A nanobody-based tracer targeting DPP6 for non-invasive imaging of human pancreatic endocrine cells

Balhuizen, Alexander; Massa, Sam; Mathijs, Iris; Turatsinze, Jean-Valéry; Vos, Jens De; Demine, Stéphane; Xavier, Catarina; Villate, Olatz; Millard, Isabelle; Egrise, Dominique; Capito, Carmen; Scharfmann, Raphaël; Veld, Pieter In 'T; Marchetti, Piero; Muyldermans, Serge; Goldman, Serge; Lahoutte, Tony; Bouwens, Luc; Eizirik, Décio L.; Devoogdt, Nick

doi:10.1038/s41598-017-15417-2

Cited by 42 publications

(44 citation statements)

References 50 publications

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“…Surrogate biomarkers of b-cell function do exist but are relatively insensitive. Imaging studies that can directly assess b-cell mass are still not available for clinical use (43)(44)(45)(46). Our study supports the use of abdominal MRI to quantify RPV BMI in subjects at high risk for type 1 diabetes to understand intersubject heterogeneity, changes over time, and association with numbers of AAB.…”

Section: Discussionsupporting

confidence: 68%

Relative Pancreas Volume Is Reduced in First-Degree Relatives of Patients With Type 1 Diabetes

et al. 2018

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OBJECTIVEPancreas size is reduced in patients at type 1 diabetes onset and in autoantibody (AAB)-positive donors without diabetes. We sought to determine whether pancreas volume (PV) imaging could improve understanding of the loss of pancreas size in first-degree relatives (FDRs) of patients with type 1 diabetes. We also examined relationships among PV, AAB status, and endocrine and exocrine functions. RESEARCH DESIGN AND METHODSWe conducted a cross-sectional study that included five groups: AAB 2 control subjects (no diabetes and no firstor second-degree relatives with type 1 diabetes) (N = 49), AAB 2 FDRs (N = 61), AAB + FDRs (N = 67 total: n = 31 with a single positive AAB [AAB + single] and n = 36 with multiple positive AABs [AAB + multiple]), and patients with recent-onset type 1 diabetes (<1 year) (N = 52). Fasting subjects underwent 1.5T pancreatic MRI, and PV and relative PV (RPV) (PV-to-BMI ratio) were analyzed between groups and for correlations with HbA 1c , C-peptide, glucose, and trypsinogen. RESULTSAll FDR groups had significantly lower RPV adjusted for BMI (RPV BMI ) than control subjects (all P < 0.05). Patients with type 1 diabetes had lower RPV BMI than AAB 2 FDR (P < 0.0001) and AAB + multiple (P £ 0.013) subjects. Transformed data indicated that trypsinogen levels were lowest in patients with type 1 diabetes. CONCLUSIONSThis study demonstrates, for the first time, all FDRs having significantly smaller RPV BMI compared with AAB 2 control subjects. Furthermore, RPV BMI was significantly lower in patients with recent-onset type 1 diabetes than in the AAB 2 FDR and AAB + multiple groups. As such, RPV BMI may be a novel noninvasive biomarker for predicting progression through stages of type 1 diabetes risk. This study highlights the potential paracrine relationships between the exocrine and endocrine pancreas in progression to type 1 diabetes in subjects at risk.Despite advances in medical diagnosis and treatment, type 1 diabetes remains one of the costliest diseases in the U.S. in terms of health care dollars spent for diabetesrelated costs (1). Immunotherapy-based intervention trials carried out in patients with new-onset type 1 diabetes have demonstrated potential for short-term benefit (e.g., anti-CD20, anti-CD3, and cytotoxic T-lymphocyte-associated antigen 4 Ig) but have failed to demonstrate long-term efficacy (2,3). The inability to provide long-term preservation of b-cell function or prevent type 1 diabetes may stem from unanswered

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Section: Discussionsupporting

confidence: 68%

Relative Pancreas Volume Is Reduced in First-Degree Relatives of Patients With Type 1 Diabetes

et al. 2018

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“…These observations suggest that exposure to pro‐inflammatory cytokines favour β‐cell expression of pro‐apoptotic splice variants and potentially lead to the formation of β‐cell neoantigens (Gonzalez‐Duque et al submitted for publication); these 2 phenomena, together, have the potential to exacerbate the autoimmune assault. Of note, characterization of splice variants present in control or stressed human β‐cells may allow the identification of novel circulating biomarkers, useful to follow up β‐cell death in vivo and of β‐cell‐specific surface biomarkers that can be used for β‐cell imaging Pro‐inflammatory cytokines favour β‐cell expression of pro‐apoptotic splice variants and potentially lead to the formation of β‐cell neoantigens. …”

