Evolution of haematopoietic cell transplantation for canine blood disorders and a platform for solid organ transplantation

Graves, Scott S.; Storb, Rainer

doi:10.1002/vms3.601

Cited by 3 publications

(2 citation statements)

References 176 publications

(208 reference statements)

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“…Therefore, a number of alternatives to immunodeficient mouse models, including rats, pigs, dogs, non-human primates or zebrafish [ 178 , 179 , 180 ]. Overall, larger animals have a longer lifespan than smaller animal models.…”

Section: Hsc-based Immune Disease Modellingmentioning

confidence: 99%

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Stem Cell-Based Disease Models for Inborn Errors of Immunity

Zbinden

Canté-Barrett

Pike-Overzet

2021

Cells

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The intrinsic capacity of human hematopoietic stem cells (hHSCs) to reconstitute myeloid and lymphoid lineages combined with their self-renewal capacity hold enormous promises for gene therapy as a viable treatment option for a number of immune-mediated diseases, most prominently for inborn errors of immunity (IEI). The current development of such therapies relies on disease models, both in vitro and in vivo, which allow the study of human pathophysiology in great detail. Here, we discuss the current challenges with regards to developmental origin, heterogeneity and the subsequent implications for disease modeling. We review models based on induced pluripotent stem cell technology and those relaying on use of adult hHSCs. We critically review the advantages and limitations of current models for IEI both in vitro and in vivo. We conclude that existing and future stem cell-based models are necessary tools for developing next generation therapies for IEI.

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Section: Hsc-based Immune Disease Modellingmentioning

confidence: 99%

“…While immunodeficient pigs can accept a number of xenografts, immune humanization in pigs remains a constant challenge and further work is required [ 187 ]. The use of canine models for HSC transplantation have been recently reviewer by Graves et al [ 180 ].…”

Section: Hsc-based Immune Disease Modellingmentioning

confidence: 99%

Stem Cell-Based Disease Models for Inborn Errors of Immunity

Zbinden

Canté-Barrett

Pike-Overzet

2021

Cells

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Evolution of haematopoietic cell transplantation for canine blood disorders and a platform for solid organ transplantation

Graves

Storb

2021

Veterinary Medicine & Sci

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Pre-clinical haematopoietic cell transplantation (HCT) studies in canines have proven to be invaluable for establishing HCT as a highly successful clinical option for the treatment of malignant and non-malignant haematological diseases in humans. Additionally, studies in canines have shown that immune tolerance, established following HCT, enabled transplantation of solid organs without the need of lifelong immunosuppression. This progress has been possible due to multiple biological similarities between dog and mankind. In this review, the hurdles that were overcome and the methods that were developed in the dog HCT model which made HCT clinically possible are examined. The results of these studies justify the question whether HCT can be used in the veterinary clinical practice for more wide-spread successful treatment of canine haematologic and non-haematologic disorders and whether it is prudent to do so.

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First, do no harm: the role of preclinical animal models in predicting adverse events in gene therapy clinical trials for Duchenne muscular dystrophy and X-Linked myotubular myopathy

Kornegay,

Stedman,

Lawlor

et al. 2024

Rare Dis Orphan Drugs J

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The occurrence of severe adverse events (SAEs) in patients with Duchenne muscular dystrophy (DMD), X-linked myotubular myopathy (XLMTM), and other neuromuscular diseases treated with adeno-associated virus (AAV) constructs has prompted studies to improve the safety and efficacy of gene therapy. Physicians have weighed the medical tenet of “first, do no harm” against the perspective of patients with progressive life-threatening conditions who may accept greater risk. Regarding SAE pathogenesis, discussion has focused on total AAV exposure and patient mutations more likely to induce immunity, while stressing the limitations of animal models in predicting adverse events. Therapeutic strategies for reducing side effects have employed more myotropic AAV serotypes and efficient transgenes. Other recommendations include excluding certain DMD gene mutations associated with SAEs and substituting less immunogenic transgenes such as utrophin (DMD) and myotubularin-related protein (XLMTM). For the sake of preclinical studies, emphasis has been placed on outbred rodents and larger animals that better predict immunity. Here, the absence of side effects in canine DMD and XLMTM models might be explained partly by phenotypic differences between affected humans and dogs. Specifically, dystrophin- and myotubularin-deficient dogs exhibit milder lesions, including less muscle fat deposition and the absence of hepatopathy, respectively, which could lead to reduced immune responses to AAV constructs. To better predict future problems, thought should be given to tracking early subclinical markers of the innate immune response, especially complement activation. Regardless of steps taken to improve the predictive value of animal models for SAEs, some questions will only be answered through human clinical trials after carefully considering the risk-benefit ratio.

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Evolution of haematopoietic cell transplantation for canine blood disorders and a platform for solid organ transplantation

Cited by 3 publications

References 176 publications

Stem Cell-Based Disease Models for Inborn Errors of Immunity

Stem Cell-Based Disease Models for Inborn Errors of Immunity

Evolution of haematopoietic cell transplantation for canine blood disorders and a platform for solid organ transplantation

First, do no harm: the role of preclinical animal models in predicting adverse events in gene therapy clinical trials for Duchenne muscular dystrophy and X-Linked myotubular myopathy

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