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  1. Article ; Online: Eye on genome editing.

    Du, Samuel W / Palczewski, Krzysztof

    The Journal of experimental medicine

    2023  Volume 220, Issue 5

    Abstract: CRISPR/Cas9 genome editing techniques have the potential to treat previously untreatable inherited genetic disorders of vision by correcting mutations that cause these afflictions. Using a prime editor, Qin et al. (2023. J. Exp. Med.https://doi.org/10 ... ...

    Abstract CRISPR/Cas9 genome editing techniques have the potential to treat previously untreatable inherited genetic disorders of vision by correcting mutations that cause these afflictions. Using a prime editor, Qin et al. (2023. J. Exp. Med.https://doi.org/10.1084/jem.20220776) restored visual functions in a mouse model (rd10) of retinitis pigmentosa.
    MeSH term(s) Mice ; Animals ; Gene Editing/methods ; Retinitis Pigmentosa/genetics ; Retinitis Pigmentosa/therapy ; Mutation/genetics ; Disease Models, Animal ; CRISPR-Cas Systems/genetics
    Language English
    Publishing date 2023-03-17
    Publishing country United States
    Document type Journal Article ; Comment
    ZDB-ID 218343-2
    ISSN 1540-9538 ; 0022-1007
    ISSN (online) 1540-9538
    ISSN 0022-1007
    DOI 10.1084/jem.20230146
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  2. Article ; Online: Genome editing, a superior therapy for inherited retinal diseases.

    Yan, Alexander L / Du, Samuel W / Palczewski, Krzysztof

    Vision research

    2023  Volume 206, Page(s) 108192

    Abstract: Gene augmentation and genome editing are promising strategies for the treatment of monogenic inherited retinal diseases. Although gene augmentation treatments are commercially available for inherited retinal diseases, there are many shortcomings that ... ...

    Abstract Gene augmentation and genome editing are promising strategies for the treatment of monogenic inherited retinal diseases. Although gene augmentation treatments are commercially available for inherited retinal diseases, there are many shortcomings that need to be addressed, like progressive retinal degeneration and diminishing efficacy over time. Innovative CRISPR-Cas9-based genome editing technologies have broadened the proportion of treatable genetic disorders and can greatly improve or complement treatment outcomes from gene augmentation. Progress in this relatively new field involves the development of therapeutics including gene disruption, ablate-and-replace strategies, and precision gene correction techniques, such as base editing and prime editing. By making direct edits to endogenous DNA, genome editing theoretically guarantees permanent gene correction and long-lasting treatment effects. Improvements to delivery modalities aimed at limiting persistent gene editor activity have displayed an improved safety profile and minimal off-target editing. Continued progress to advance precise gene correction and associated delivery strategies will establish genome editing as the preferred treatment for genetic retinal disorders. This commentary describes the applications, strengths, and drawbacks of conventional gene augmentation approaches, recent advances in precise genome editing in the retina, and promising preclinical strategies to facilitate the use of robust genome editing therapies in human patients.
    MeSH term(s) Humans ; Gene Editing/methods ; CRISPR-Cas Systems/genetics ; Genetic Therapy/methods ; Retinal Diseases/genetics ; Retinal Diseases/therapy ; Retina
    Language English
    Publishing date 2023-02-15
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 200427-6
    ISSN 1878-5646 ; 0042-6989
    ISSN (online) 1878-5646
    ISSN 0042-6989
    DOI 10.1016/j.visres.2023.108192
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  3. Article ; Online: MicroRNA regulation of critical retinal pigment epithelial functions.

    Du, Samuel W / Palczewski, Krzysztof

    Trends in neurosciences

    2021  Volume 45, Issue 1, Page(s) 78–90

    Abstract: MicroRNAs are short, evolutionarily conserved noncoding RNAs that are critical for the control of normal cellular physiology. In the retina, photoreceptors are highly specialized neurons that transduce light into electrical signals. Photoreceptors, ... ...

