the lysosomal enzyme galactosylceramidase (GALC). In the absence of GALC, the cytotoxic glycosphingolipid, psychosine (psy), accumulates in the nervous system. Psychosine ...

Abstract	Globoid cell leukodystrophy (GLD) is a neurological disease caused by deficiency of the lysosomal enzyme galactosylceramidase (GALC). In the absence of GALC, the cytotoxic glycosphingolipid, psychosine (psy), accumulates in the nervous system. Psychosine accumulation preferentially affects oligodendrocytes, leading to progressive demyelination and infiltration of activated monocytes/macrophages into the CNS. GLD is characterized by motor defects, cognitive deficits, seizures, and death by 2-5 years of age. It has been hypothesized that psychosine accumulation, primarily within lipid rafts, results in the pathogenic cascade in GLD. However, the mechanism of psychosine toxicity has yet to be elucidated. Therefore, we synthesized the enantiomer of psychosine (ent-psy) to use as a probe to distinguish between protein-psy (stereo-specific enantioselective) or membrane-psy (stereo-insensitive nonenantioselective) interactions. The enantiomer of psychosine has equal or greater toxicity compared with psy, suggesting that psy exerts its toxicity through a nonenantioselective mechanism. Finally, in this study we demonstrate that psy and ent-psy localize to lipid rafts, perturb natural and artificial membrane integrity, and inhibit protein Kinase C translocation to the plasma membrane. Although other mechanisms may play a role in disease, these data strongly suggest that psy exerts its effects primarily through membrane perturbation rather than through specific protein-psy interactions.
MeSH term(s)	Animals ; Apoptosis/drug effects ; Cell Line ; Cell Membrane/drug effects ; Cell Membrane/metabolism ; Cell Survival/drug effects ; Cytotoxins/chemistry ; Cytotoxins/metabolism ; Cytotoxins/toxicity ; Humans ; Leukodystrophy, Globoid Cell/metabolism ; Liposomes/metabolism ; Protein Kinase C/metabolism ; Protein Transport/drug effects ; Psychosine/chemistry ; Psychosine/metabolism ; Psychosine/toxicity ; Stereoisomerism
Chemical Substances	Cytotoxins ; Liposomes ; Psychosine (2238-90-6) ; Protein Kinase C (EC 2.7.11.13)
Language	English
Publishing date	2013-09-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80154-9
ISSN	1539-7262 ; 0022-2275
ISSN (online)	1539-7262
ISSN	0022-2275
DOI	10.1194/jlr.M039610
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Article ; Online: Bone marrow transplantation increases efficacy of central nervous system-directed enzyme replacement therapy in the murine model of globoid cell leukodystrophy.

Qin, Elizabeth Y / Hawkins-Salsbury, Jacqueline A / Jiang, Xuntian / Reddy, Adarsh S / Farber, Nuri B / Ory, Daniel S / Sands, Mark S

Molecular genetics and metabolism

2012 Volume 107, Issue 1-2, Page(s) 186–196

Abstract: Globoid cell leukodystrophy (GLD, Krabbe disease), is an autosomal recessive, neurodegenerative disease caused by the deficiency of the lysosomal enzyme galactocerebrosidase (GALC). In the absence of GALC, the toxic metabolite psychosine accumulates in ... ...

Abstract	Globoid cell leukodystrophy (GLD, Krabbe disease), is an autosomal recessive, neurodegenerative disease caused by the deficiency of the lysosomal enzyme galactocerebrosidase (GALC). In the absence of GALC, the toxic metabolite psychosine accumulates in the brain and causes the death of the myelin-producing cells, oligodendrocytes. Currently, the only therapy for GLD is hematopoietic stem cell transplantation using bone marrow (BMT) or umbilical cord blood. However, this is only partially effective. Previous studies have shown that enzyme replacement therapy (ERT) provides some therapeutic benefit in the murine model of GLD, the Twitcher mouse. Experiments have also shown that two disparate therapies can produce synergistic effects when combined. The current study tests the hypothesis that BMT will increase the therapeutic effects of ERT when these two treatments are combined. Twitcher mice were treated with either ERT alone or both ERT and BMT during the first 2-4 days of life. Recombinant enzyme was delivered by intracerebroventricular (ICV) and intrathecal (IT) injections. Twitcher mice receiving ERT had supraphysiological levels of GALC activity in the brain 24h after injection. At 36 days of age, ERT-treated Twitcher mice had reduced psychosine levels, reduced neuroinflammation, improved motor function, and increased lifespan. Twitcher mice receiving both ERT and BMT had significantly increased lifespan, improved motor function, reduced psychosine levels, and reduced neuroinflammation in certain areas of the brain compared to untreated or ERT-treated Twitcher mice. Together, these results indicate that BMT enhances the efficacy of ERT in GLD.
MeSH term(s)	Animals ; Bone Marrow Transplantation ; Brain/metabolism ; Brain/pathology ; Central Nervous System/metabolism ; Central Nervous System/pathology ; Disease Models, Animal ; Enzyme Replacement Therapy ; Galactosylceramidase/administration & dosage ; Galactosylceramidase/metabolism ; Inflammation/metabolism ; Inflammation/pathology ; Leukodystrophy, Globoid Cell/mortality ; Leukodystrophy, Globoid Cell/therapy ; Mice ; Mice, Knockout ; Psychosine/metabolism ; Transplantation Conditioning
Chemical Substances	Psychosine (2238-90-6) ; Galactosylceramidase (EC 3.2.1.46)
Language	English
Publishing date	2012-06-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1418518-0
ISSN	1096-7206 ; 1096-7192
ISSN (online)	1096-7206
ISSN	1096-7192
DOI	10.1016/j.ymgme.2012.05.021
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Article ; Online: Mechanism-based combination treatment dramatically increases therapeutic efficacy in murine globoid cell leukodystrophy.

