Genetically modified pig models for neurodegenerative disorders

Holm, Ida E.; Alstrup, Aage Kristian Olsen; Luo, Yonglun

doi:10.1002/path.4654

Cited by 100 publications

(80 citation statements)

References 194 publications

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“…Xenotransplantation of peripheral nerves may also be a promising solution for reconstructing large peripheral nerve injuries. 60 While various organs have been proposed to be good candidates for xenotransplantation (such as pancreatic islets, kidneys, heart and liver), 61–63 high immunological rejection due to cross species incompatibility remains a major challenge. 64 …”

Section: Methodsmentioning

confidence: 99%

Biomimetic neural scaffolds: a crucial step towards optimal peripheral nerve regeneration

et al. 2018

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Peripheral nerve injury is a common disease that affects more than 20 million people in the United States alone and remains a major burden to society. The current gold standard treatment for critical-sized nerve defects is autologous nerve graft transplantation; however, this method is limited in many ways and does not always lead to satisfactory outcomes. The limitations of autografts have prompted investigations into artificial neural scaffolds as replacements, and some neural scaffold devices have progressed to widespread clinical use; scaffold technology overall has yet to be shown to be consistently on a par with or superior to autografts. Recent advances in biomimetic scaffold technologies have opened up many new and exciting opportunities, and novel improvements in material, fabrication technique, scaffold architecture, and lumen surface modifications that better reflect biological anatomy and physiology have independently been shown to benefit overall nerve regeneration. Furthermore, biomimetic features of neural scaffolds have also been shown to work synergistically with other nerve regeneration therapy strategies such as growth factor supplementation, stem cell transplantation, and cell surface glycoengineering. This review summarizes the current state of neural scaffolds, highlights major advances in biomimetic technologies, and discusses future opportunities in the field of peripheral nerve regeneration.

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Section: Methodsmentioning

confidence: 99%

Biomimetic neural scaffolds: a crucial step towards optimal peripheral nerve regeneration

et al. 2018

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“…In line with possibility, a porcine model of controlled cortical impact was reproducible and clinically relevant with respect to multi-parametric neuromonitoring and histological outcomes [230, 231]. With the advent of improved genetic tools, such as CRISPR/Cas9 technology [232–235], future work will combine the genetic and mechanistic benefits of rodents with the anatomical and physiological advantages of a porcine TBI model.…”

Section: Translational Implicationsmentioning

confidence: 99%

White matter damage after traumatic brain injury: A role for damage associated molecular patterns

Braun

Vaibhav

Saad

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Traumatic brain injury (TBI) is a leading cause of mortality and long-term morbidity worldwide. Despite decades of pre-clinical investigation, therapeutic strategies focused on acute neuroprotection failed to improve TBI outcomes. This lack of translational success has necessitated a reassessment of the optimal targets for intervention, including a heightened focus on secondary injury mechanisms. Chronic immune activation correlates with progressive neurodegeneration for decades after TBI; however, significant challenges remain in functionally and mechanistically defining immune activation after TBI. In this review, we explore the burgeoning evidence implicating the acute release of damage associated molecular patterns (DAMPs), such as adenosine 5′-triphosphate (ATP), high mobility group box protein 1 (HMGB1), S100 proteins, and hyaluronic acid in the initiation of progressive neurological injury, including white matter loss after TBI. The role that pattern recognition receptors, including toll-like receptor and purinergic receptors, play in progressive neurological injury after TBI is detailed. Finally, we provide support for the notion that resident and infiltrating macrophages are critical cellular targets linking acute DAMP release with adaptive immune responses and chronic injury after TBI. The therapeutic potential of targeting DAMPs and barriers to clinical translational, in the context of TBI patient management, are discussed.

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“…Rodent models have collectively provided valuable information related to target validation and drug therapy [2,3,4]. However, large animal models are expected to simulate the disease more faithfully and moreover enable the usage of medical techniques and equipment applicable for human patients [5]. …”

Section: Introductionmentioning

confidence: 99%

Mutated Huntingtin Causes Testicular Pathology in Transgenic Minipig Boars

Macakova

Bohuslavová²,

Vochozková³

et al. 2016

Neurodegener Dis

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Background: Huntington's disease is induced by CAG expansion in a single gene coding the huntingtin protein. The mutated huntingtin (mtHtt) primarily causes degeneration of neurons in the brain, but it also affects peripheral tissues, including testes. Objective: We studied sperm and testes of transgenic boars expressing the N-terminal region of human mtHtt. Methods: In this study, measures of reproductive parameters and electron microscopy (EM) images of spermatozoa and testes of transgenic (TgHD) and wild-type (WT) boars of F1 (24-48 months old) and F2 (12-36 months old) generations were compared. In addition, immunofluorescence, immunohistochemistry, Western blot, hormonal analysis and whole-genome sequencing were done in order to elucidate the effects of mtHtt. Results: Evidence for fertility failure of both TgHD generations was observed at the age of 13 months. Reproductive parameters declined and progressively worsened with age. EM revealed numerous pathological features in sperm tails and in testicular epithelium from 24- and 36-month-old TgHD boars. Moreover, immunohistochemistry confirmed significantly lower proliferation activity of spermatogonia in transgenic testes. mtHtt was highly expressed in spermatozoa and testes of TgHD boars and localized in all cells of seminiferous tubules. Levels of fertility-related hormones did not differ in TgHD and WT siblings. Genome analysis confirmed that insertion of the lentiviral construct did not interrupt any coding sequence in the pig genome. Conclusions: The sperm and testicular degeneration of TgHD boars is caused by gain-of-function of the highly expressed mtHtt.

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Genetically modified pig models for neurodegenerative disorders

Cited by 100 publications

References 194 publications

Biomimetic neural scaffolds: a crucial step towards optimal peripheral nerve regeneration

Biomimetic neural scaffolds: a crucial step towards optimal peripheral nerve regeneration

White matter damage after traumatic brain injury: A role for damage associated molecular patterns

Mutated Huntingtin Causes Testicular Pathology in Transgenic Minipig Boars

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