    Abstract MicroRNAs are short, evolutionarily conserved noncoding RNAs that are critical for the control of normal cellular physiology. In the retina, photoreceptors are highly specialized neurons that transduce light into electrical signals. Photoreceptors, however, are unable to process visual stimuli without the support of the retinal pigment epithelium (RPE). The RPE performs numerous functions to aid the retina, including the generation of visual chromophore and metabolic support. Recent work has underscored how microRNAs enable vision through their contributions to RPE functions. This review focuses on the biogenesis and control of microRNAs in rodents and humans, the roles microRNAs play in RPE function and degeneration, and how microRNAs could serve as potential therapeutics and biomarkers for visual diseases.
    MeSH term(s) Humans ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Retina ; Retinal Pigment Epithelium/metabolism ; Retinal Pigments/metabolism ; Vision, Ocular
    Chemical Substances MicroRNAs ; Retinal Pigments
    Language English
    Publishing date 2021-11-06
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 282488-7
    ISSN 1878-108X ; 0378-5912 ; 0166-2236
    ISSN (online) 1878-108X
    ISSN 0378-5912 ; 0166-2236
    DOI 10.1016/j.tins.2021.10.008
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  4. Article ; Online: Conditional deletion of miR-204 and miR-211 in murine retinal pigment epithelium results in retinal degeneration.

    Du, Samuel W / Komirisetty, Ravikiran / Lewandowski, Dominik / Choi, Elliot H / Panas, Damian / Suh, Susie / Tabaka, Marcin / Radu, Roxana A / Palczewski, Krzysztof

    The Journal of biological chemistry

    2024  , Page(s) 107344

    Abstract: MicroRNAs (miRs) are short, evolutionarily conserved non-coding RNAs that canonically downregulate expression of target genes. The miR family composed of miR-204 and miR-211 is among the most highly expressed in the retinal pigment epithelium (RPE) in ... ...

    Abstract MicroRNAs (miRs) are short, evolutionarily conserved non-coding RNAs that canonically downregulate expression of target genes. The miR family composed of miR-204 and miR-211 is among the most highly expressed in the retinal pigment epithelium (RPE) in both mouse and human, and also retains high sequence identity. To assess the role of this miR family in the developed mouse eye, we generated two floxed conditional knockout mouse lines crossed to the RPE65-ERT2-Cre driver mouse line to perform an RPE-specific conditional knockout of this miR family in adult mice. After Cre-mediated deletion, we observed retinal structural changes by optical coherence tomography; dysfunction and loss of photoreceptors by retinal imaging; and retinal inflammation marked by subretinal infiltration of immune cells by imaging and immunostaining. Single-cell RNA sequencing of diseased RPE and retinas showed potential miR-regulated target genes, as well as changes in non-coding RNAs in the RPE, rod photoreceptors, and Müller glia. This work thus highlights the role of miR-204 and miR-211 in maintaining RPE function and how the loss of miRs in the RPE exerts effects on the neural retina, leading to inflammation and retinal degeneration.
    Language English
    Publishing date 2024-05-03
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1016/j.jbc.2024.107344
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  5. Article ; Online: NADPH oxidase exerts a B cell-intrinsic contribution to lupus risk by modulating endosomal TLR signals.

    Liu, Shuozhi / Lagos, Jonathan / Shumlak, Natali M / Largent, Andrea D / Lewis, Sebastien T E / Holder, Ursula / Du, Samuel W / Liu, Yifan / Hou, Baidong / Acharya, Mridu / Jackson, Shaun W

    The Journal of experimental medicine

    2024  Volume 221, Issue 4

    Abstract: Genome-wide association studies in systemic lupus erythematosus (SLE) have linked loss-of-function mutations in phagocytic NADPH oxidase complex (NOX2) genes, including NCF1 and NCF2, to disease pathogenesis. The prevailing model holds that reduced NOX2 ... ...

    Abstract Genome-wide association studies in systemic lupus erythematosus (SLE) have linked loss-of-function mutations in phagocytic NADPH oxidase complex (NOX2) genes, including NCF1 and NCF2, to disease pathogenesis. The prevailing model holds that reduced NOX2 activity promotes SLE via defective efferocytosis, the immunologically silent clearance of apoptotic cells. Here, we describe a parallel B cell-intrinsic mechanism contributing to breaks in tolerance. In keeping with an important role for B cell Toll-like receptor (TLR) pathways in lupus pathogenesis, NOX2-deficient B cells exhibit enhanced signaling downstream of endosomal TLRs, increased humoral responses to nucleic acid-containing antigens, and the propensity toward humoral autoimmunity. Mechanistically, TLR-dependent NOX2 activation promotes LC3-mediated maturation of TLR-containing endosomes, resulting in signal termination. CRISPR-mediated disruption of NCF1 confirmed a direct role for NOX2 in regulating endosomal TLR signaling in primary human B cells. Together, these data highlight a new B cell-specific mechanism contributing to autoimmune risk in NCF1 and NCF2 variant carriers.
    MeSH term(s) Humans ; NADPH Oxidases/genetics ; Genome-Wide Association Study ; Autoimmunity/genetics ; Endosomes ; Lupus Erythematosus, Systemic/genetics
    Chemical Substances NADPH Oxidases (EC 1.6.3.-)
    Language English
    Publishing date 2024-03-05
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218343-2
    ISSN 1540-9538 ; 0022-1007
    ISSN (online) 1540-9538
    ISSN 0022-1007
    DOI 10.1084/jem.20230774
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  6. Article ; Online: Retinylidene chromophore hydrolysis from mammalian visual and non-visual opsins.

