Pig models of neurodegenerative disorders: Utilization in cell replacement‐based preclinical safety and efficacy studies

Abstract

An important component for successful translation of cell replacement-based therapies into clinical practice is the utilization of large animal models to conduct efficacy and/or safety cell dosing studies. Over the past few decades, several large animal models (dog, cat, nonhuman primate) were developed and employed in cell replacement studies; however, none of these models appears to provide a readily available platform to conduct effective and large-scale preclinical studies. In recent years, numerous pig models of neurodegenerative disorders were developed using both a transgenic approach as well as invasive surgical techniques. The pig model (naïve noninjured animals) was recently used successfully to define the safety and optimal dosing of human spinal stem cells after grafting into the central nervous system (CNS) in immunosuppressed animals. The data from these studies were used in the design of a human clinical protocol used in amyotrophic lateral sclerosis (ALS) patients in a Phase I clinical trial. In addition, a highly inbred (complete major histocompatibility complex [MHC] match) strain of miniature pigs is available which permits the design of comparable MHC combinations between the donor cells and the graft recipient as used in human patients. Jointly, these studies show that the pig model can represent an effective large animal model to be used in preclinical cell replacement modeling. This review summarizes the available pig models of neurodegenerative disorders and the use of some of these models in cell replacement studies. The challenges and potential future directions in more effective use of the pig neurodegenerative models are also discussed.

Molecular neuropathology of the synapse in sheep with CLN5 Batten disease

“…2013; Dolezalova et al. 2014). Demonstration of therapeutic effectiveness of a given treatment in a large animal model would provide a robust basis for subsequent translation to cohorts of human patients.…”

“…2013; Dolezalova et al. 2014). The growing availability of large animal models of neurodegeneration, including sheep and pigs, offers one solution to this problem, but it has yet to be established if the mechanisms underlying synaptic pathophysiology that have been identified in rodent and Drosophila models are conserved in larger species.…”

Mutated Huntingtin Causes Testicular Pathology in Transgenic Minipig Boars

“…Minipigs represent a desirable model for longitudinal safety studies and preclinical drug trials to fill the gap between rodent models and patients [6,7]. The advantage of minipigs is their resemblance with the human brain as well as with the whole body in terms of size, anatomy and physiology.…”

Time Course of Spinal Doublecortin Expression in Developing Rat and Porcine Spinal Cord: Implication in In Vivo Neural Precursor Grafting Studies

“…Animals were then placed into prone position and prepared for spinal cell grafting. To immobilize the lumbar spinal cord, animals were mounted into a spinal immobilization apparatus and the lumbar portion of the animal was lifted 5 00 above the operating table to eliminate respiration-caused spinal cord pulsation (Dolezalova et al 2014). A dorsal laminectomy of L2-L5 vertebrae, corresponding to L3-L6 spinal segments, was then performed and epidural fat removed using cotton swabs.…”