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. 2021 Jun;15(6):556-566.
doi: 10.1002/term.3193. Epub 2021 Apr 13.

Photoreceptor precursor cell integration into rodent retina after treatment with novel glycopeptide PKX-001

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Photoreceptor precursor cell integration into rodent retina after treatment with novel glycopeptide PKX-001

Ishaq A Viringipurampeer et al. J Tissue Eng Regen Med. 2021 Jun.

Abstract

Cell replacement therapy is emerging as an important approach in novel treatments for neurodegenerative diseases. Many problems remain, in particular improvements are needed in the survival of transplanted cells and increasing functional integration into host tissue. These problems arise because of immune rejection, suboptimal precursor cell type, trauma during cell transplantation, and toxic compounds released by dying tissues and nutritional deficiencies. We recently developed an ex vivo system to facilitate identification of factors contributing to the death of transplanted neuronal (photoreceptor) and showed 2.8-fold improvement in transplant cell survival after pretreatment with a novel glycopeptide (PKX-001). In this study, we extended these studies to look at cell survival, maturation, and functional integration in an in vivo rat model of rhodopsin-mutant retinitis pigmentosa causing blindness. We found that only when human photoreceptor precursor cells were preincubated with PKX-001 prior to transplantation, did the cells integrate and mature into cone photoreceptors expressing S-opsin or L/M opsin. In addition, ribbon synapses were observed in the transplanted cells suggesting they were making synaptic connections with the host tissue. Furthermore, optokinetic tracking and electroretinography responses in vivo were significantly improved compared to cell transplants without PKX-001 pre-treatment. These data demonstrate that PKX-001 promotes significant long-term stem cell survival in vivo, providing a platform for further investigation towards the clinical application to repair damaged or diseased retina.

Keywords: blindness; glycopeptide; neurodegeneration; opsin; photoreceptor precursor cell; retinal degeneration.

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. 2017 Sep;11(9):2658-2662.
doi: 10.1002/term.2176. Epub 2016 May 27.

Anti-ageing glycoprotein promotes long-term survival of transplanted neurosensory precursor cells

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Anti-ageing glycoprotein promotes long-term survival of transplanted neurosensory precursor cells

Anat Yanai et al. J Tissue Eng Regen Med. 2017 Sep.

Abstract

Cell therapy, to replace lost tissue, is a promising approach for the treatment of various neurodegenerative diseases. Many studies suggest, however, that the percentage of transplanted cells that survive and undergo functional integration remains low as a result of immune rejection, suboptimal precursor cell type, trauma during cell transplantation, toxic compounds released by dying tissues or nutritional deficiencies. We recently developed an ex vivo system to facilitate identification of factors contributing to the death of transplanted neuronal (photoreceptor) cells and compounds that block these toxic effects. In this system, photoreceptor precursor cells (PPCs) are sandwiched between a neurosensory retinal explant and retinal pigment epithelium derived from human embryonic stem cells. Explant medium was collected to identify toxic components and PPC survival was assessed by flow cytometry. We also assessed the potential for AAGP™, a cryopreservative molecule, to improve PPC survival. We identified elevated prostaglandin E2 (PGE2) in the explant medium and demonstrated that AAGP™ reduced PGE2 levels by 2.6-fold. A pro-inflammatory stress assay suggested that this may result from AAGP™ inhibition of cyclo-oxygenase-2 (COX-2) expression. We confirmed that PGE2 reduced the viability of cultured PPCs by 44% and found that the survival rate of PPCs pretreated with AAGP™ was 2.8-fold higher than in untreated PPCs. These data suggest that PGE2 release from necrotic tissue may be one factor that reduces the survival of transplanted precursor cells and that the pro-survival molecule AAGP™ may improve long-term transplanted cell viability. Copyright © 2016 John Wiley & Sons, Ltd.

Keywords: cell therapy; ex vivo system; functional integration; neurodegeneration; neurosensory precursor cells; pro-survival compound.

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. 2016 Feb;65(2):451-62.
doi: 10.2337/db15-0764. Epub 2015 Nov 18.

Antiaging Glycopeptide Protects Human Islets Against Tacrolimus-Related Injury and Facilitates Engraftment in Mice

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Antiaging Glycopeptide Protects Human Islets Against Tacrolimus-Related Injury and Facilitates Engraftment in Mice

Boris L Gala-Lopez et al. Diabetes. 2016 Feb.

Abstract

Clinical islet transplantation has become an established treatment modality for selected patients with type 1 diabetes. However, a large proportion of transplanted islets is lost through multiple factors, including immunosuppressant-related toxicity, often requiring more than one donor to achieve insulin independence. On the basis of the cytoprotective capabilities of antifreeze proteins (AFPs), we hypothesized that supplementation of islets with synthetic AFP analog antiaging glycopeptide (AAGP) would enhance posttransplant engraftment and function and protect against tacrolimus (Tac) toxicity. In vitro and in vivo islet Tac exposure elicited significant but reversible reduction in insulin secretion in both mouse and human islets. Supplementation with AAGP resulted in improvement of islet survival (Tac(+) vs. Tac+AAGP, 31.5% vs. 67.6%, P < 0.01) coupled with better insulin secretion (area under the curve: Tac(+) vs. Tac+AAGP, 7.3 vs. 129.2 mmol/L/60 min, P < 0.001). The addition of AAGP reduced oxidative stress, enhanced insulin exocytosis, improved apoptosis, and improved engraftment in mice by decreasing expression of interleukin (IL)-1β, IL-6, keratinocyte chemokine, and tumor necrosis factor-α. Finally, transplant efficacy was superior in the Tac+AAGP group and was similar to islets not exposed to Tac, despite receiving continuous treatment for a limited time. Thus, supplementation with AAGP during culture improves islet potency and attenuates long-term Tac-induced graft dysfunction.

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