    Hong, John D / Salom, David / Choi, Elliot H / Du, Samuel W / Tworak, Aleksander / Smidak, Roman / Gao, Fangyuan / Solano, Yasmeen J / Zhang, Jianye / Kiser, Philip D / Palczewski, Krzysztof

    The Journal of biological chemistry

    2024  Volume 300, Issue 3, Page(s) 105678

    Abstract: Rhodopsin (Rho) and cone opsins are essential for detection of light. They respond via photoisomerization, converting their Schiff-base-adducted 11-cis-retinylidene chromophores to the all-trans configuration, eliciting conformational changes to activate ...

    Abstract Rhodopsin (Rho) and cone opsins are essential for detection of light. They respond via photoisomerization, converting their Schiff-base-adducted 11-cis-retinylidene chromophores to the all-trans configuration, eliciting conformational changes to activate opsin signaling. Subsequent Schiff-base hydrolysis releases all-trans-retinal, initiating two important cycles that maintain continuous vision-the Rho photocycle and visual cycle pathway. Schiff-base hydrolysis has been thoroughly studied with photoactivated Rho but not with cone opsins. Using established methodology, we directly measured the formation of Schiff-base between retinal chromophores with mammalian visual and nonvisual opsins of the eye. Next, we determined the rate of light-induced chromophore hydrolysis. We found that retinal hydrolysis from photoactivated cone opsins was markedly faster than from photoactivated Rho. Bovine retinal G protein-coupled receptor (bRGR) displayed rapid hydrolysis of its 11-cis-retinylidene photoproduct to quickly supply 11-cis-retinal and re-bind all-trans-retinal. Hydrolysis within bRGR in native retinal pigment epithelium microsomal membranes was >6-times faster than that of bRGR purified in detergent micelles. N-terminal-targeted antibodies significantly slowed bRGR hydrolysis, while C-terminal antibodies had no effect. Our study highlights the much faster photocycle of cone opsins relative to Rho and the crucial role of RGR in chromophore recycling in daylight. By contrast, in our experimental conditions, bovine peropsin did not form pigment in the presence of all-trans-retinal nor with any mono-cis retinal isomers, leaving uncertain the role of this opsin as a light sensor.
    MeSH term(s) Animals ; Cattle ; Cone Opsins ; Hydrolysis ; Opsins/chemistry ; Retinaldehyde/chemistry ; Retinoids ; Rhodopsin
    Chemical Substances Cone Opsins ; Opsins ; Retinaldehyde (RR725D715M) ; Retinoids ; retinylidene chromophore ; Rhodopsin (9009-81-8)
    Language English
    Publishing date 2024-01-23
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1016/j.jbc.2024.105678
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  7. Article ; Online: Engineered virus-like particles for transient delivery of prime editor ribonucleoprotein complexes in vivo.

    An, Meirui / Raguram, Aditya / Du, Samuel W / Banskota, Samagya / Davis, Jessie R / Newby, Gregory A / Chen, Paul Z / Palczewski, Krzysztof / Liu, David R

    Nature biotechnology

    2024  

    Abstract: Prime editing enables precise installation of genomic substitutions, insertions and deletions in living systems. Efficient in vitro and in vivo delivery of prime editing components, however, remains a challenge. Here we report prime editor engineered ... ...

    Abstract Prime editing enables precise installation of genomic substitutions, insertions and deletions in living systems. Efficient in vitro and in vivo delivery of prime editing components, however, remains a challenge. Here we report prime editor engineered virus-like particles (PE-eVLPs) that deliver prime editor proteins, prime editing guide RNAs and nicking single guide RNAs as transient ribonucleoprotein complexes. We systematically engineered v3 and v3b PE-eVLPs with 65- to 170-fold higher editing efficiency in human cells compared to a PE-eVLP construct based on our previously reported base editor eVLP architecture. In two mouse models of genetic blindness, single injections of v3 PE-eVLPs resulted in therapeutically relevant levels of prime editing in the retina, protein expression restoration and partial visual function rescue. Optimized PE-eVLPs support transient in vivo delivery of prime editor ribonucleoproteins, enhancing the potential safety of prime editing by reducing off-target editing and obviating the possibility of oncogenic transgene integration.
    Language English
    Publishing date 2024-01-08
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1311932-1
    ISSN 1546-1696 ; 1087-0156
    ISSN (online) 1546-1696
    ISSN 1087-0156
    DOI 10.1038/s41587-023-02078-y
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  8. Article: Engineered virus-like particles for efficient in vivo delivery of therapeutic proteins

