Person: Sandberg, Michael
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Sandberg
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Michael
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Sandberg, Michael
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Publication Photoreceptor Rescue by an Abbreviated Human RPGR Gene in a Murine Model of X-linked Retinitis Pigmentosa(2015) Pawlyk, Basil; Adamian, Michael; Sun, Xun; Bulgakov, Oleg V.; Shu, Xinhua; Smith, Alexander J.; Berson, Eliot L.; Ali, Robin R.; Khani, Shahrokh; F.Wright, Alan; Sandberg, Michael; Li, TiansenThe X-linked RP3 gene codes for the ciliary protein RPGR and accounts for over 10% of inherited retinal degenerations. The critical RPGR-ORF15 splice variant contains a highly repetitive purine-rich linker region that renders it unstable and difficult to adapt for gene therapy. To test the hypothesis that the precise length of the linker region is not critical for function, we evaluated whether AAV-mediated replacement gene therapy with a human ORF15 variant containing in-frame shortening of the linker region could reconstitute RPGR function in vivo. We delivered human RPGR-ORF15 replacement genes with deletion of most (314-codons, “short form”) or 1/3 (126-codons, “long form”) of the linker region to Rpgr null mice. Human RPGR-ORF15 expression was detected post-treatment with both forms of ORF15 transgenes. However, only the long form correctly localized to the connecting cilia and led to significant functional and morphological rescue of rods and cones. Thus the highly repetitive region of RPGR is functionally important but that moderate shortening of its length, which confers the advantage of added stability, preserves its function. These findings provide a theoretical basis for optimizing replacement gene design in clinical trials for X-linked RP3.Publication Evidence for Baseline Retinal Pigment Epithelium Pathology in the Trp1-Cre Mouse(Elsevier BV, 2012) Thanos, Aristomenis; Morizane, Yuki; Murakami, Yusuke; Giani, Andrea; Mantopoulos, Dimosthenis; Kayama, Maki; Roh, Mi In; Michaud, Norman; Pawlyk, Basil; Sandberg, Michael; Young, Lucy; Miller, Joan; Vavvas, DemetriosThe increasing popularity of the Cre/loxP recombination system has led to the generation of numerous transgenic mouse lines in which Cre recombinase is expressed under the control of organ- or cell-specific promoters. Alterations in retinal pigment epithelium (RPE), a multifunctional cell monolayer that separates the retinal photoreceptors from the choroid, are prevalent in the pathogenesis of a number of ocular disorders, including age-related macular degeneration. To date, six transgenic mouse lines have been developed that target Cre to the RPE under the control of various gene promoters. However, multiple lines of evidence indicate that high levels of Cre expression can be toxic to mammalian cells. In this study, we report that in the Trp1-Cre mouse, a commonly used transgenic Cre strain for RPE gene function studies, Cre recombinase expression alone leads to RPE dysfunction and concomitant disorganization of RPE layer morphology, large areas of RPE atrophy, retinal photoreceptor dysfunction, and microglial cell activation in the affected areas. The phenotype described herein is similar to previously published reports of conditional gene knockouts that used the Trp1-Cre mouse, suggesting that Cre toxicity alone could account for some of the reported phenotypes and highlighting the importance of the inclusion of Cre-expressing mice as controls in conditional gene targeting studies.Publication Search for a Correlation between Telomere Length and Severity of Retinitis Pigmentosa due to the Dominant Rhodopsin Pro23His Mutation(Molecular Vision, 2009) Hartong, Dyonne T.; McGee, Terri L.; Sandberg, Michael; Berson, Eliot L.; Asselbergs, Folkert W.; van der Harst, Pim; De Vivo, Immaculata; Dryja, ThaddeusPurpose: Great variation exists in the age of onset of symptoms and the severity of disease at a given age in patients with retinitis pigmentosa (RP). The final pathway for this disease may involve apoptotic photoreceptor cell death. Telomere length is associated with biologic aging, senescence, and apoptosis. We evaluated whether the length of telomeres in leukocytes correlated with the severity of RP in patients with the Pro23His rhodopsin mutation who have shown marked heterogeneity in disease severity.Methods We evaluated 122 patients with the Pro23His rhodopsin mutation. The patients’ retinal function was stratified according