Central Nervous System-directed AAV2/5-Mediated Gene Therapy Synergizes with Bone Marrow Transplantation in the Murine Model of Globoid-cell Leukodystrophy

Lin, Dar-Shong; Donsante, Anthony; Macauley, Shannon L.; Levy, Beth; Vogler, Carole; Sands, Mark S.

doi:10.1038/sj.mt.6300026

Cited by 72 publications

(118 citation statements)

References 30 publications

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“…As previously reported, an increased number of CD68-positive macrophages and activated microglia are found in the brains of Twitcher mice compared with WT controls at 36 d (Lin et al, 2007;Reddy et al, 2011). Triple treatment dramatically decreased CD68 staining at 36 d (Fig.…”

Section: Microglial and Astrocyte Activationsupporting

confidence: 62%

“…1 top left). We previously showed that BMT or CNS-directed AAV-mediated gene therapy initiated in newborn Twitcher mice increased the median life span to ϳ45 and ϳ70 d, respectively (Lin et al, 2007;Reddy et al, 2011). In the current study, the median lifespan for mice treated with L-cycloserine alone or L-cycloserine plus CNS-directed gene therapy is ϳ57 and ϳ70 d, respectively.…”

Section: Lifespanmentioning

confidence: 99%

“…Combination therapies that target both primary and secondary mechanisms have been more successful. Intracranial gene therapy targeting the primary defect synergized with bone marrow transplantation (BMT) to nearly triple the lifespan of the Twitcher mouse (Lin et al, 2007). Subsequent improvements in the route of gene therapy delivery further extended the life span (Reddy et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

“…Despite the availability of the Twitcher mouse, development of effective therapies has been slow. Virtually all single-therapy approaches, including BMT (Yeager et al, 1984), gene therapy (Lin et al, 2005(Lin et al, , 2007Galbiati et al, 2009;Gentner et al, 2010;Reddy et al, 2011;Rafi et al, 2012), substrate reduction (LeVine et al, 2000;Biswas and LeVine, 2002), antioxidants (Hawkins-Salsbury et al, 2012a), steroids (Kagitani-Shimono et al, 2005;Luzi et al, 2009), enzyme replacement (Lee et al, 2005;Qin et al, 2012), and neuronal (Pellegatta et al, 2006) or mesenchymal (Ripoll et al, 2011) progenitor cells, have met with minimal to modest success.…”

Section: Introductionmentioning

confidence: 99%

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Mechanism-Based Combination Treatment Dramatically Increases Therapeutic Efficacy in Murine Globoid Cell Leukodystrophy

Hawkins-Salsbury¹,

Shea²,

Jiang³

et al. 2015

J. Neurosci.

127

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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.

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Section: Microglial and Astrocyte Activationsupporting

confidence: 62%

Section: Lifespanmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Mechanism-Based Combination Treatment Dramatically Increases Therapeutic Efficacy in Murine Globoid Cell Leukodystrophy

Hawkins-Salsbury¹,

Shea²,

Jiang³

et al. 2015

J. Neurosci.

127

View full text Add to dashboard Cite

show abstract

“…Improvements in the accelerating rotor-rod test were also evident in Twitcher mice, a model of globoid-cell leukodystrophy, transplanted at 3 days of age (4 Gy; 1 Â 10 6 donor cells), Fig. 2 (continued) despite brain galactosylceramidase activity not being significantly increased following treatment (Lin et al 2007). Twitcher mice transplanted at 8-11 days of age (9 Gy; 3-5 Â 10 7 donor cells delivered intraperitoneally) generated up to 15% normal levels of galactosylceramidase activity in the brain, which was sufficient to prevent hindlimb paralysis (Hoogerbrugge et al 1988).…”