    Banskota, Samagya / Raguram, Aditya / Suh, Susie / Du, Samuel W. / Davis, Jessie R. / Choi, Elliot H. / Wang, Xiao / Nielsen, Sarah C. / Newby, Gregory A. / Randolph, Peyton B. / Osborn, Mark J. / Musunuru, Kiran / Palczewski, Krzysztof / Liu, David R.

    Cell. 2022 Jan. 20, v. 185, no. 2

    2022  

    Abstract: Methods to deliver gene editing agents in vivo as ribonucleoproteins could offer safety advantages over nucleic acid delivery approaches. We report the development and application of engineered DNA-free virus-like particles (eVLPs) that efficiently ... ...

    Abstract Methods to deliver gene editing agents in vivo as ribonucleoproteins could offer safety advantages over nucleic acid delivery approaches. We report the development and application of engineered DNA-free virus-like particles (eVLPs) that efficiently package and deliver base editor or Cas9 ribonucleoproteins. By engineering VLPs to overcome cargo packaging, release, and localization bottlenecks, we developed fourth-generation eVLPs that mediate efficient base editing in several primary mouse and human cell types. Using different glycoproteins in eVLPs alters their cellular tropism. Single injections of eVLPs into mice support therapeutic levels of base editing in multiple tissues, reducing serum Pcsk9 levels 78% following 63% liver editing, and partially restoring visual function in a mouse model of genetic blindness. In vitro and in vivo off-target editing from eVLPs was virtually undetected, an improvement over AAV or plasmid delivery. These results establish eVLPs as promising vehicles for therapeutic macromolecule delivery that combine key advantages of both viral and nonviral delivery.
    Keywords blindness ; blood serum ; genes ; glycoproteins ; humans ; liver ; mice ; plasmids ; ribonucleoproteins ; therapeutics
    Language English
    Dates of publication 2022-0120
    Size p. 250-265.e16.
    Publishing place Elsevier Inc.
    Document type Article
    ZDB-ID 187009-9
    ISSN 1097-4172 ; 0092-8674
    ISSN (online) 1097-4172
    ISSN 0092-8674
    DOI 10.1016/j.cell.2021.12.021
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  9. Article ; Online: Engineered virus-like particles for efficient in vivo delivery of therapeutic proteins.

    Banskota, Samagya / Raguram, Aditya / Suh, Susie / Du, Samuel W / Davis, Jessie R / Choi, Elliot H / Wang, Xiao / Nielsen, Sarah C / Newby, Gregory A / Randolph, Peyton B / Osborn, Mark J / Musunuru, Kiran / Palczewski, Krzysztof / Liu, David R

    Cell

    2022  Volume 185, Issue 2, Page(s) 250–265.e16

    Abstract: Methods to deliver gene editing agents in vivo as ribonucleoproteins could offer safety advantages over nucleic acid delivery approaches. We report the development and application of engineered DNA-free virus-like particles (eVLPs) that efficiently ... ...

    Abstract Methods to deliver gene editing agents in vivo as ribonucleoproteins could offer safety advantages over nucleic acid delivery approaches. We report the development and application of engineered DNA-free virus-like particles (eVLPs) that efficiently package and deliver base editor or Cas9 ribonucleoproteins. By engineering VLPs to overcome cargo packaging, release, and localization bottlenecks, we developed fourth-generation eVLPs that mediate efficient base editing in several primary mouse and human cell types. Using different glycoproteins in eVLPs alters their cellular tropism. Single injections of eVLPs into mice support therapeutic levels of base editing in multiple tissues, reducing serum Pcsk9 levels 78% following 63% liver editing, and partially restoring visual function in a mouse model of genetic blindness. In vitro and in vivo off-target editing from eVLPs was virtually undetected, an improvement over AAV or plasmid delivery. These results establish eVLPs as promising vehicles for therapeutic macromolecule delivery that combine key advantages of both viral and nonviral delivery.
    MeSH term(s) Animals ; Base Sequence ; Blindness/genetics ; Blindness/therapy ; Brain/metabolism ; DNA/metabolism ; Disease Models, Animal ; Drug Delivery Systems ; Fibroblasts/metabolism ; Gene Editing ; Genetic Engineering ; HEK293 Cells ; Humans ; Liver/pathology ; Mice ; Mice, Inbred C57BL ; Proprotein Convertase 9/metabolism ; Proteins/therapeutic use ; Retinal Pigment Epithelium/pathology ; Retroviridae ; Virion/genetics ; Virion/ultrastructure ; Vision, Ocular
    Chemical Substances Proteins ; DNA (9007-49-2) ; Proprotein Convertase 9 (EC 3.4.21.-)
    Language English
    Publishing date 2022-01-11
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 187009-9
    ISSN 1097-4172 ; 0092-8674
    ISSN (online) 1097-4172
    ISSN 0092-8674
    DOI 10.1016/j.cell.2021.12.021
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  10. Article ; Online: Integrated B Cell, Toll-like, and BAFF Receptor Signals Promote Autoantibody Production by Transitional B Cells.