Section: Alternative Splicing Autoimmunity and The Triggering Of T1dmentioning

confidence: 99%

“…Deciphering the role of alternative splicing in T1D may uncover a new line of therapeutic approaches based on splicing modulatory molecules that can be targeted to β‐cells by using cell surface biomarkers …”

Section: Splicing Modulation—a Novel Approach To Prevent β‐Cell Loss mentioning

confidence: 99%

“…Deciphering the role of alternative splicing in T1D may uncover a new line of therapeutic approaches based on splicing modulatory molecules 103 that can be targeted to β-cells by using cell surface biomarkers. 86,87 RNA splicing is an interesting point for intervention since it is an early step in gene expression and represents a non-permanent (ie, do not modify the genome) therapeutic approach. A number of tools have been developed to modulate splicing, but here we will focus on 2 main strategies-antisense oligonucleotides (AONs) and small molecules, 103,104 both already under clinical testing for treatment of 2 monogenic neuromuscular diseases where alternative splicing modulation is used in an attempt to rescue gene expression.…”

Section: Splicing Modulation-a Novel Approach To Prevent β-Cell Losmentioning

confidence: 99%

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When one becomes many—Alternative splicing in β‐cell function and failure

Alvelos

Juan-Mateu

Colli

et al. 2018

Diabetes Obesity Metabolism

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Pancreatic β-cell dysfunction and death are determinant events in type 1 diabetes (T1D), but the molecular mechanisms behind β-cell fate remain poorly understood. Alternative splicing is a post-translational mechanism by which a single gene generates different mRNA and protein isoforms, expanding the transcriptome complexity and enhancing protein diversity. Neuron-specific and certain serine/arginine-rich RNA binding proteins (RBP) are enriched in β-cells, playing crucial roles in the regulation of insulin secretion and β-cell survival. Moreover, alternative exon networks, regulated by inflammation or diabetes susceptibility genes, control key pathways and processes for the correct function and survival of β-cells. The challenge ahead of us is to understand the precise role of alternative splicing regulators and splice variants on β-cell function, dysfunction and death and develop tools to modulate it.

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“…Transplanted islets have previously been tracked in vivo through cellular labeling with fluorescent dyes, nanoparticle‐based contrast agents, or radiolabels 15–23. Co‐encapsulation of contrast agents within hydrogels capsules has also been used to locate encapsulated islets via magnetic resonance imaging (MRI) in vitro21,24 and recently, to track the movement of unconstrained capsules implanted in vivo 25.…”

mentioning

confidence: 99%

Magnetic Retrieval of Encapsulated Beta Cell Transplants from Diabetic Mice Using Dual‐Function MRI Visible and Retrievable Microcapsules

et al. 2020

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Encapsulated beta cell transplantation offers a potential cure for a subset of diabetic patients. Once transplanted, beta cell grafts can help to restore glycemic control; however, locating and retrieving cells in the event of graft failure may pose a surgical challenge. Here, a dual‐function nanoparticle‐loaded hydrogel microcapsule is developed that enables graft retrieval under an applied magnetic field. Additionally, this system facilitates graft localization via magnetic resonance imaging (MRI), and graft isolation from the immune system. Iron oxide nanoparticles encapsulated within alginate hydrogel capsules containing viable islets are transplanted and the in vitro and in vivo retrieval of capsules containing nanoparticles functionalized with various ligands are compared. Capsules containing islets co‐encapsulated with COOH‐coated nanoparticles restore normal glycemia in immunocompetent diabetic mice for at least 6 weeks, can be visualized using MRI, and are retrievable in a magnetic field. Application of a magnetic field for 90 s via a magnetically assisted retrieval device facilitates rapid retrieval of up to 94% (±3.1%) of the transplant volume 24 h after surgical implantation. This strategy aids monitoring of cell‐capsule locations in vivo, facilitates graft removal at the end of the transplant lifetime, and may be applicable to many encapsulated cell transplant systems.

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A nanobody-based tracer targeting DPP6 for non-invasive imaging of human pancreatic endocrine cells

Cited by 42 publications

References 50 publications

Relative Pancreas Volume Is Reduced in First-Degree Relatives of Patients With Type 1 Diabetes

Relative Pancreas Volume Is Reduced in First-Degree Relatives of Patients With Type 1 Diabetes

When one becomes many—Alternative splicing in β‐cell function and failure

Magnetic Retrieval of Encapsulated Beta Cell Transplants from Diabetic Mice Using Dual‐Function MRI Visible and Retrievable Microcapsules

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