Intravenous administration of AAV2/9 to the fetal and neonatal mouse leads to differential targeting of CNS cell types and extensive transduction of the nervous system

Rahim, Afidah Abdul; Wong, Andrew; Hoefer, Klemens; Buckley, Smk; Mattar, Citra Nurfarah Zaini; Cheng, Seng H.; Chan, Jerry Ky; Cooper, Jonathan D.; Waddington, Simon N.

doi:10.1096/fj.11-182311

Cited by 85 publications

(88 citation statements)

References 45 publications

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“…Cells were transfected on days 14-18 and 20-24 for day 20 and 28 transplants, respectively. AAV2/9 transduces many fetal and neonatal neuronal cell types [22] as well as the majority of retinal cell types including photoreceptors [23]. We confirmed this in vitro and found at day 20 and day 28, an average 45% of the cells, including many neuronal cells, was labeled with GFP (Supporting Information Fig.…”

Section: Esc-derived Retinal Cells Transplanted To the Adult Retinasupporting

confidence: 76%

Defining the Integration Capacity of Embryonic Stem Cell-Derived Photoreceptor Precursors

West¹,

Gonzalez‐Cordero²,

Hippert³

et al. 2012

Stem Cells

118

116

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Retinal degeneration is a leading cause of irreversible blindness in the developed world. Differentiation of retinal cells, including photoreceptors, from both mouse and human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), potentially provide a renewable source of cells for retinal transplantation. Previously, we have shown both the functional integration of transplanted rod photoreceptor precursors, isolated from the postnatal retina, in the adult murine retina, and photoreceptor cell generation by stepwise treatment of ESCs with defined factors. In this study, we assessed the extent to which this protocol recapitulates retinal development and also evaluated differentiation and integration of ESC-derived retinal cells following transplantation using our established procedures. Optimized retinal differentiation via isolation of Rax.GFP retinal progenitors recreated a retinal niche and increased the yield of Crx 1 and Rhodopsin 1 photoreceptors. Rod birth peaked at day 20 of culture and expression of the early photoreceptor markers Crx and Nrl increased until day 28. Nrl levels were low in ESC-derived populations compared with developing retinae. Transplantation of early stage retinal cultures produced large tumors, which were avoided by prolonged retinal differentiation (up to day 28) prior to transplantation. Integrated mature photoreceptors were not observed in the adult retina, even when more than 60% of transplanted ESCderived cells expressed Crx. We conclude that exclusion of proliferative cells from ESC-derived cultures is essential for effective transplantation. Despite showing expression profiles characteristic of immature photoreceptors, the ESC-derived precursors generated using this protocol did not display transplantation competence equivalent to precursors from the postnatal retina. STEM CELLS

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Section: Esc-derived Retinal Cells Transplanted To the Adult Retinasupporting

confidence: 76%

Defining the Integration Capacity of Embryonic Stem Cell-Derived Photoreceptor Precursors

West¹,

Gonzalez‐Cordero²,

Hippert³

et al. 2012

Stem Cells

118

116

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“…However, the efficiency of CNS transduction was apparently reduced in older mice and larger animal species, and the effi cacy was not broadly applicable to other LSDs. For example, intravenous delivery of a recombinant AAV9 vector encoding perinatally to arrest the degeneration ( 51,52 ). Indeed, in the context of bone marrow transplantation for mucopolysaccharidosis (MPS) I, it is generally agreed that the procedure must be performed before patients reach 2 years of age for maximal cognitive benefi t ( 53,54 ).…”

Section: Prospects Of Systemically Delivered Aav Vectors To Address Tmentioning

confidence: 99%

Gene therapy for the neurological manifestations in lysosomal storage disorders

Cheng¹

2014

Journal of Lipid Research

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precise mechanistic links between these altered biochemical and cellular states and disease pathophysiology and pathogenesis remain unclear. Typically, disease severity is correlated with the level of residual activity, with individuals harboring lower levels presenting with more aggressive and severe disease manifestations. A large percentage of individuals, particularly those with signifi cantly diminished lysosomal function, also exhibit CNS involvement, the extent of which is dependent on the nature of the specifi c storage metabolites and the differential sensitivity of the resident cell types to the accumulated substrates. Although individually each LSD may be relatively rare, as a group, these disorders have an incidence of approximately 1 per 5,000 live births ( 4, 5 ).Of the approximately 50 LSDs that have been identifi ed thus far, the majority (greater than 70%) exhibit significant CNS involvement ( 6 ). This fi nding is not surprising given that lysosomes and related organelles are ubiquitously present in most cell types and are involved not only in recycling cellular debris but also in maintaining cellular homeostasis ( 7-9 ). Irrespective of the LSD, these CNS diseases are typically characterized by generalized infl ammation and neurodegeneration in multiple brain regions. In a subset of the diseases, altered calcium homeostasis and oxidative stress may also contribute to the overall pathology ( 10 ). Moreover, each specifi c disease may initially present with a unique temporal and spatial alteration that is dictated by the nature of the storage metabolites prior to the development of a more generalized global derangement ( 11 ). In some diseases, the symptoms are evident in neonates, whereas in others, they become apparent only in early childhood. Consequently, some LSDs may require early therapeutic intervention to affect broad and potentially all regions of the CNS. The lysosomal storage disorders (LSDs) are a heterogeneous group of inherited metabolic diseases that result from a defi ciency in one or more of the 80 enzymes or transporters that normally reside within the lysosomal compartment ( 1-3 ). A reduction or loss of one or more of these activities results in the progressive and relentless accumulation of undegraded macromolecules, a consequent derangement of proper lysosomal and autophagosomal functions, and ultimately, cellular demise. However, the

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“…Importantly, recent reports have shown that the central nervous system can be very effectively transduced via systemic administration [17][18][19] and the higher doses and use of self-complimentary vector genomes in these studies 20 may have contributed to this capability. These results suggest that improving the vector delivery system holds promise for enhancing retinal transduction while limiting the number of viral particles necessary to achieve sufficient levels of protein expression.…”

Section: Introductionmentioning

confidence: 99%

Enhanced gene delivery to the neonatal retina through systemic administration of tyrosine-mutated AAV9

et al. 2011

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Delivery of therapeutic genes to a large region of the retina with minimal damage from intraocular surgery is a central goal of treatment for retinal degenerations. Recent studies have shown that AAV9 can reach the central nervous system (CNS) and retina when administered systemically to neonates, which is a promising strategy for some retinal diseases. We investigated whether the retinal transduction efficiency of systemically delivered AAV9 could be improved by mutating capsid surface tyrosines, previously shown to increase the infectivity of several AAV vectors. Specifically, we evaluated retinal transduction following neonatal intravascular administration of AAV9 vectors containing tyrosine to phenylalanine mutations at two highly conserved sites. Our results show that a novel, double tyrosine mutant of AAV9 significantly enhanced gene delivery to the CNS and retina, and that gene expression can be restricted to rod photoreceptor cells by incorporating a rhodopsin promoter. This approach provides a new methodology for the development of retinal gene therapies or creation of animal models of neurodegenerative disease.

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Intravenous administration of AAV2/9 to the fetal and neonatal mouse leads to differential targeting of CNS cell types and extensive transduction of the nervous system

Cited by 85 publications

References 45 publications

Defining the Integration Capacity of Embryonic Stem Cell-Derived Photoreceptor Precursors

Defining the Integration Capacity of Embryonic Stem Cell-Derived Photoreceptor Precursors

Gene therapy for the neurological manifestations in lysosomal storage disorders

Enhanced gene delivery to the neonatal retina through systemic administration of tyrosine-mutated AAV9

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