to their 30-Hz cone electroretinogram (ERG). The length of telomeres in leukocytes was measured by the quantitative real time polymerase chain reaction (qRT–PCR) method in the 15 patients with the highest age-adjusted 30-Hz ERG amplitudes and in the 15 patients with the lowest amplitudes. Results: Mean leukocyte telomere length was similar in the 15 patients with the highest cone ERG amplitudes (median: 0.40 units; interquartile range 0.36–0.56) and the 15 patients with the lowest cone amplitudes (median: 0.41 units; inter quartile range 0.34 −0.64; p=0.95). Conclusions: We found no evidence for an association between telomere length and the severity of RP as monitored by the cone ERG in patients with the Pro23His rhodopsin mutation.Publication AAV-Mediated Gene Delivery in Adult GM1-Gangliosidosis Mice Corrects Lysosomal Storage in CNS and Improves Survival(Public Library of Science, 2010) Baek, Rena C.; Broekman, Marike L. D.; Leroy, Stanley G.; Tierney, Laryssa A.; Sandberg, Michael; d'Azzo, Alessandra; Seyfried, Thomas N.; Sena-Esteves, MiguelBackground: GM1-gangliosidosis is a glycosphingolipid (GSL) lysosomal storage disease caused by a genetic deficiency of acid β-galactosidase (βgal), which results in the accumulation of GM1-ganglioside and its asialo-form (GA1) primarily in the CNS. Age of onset ranges from infancy to adulthood, and excessive ganglioside accumulation produces progressive neurodegeneration and psychomotor retardation in humans. Currently, there are no effective therapies for the treatment of GM1-gangliosidosis. Methodology/Principal Findings: In this study we examined the effect of thalamic infusion of AAV2/1-βgal vector in adult GM1 mice on enzyme distribution, activity, and GSL content in the CNS, motor behavior, and survival. Six to eight week-old GM1 mice received bilateral injections of AAV vector in the thalamus, or thalamus and deep cerebellar nuclei (DCN) with pre-determined endpoints at 1 and 4 months post-injection, and the humane endpoint, or 52 weeks of age. Enzyme activity was elevated throughout the CNS of AAV-treated GM1 mice and GSL storage nearly normalized in most structures analyzed, except in the spinal cord which showed ∼50% reduction compared to age-matched untreated GM1 mice spinal cord. Survival was significantly longer in AAV-treated GM1 mice (52 wks) than in untreated mice. However the motor performance of AAV-treated GM1 mice declined over time at a rate similar to that observed in untreated GM1 mice. Conclusions/Significance: Our studies show that the AAV-modified thalamus can be used as a ‘built-in’ central node network for widespread distribution of lysosomal enzymes in the mouse cerebrum. In addition, this study indicates that thalamic delivery of AAV vectors should be combined with additional targets to supply the cerebellum and spinal cord with therapeutic levels of enzyme necessary to achieve complete correction of the neurological phenotype in GM1 mice.Publication The Genetic Basis of Pericentral Retinitis Pigmentosa—A Form of Mild Retinitis Pigmentosa(MDPI, 2017) Comander, Jason; Weigel-DiFranco, Carol; Maher, Matthew; Place, Emily; Wan, Aliete; Harper, Shyana; Sandberg, Michael; Navarro-Gomez, Daniel; Pierce, EricPericentral retinitis pigmentosa (RP) is an atypical form of RP that affects the near-peripheral retina first and tends to spare the far periphery. This study was performed to further define the genetic basis of this phenotype. We identified a cohort of 43 probands with pericentral RP based on a comprehensive analysis of their retinal phenotype. Genetic analyses of DNA samples from these patients were performed using panel-based next-generation sequencing, copy number variations, and whole exome sequencing (WES). Mutations provisionally responsible for disease were found in 19 of the 43 families (44%) analyzed. These include mutations in RHO (five patients), USH2A (four patients), and PDE6B (two patients). Of 28 putatively pathogenic alleles, 15 (54%) have been previously identified in patients with more common forms of typical RP, while the remaining 13 mutations (46%) were novel. Burden testing of WES data successfully identified HGSNAT as a cause of pericentral RP in at least two patients, suggesting it is also a relatively common cause of pericentral RP. While additional sequencing might uncover new genes specifically associated with pericentral RP, the current results suggest that genetically pericentral RP is not a separate clinical entity, but rather is part of the spectrum of mild RP phenotypes.