Hawkins-Salsbury, Jacqueline A / Shea, Lauren / Jiang, Xuntian / Hunter, Daniel A / Guzman, A Miguel / Reddy, Adarsh S / Qin, Elizabeth Y / Li, Yedda / Gray, Steven J / Ory, Daniel S / Sands, Mark S

The Journal of neuroscience : the official journal of the Society for Neuroscience

2015 Volume 35, Issue 16, Page(s) 6495–6505

Abstract: Globoid cell leukodystrophy (GLD, Krabbe disease) is a lysosomal storage disease (LSD) caused by a deficiency in galactocerebrosidase (GALC) activity. In the absence of GALC activity, the cytotoxic lipid, galactosylsphingosine (psychosine), accumulates ... ...

Abstract	Globoid cell leukodystrophy (GLD, Krabbe disease) is a lysosomal storage disease (LSD) caused by a deficiency in galactocerebrosidase (GALC) activity. In the absence of GALC activity, the cytotoxic lipid, galactosylsphingosine (psychosine), accumulates in the CNS and peripheral nervous system. Oligodendrocytes and Schwann cells are particularly sensitive to psychosine, thus leading to a demyelinating phenotype. Although hematopoietic stem-cell transplantation provides modest benefit in both presymptomatic children and the murine model (Twitcher), there is no cure for GLD. In addition, GLD has been relatively refractory to virtually every experimental therapy attempted. Here, Twitcher mice were simultaneously treated with CNS-directed gene therapy, substrate reduction therapy, and bone marrow transplantation to target the primary pathogenic mechanism (GALC deficiency) and two secondary consequences of GALC deficiency (psychosine accumulation and neuroinflammation). Simultaneously treating multiple pathogenic targets resulted in an unprecedented increase in life span with improved motor function, persistent GALC expression, nearly normal psychosine levels, and decreased neuroinflammation. Treating the primary pathogenic mechanism and secondary targets will likely improve therapeutic efficacy for other LSDs with complex pathological and clinical presentations.
MeSH term(s)	Animals ; Body Weight/drug effects ; Body Weight/genetics ; Bone Marrow Transplantation ; Brain/drug effects ; Brain/metabolism ; Combined Modality Therapy ; Cycloserine/therapeutic use ; Cytokines/metabolism ; Female ; Galactosylceramidase/genetics ; Galactosylceramidase/metabolism ; Genetic Therapy ; Leukodystrophy, Globoid Cell/drug therapy ; Leukodystrophy, Globoid Cell/genetics ; Leukodystrophy, Globoid Cell/pathology ; Leukodystrophy, Globoid Cell/therapy ; Male ; Mice ; Mice, Inbred Strains ; Motor Skills/drug effects ; Myelin Sheath/drug effects ; Myelin Sheath/physiology ; Psychosine/metabolism ; Sciatic Nerve/metabolism
Chemical Substances	Cytokines ; Psychosine (2238-90-6) ; Cycloserine (95IK5KI84Z) ; Galactosylceramidase (EC 3.2.1.46)
Language	English
Publishing date	2015-04-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	604637-x
ISSN	1529-2401 ; 0270-6474
ISSN (online)	1529-2401
ISSN	0270-6474
DOI	10.1523/JNEUROSCI.4199-14.2015
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Article ; Online: Bone marrow transplantation augments the effect of brain- and spinal cord-directed adeno-associated virus 2/5 gene therapy by altering inflammation in the murine model of globoid-cell leukodystrophy.

Reddy, Adarsh S / Kim, Joong H / Hawkins-Salsbury, Jacqueline A / Macauley, Shannon L / Tracy, Elisabeth T / Vogler, Carole A / Han, Xialin / Song, Sheng-Kwei / Wozniak, David F / Fowler, Stephen C / Klein, Robyn S / Sands, Mark S

The Journal of neuroscience : the official journal of the Society for Neuroscience

2011 Volume 31, Issue 27, Page(s) 9945–9957

Abstract: Globoid-cell leukodystrophy (GLD) is an inherited demyelinating disease caused by the deficiency of the lysosomal enzyme galactosylceramidase (GALC). A previous study in the murine model of GLD (twitcher) demonstrated a dramatic synergy between CNS- ... ...