    Du, Samuel W / Jacobs, Holly M / Arkatkar, Tanvi / Rawlings, David J / Jackson, Shaun W

    Journal of immunology (Baltimore, Md. : 1950)

    2018  Volume 201, Issue 11, Page(s) 3258–3268

    Abstract: The B cell survival cytokine BAFF has been linked with the pathogenesis of systemic lupus erythematosus (SLE). BAFF binds distinct BAFF-family surface receptors, including the BAFF-R and transmembrane activator and CAML interactor (TACI). Although ... ...

    Abstract The B cell survival cytokine BAFF has been linked with the pathogenesis of systemic lupus erythematosus (SLE). BAFF binds distinct BAFF-family surface receptors, including the BAFF-R and transmembrane activator and CAML interactor (TACI). Although originally characterized as a negative regulator of B cell activation, TACI signals are critical for class-switched autoantibody (autoAb) production in BAFF transgenic mice. Consistent with this finding, a subset of transitional splenic B cells upregulate surface TACI expression and contribute to BAFF-driven autoAb. In the current study, we interrogated the B cell signals required for transitional B cell TACI expression and Ab production. Surprisingly, despite established roles for dual BCR and TLR signals in autoAb production in SLE, signals downstream of these receptors exerted distinct impacts on transitional B cell TACI expression and autoAb titers. Whereas loss of BCR signals prevented transitional B cell TACI expression and resulted in loss of serum autoAb across all Ig isotypes, lack of TLR signals exerted a more limited impact restricted to autoAb class-switch recombination without altering transitional B cell TACI expression. Finally, in parallel with the protective effect of TACI deletion, loss of BAFF-R signaling also protected against BAFF-driven autoimmunity. Together, these findings highlight how multiple signaling pathways integrate to promote class-switched autoAb production by transitional B cells, events that likely impact the pathogenesis of SLE and other BAFF-dependent autoimmune diseases.
    MeSH term(s) Animals ; Autoantibodies/metabolism ; B-Cell Activating Factor/genetics ; B-Cell Activating Factor/metabolism ; B-Cell Activation Factor Receptor/genetics ; Disease Models, Animal ; Glomerulonephritis, IGA/immunology ; Humans ; Immunoglobulin Class Switching ; Lupus Erythematosus, Systemic/immunology ; Lymphocyte Activation ; Membrane Glycoproteins/genetics ; Membrane Glycoproteins/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Precursor Cells, B-Lymphoid/physiology ; Receptor Cross-Talk ; Receptors, Antigen, B-Cell/genetics ; Receptors, Antigen, B-Cell/metabolism ; Signal Transduction ; Toll-Like Receptor 7/genetics ; Toll-Like Receptor 7/metabolism ; Transmembrane Activator and CAML Interactor Protein/genetics ; Transmembrane Activator and CAML Interactor Protein/metabolism
    Chemical Substances Autoantibodies ; B-Cell Activating Factor ; B-Cell Activation Factor Receptor ; Membrane Glycoproteins ; Receptors, Antigen, B-Cell ; Tlr7 protein, mouse ; Tnfrsf13b protein, mouse ; Tnfrsf13c protein, mouse ; Tnfsf13b protein, mouse ; Toll-Like Receptor 7 ; Transmembrane Activator and CAML Interactor Protein
    Language English
    Publishing date 2018-10-29
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 3056-9
    ISSN 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
    ISSN (online) 1550-6606
    ISSN 0022-1767 ; 1048-3233 ; 1047-7381
    DOI 10.4049/jimmunol.1800393
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