Section: Discussionmentioning

confidence: 99%

Neonatal Bone Marrow Transplantation in MPS IIIA Mice

et al. 2012

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Patients with some neurological lysosomal storage disorders (LSD) exhibit improved clinical signs following bone marrow transplantation (BMT). The failure of mucopolysaccharidosis (MPS) type IIIA patients and adult mice with the condition to respond to this treatment may relate to factors such as impaired migration of donorderived cells into the brain, insufficient enzyme production and/or secretion by the donor-derived microglial cells, or the age at which treatment is initiated. To explore these possibilities, we treated neonatal MPS IIIA mice with whole unfractionated bone marrow and observed that nucleated blood cell reconstitution occurred to a similar degree in MPS IIIA mice receiving green fluorescent protein (GFP)-expressing normal (treatment group) or MPS IIIA-GFP marrow (control group) and normal mice receiving normal-GFP marrow (control group). Further, similar distribution patterns of GFP + normal or MPS IIIA donor-derived cells were observed throughout the MPS IIIA mouse brain. We demonstrate that N-sulfoglucosamine sulfohydrolase (SGSH), the enzyme deficient in MPS IIIA, is produced and secreted in a manner proportional to that of other lysosomal enzymes. However, despite this, overall brain SGSH activity was unchanged in MPS IIIA mice treated with normal marrow and the lysosomal storage burden in whole brain homogenates did not decrease, most likely due to donor-derived cells comprising <0.24% of total recipient brain cells in all groups. This suggests that the failure of MPS IIIA patients and mice to respond to BMT may occur as a result of insufficient donor-derived enzyme production and/or uptake by host brain cells.

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Synergistic effects of central nervous system‐directed gene therapy and bone marrow transplantation in the murine model of infantile neuronal ceroid lipofuscinosis

Macauley

Roberts

Wong

et al. 2012

Annals of Neurology

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Objective Infantile neuronal ceroid lipofusciniosis (INCL) is an inherited childhood neurodegenerative disorder caused by the loss of palmitoyl protein thioesterase-1 (PPT1) activity. Affected children suffer from blindness, epilepsy, motor dysfunction, cognitive decline, and premature death. The Ppt1−/− mouse shares the histological and clinical features of INCL. Previous single-therapy approaches using small molecule drugs, gene therapy, or neuronal stem cells resulted in partial histological correction, with minimal improvements in motor function or lifespan. Here, we combined CNS-directed AAV2/5-mediated gene therapy with bone marrow transplantation (BMT) in the INCL mouse. Methods At birth, Ppt1−/− and WT mice were given either intracranial injections of AAV2/5-PPT1 or bone marrow transplantation, separately as well as in combination. To assess function, we measured monthly rotorod performance monthly as well as lifespan. At terminal timepoints, we evaluated the therapeutic effects on several INCL specific parameters, such as cortical thickness, autofluorescent accumulation, and glial activation. Finally, we determined levels of PPT1 enzyme activity and bone marrow engraftment in treated mice. Results AAV2/5-mediated gene therapy alone resulted in significant histological correction, improved motor function, and increased life span. Interestingly, the addition of BMT further increased the lifespan of treated mice and led to dramatic, sustained improvements in motor function. These data are truly striking given the fact that BMT alone is ineffective yet it synergizes with CNS-directed gene therapy to dramatically increase efficacy and lifespan. Interpretation AAV2/5-mediated gene therapy in combination with BMT provides an unprecedented increase in lifespan as well as dramatic improvement on functional and histological parameters.

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Central Nervous System-directed AAV2/5-Mediated Gene Therapy Synergizes with Bone Marrow Transplantation in the Murine Model of Globoid-cell Leukodystrophy

Cited by 72 publications

References 30 publications

Mechanism-Based Combination Treatment Dramatically Increases Therapeutic Efficacy in Murine Globoid Cell Leukodystrophy

Mechanism-Based Combination Treatment Dramatically Increases Therapeutic Efficacy in Murine Globoid Cell Leukodystrophy

Neonatal Bone Marrow Transplantation in MPS IIIA Mice

Synergistic effects of central nervous system‐directed gene therapy and bone marrow transplantation in the murine model of infantile neuronal ceroid lipofuscinosis

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