Abstract	Globoid-cell leukodystrophy (GLD) is an inherited demyelinating disease caused by the deficiency of the lysosomal enzyme galactosylceramidase (GALC). A previous study in the murine model of GLD (twitcher) demonstrated a dramatic synergy between CNS-directed adeno-associated virus 2/5 (AAV2/5) gene therapy and myeloreductive bone marrow transplantation (BMT). However, the mechanism by which these two disparate therapeutic approaches synergize is not clear. In addition, the therapeutic efficacy may have been limited since the CNS-directed gene therapy was restricted to the forebrain and thalamus. In the current study, intrathecal and intracerebellar injections were added to the therapeutic regimen and the mechanism of synergy between BMT and gene therapy was determined. Although AAV2/5 alone provided supraphysiological levels of GALC activity and reduced psychosine levels in both the brain and spinal cord, it significantly increased CNS inflammation. Bone marrow transplantation alone provided essentially no GALC activity to the CNS and did not reduce psychosine levels. When AAV2/5 is combined with BMT, there are sustained improvements in motor function and the median life span is increased to 123 d (range, 92-282 d) compared with 41 d in the untreated twitcher mice. Interestingly, addition of BMT virtually eliminates both the disease and AAV2/5-associated inflammatory response. These data suggest that the efficacy of AAV2/5-mediated gene therapy is limited by the associated inflammatory response and BMT synergizes with AAV2/5 by modulating inflammation.
MeSH term(s)	Analysis of Variance ; Animals ; Animals, Newborn ; Bone Marrow Transplantation/methods ; Brain/metabolism ; Dependovirus/genetics ; Diffusion Tensor Imaging/methods ; Disease Models, Animal ; Flow Cytometry/methods ; Galactosylceramidase/biosynthesis ; Galactosylceramidase/deficiency ; Genetic Therapy/methods ; Genetic Vectors/physiology ; Indoles ; Inflammation/etiology ; Inflammation/therapy ; Kaplan-Meier Estimate ; Leukodystrophy, Globoid Cell/complications ; Leukodystrophy, Globoid Cell/genetics ; Leukodystrophy, Globoid Cell/pathology ; Leukodystrophy, Globoid Cell/therapy ; Longevity/genetics ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Periodic Acid ; Psychosine/metabolism ; Spinal Cord/metabolism ; Tremor/etiology
Chemical Substances	Indoles ; Periodic Acid (10450-60-9) ; Luxol Fast Blue MBS (1328-51-4) ; Psychosine (2238-90-6) ; Galactosylceramidase (EC 3.2.1.46)
Language	English
Publishing date	2011-07-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	604637-x
ISSN	1529-2401 ; 0270-6474
ISSN (online)	1529-2401
ISSN	0270-6474
DOI	10.1523/JNEUROSCI.1802-11.2011
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Article: Bone marrow transplantation increases efficacy of central nervous system-directed enzyme replacement therapy in the murine model of globoid cell leukodystrophy

Qin, Elizabeth Y / Hawkins-Salsbury, Jacqueline A / Jiang, Xuntian / Reddy, Adarsh S / Farber, Nuri B / Ory, Daniel S / Sands, Mark S

Molecular genetics and metabolism. 2012 , v. 107, no. 1-2

2012

Abstract	Globoid cell leukodystrophy (GLD, Krabbe disease), is an autosomal recessive, neurodegenerative disease caused by the deficiency of the lysosomal enzyme galactocerebrosidase (GALC). In the absence of GALC, the toxic metabolite psychosine accumulates in the brain and causes the death of the myelin-producing cells, oligodendrocytes. Currently, the only therapy for GLD is hematopoietic stem cell transplantation using bone marrow (BMT) or umbilical cord blood. However, this is only partially effective. Previous studies have shown that enzyme replacement therapy (ERT) provides some therapeutic benefit in the murine model of GLD, the Twitcher mouse. Experiments have also shown that two disparate therapies can produce synergistic effects when combined. The current study tests the hypothesis that BMT will increase the therapeutic effects of ERT when these two treatments are combined. Twitcher mice were treated with either ERT alone or both ERT and BMT during the first 2–4days of life. Recombinant enzyme was delivered by intracerebroventricular (ICV) and intrathecal (IT) injections. Twitcher mice receiving ERT had supraphysiological levels of GALC activity in the brain 24h after injection. At 36days of age, ERT-treated Twitcher mice had reduced psychosine levels, reduced neuroinflammation, improved motor function, and increased lifespan. Twitcher mice receiving both ERT and BMT had significantly increased lifespan, improved motor function, reduced psychosine levels, and reduced neuroinflammation in certain areas of the brain compared to untreated or ERT-treated Twitcher mice. Together, these results indicate that BMT enhances the efficacy of ERT in GLD.
Keywords	animal models ; blood ; bone marrow ; bone marrow transplant ; brain ; cell transplantation ; death ; longevity ; metabolites ; mice ; neurodegenerative diseases ; stem cells ; synergism ; toxicity ; umbilical cord
Language	English
Dates of publication	2012-09
Size	p. 186-196.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	1418518-0
ISSN	1096-7206 ; 1096-7192
ISSN (online)	1096-7206
ISSN	1096-7192
DOI	10.1016/j.ymgme.2012.05.021
Database	NAL-Catalogue (AGRICOLA)

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