It is an exciting era for human stem cell replacement therapies, with an abundance of preclinical data suggesting that cell transplants may provide a valid means of improving disease outcomes and with first-in-person clinical trials commencing around the world (Barker, Parmar, Studer, & Takahashi, 2017). The concept of cell therapies is predicated on the idea that transplantation of live cells into the brain can replace those cells lost to the disease. And, indeed, for Parkinson's disease (PD), it is now well established that human fetal and stem cell-derived neurons can survive long term in rodent models and in people with PD (Lane et al., 2022; Li et al., 2016), they can integrate into the host circuitry (Grealish et al., 2015) and they can alleviate functional deficits (Kirkeby et al., 2012; Kriks et al., 2011; Lelos, Morgan, et al., 2016; Lelos, Robertson, et al., 2016). While cell therapies for PD are perhaps the most clinically advanced, considerable work is being undertaken in other neurological diseases as well, such as Huntington's (HD) and stroke, demonstrating that cell therapies may be broadly applicable to a wide range of neurodegenerative conditions.

In order to progress cell therapies from an in vitro concept to a clinical treatment, it is fundamentally necessary to validate the safety and efficacy of a novel cell product in rodent models. Only after rigorous preclinical assessment, can clinical translation commence. As a result, a wide variety of preclinical models have been established, each one designed to address a particular scientific question, but equally each one associated with caveats and compromises.

Significant advances in the development of animal models of disease have seen the move from more crude neurotoxin models, which discretely damage specific neurons, to more sophisticated genetically modified rodent models and viral vector technologies, which more closely mimic the neuropathological features of the disease. Despite this advance in modeling disease, there are several specific challenges associated with the use of animal models for testing cell therapies. This chapter will explore some of these key challenges and will use PD and HD as prototypic conditions to highlight some disease-specific considerations. The primary focus will be on the use of mouse and rat models, given that these are the most readily accessible to the majority of researchers and they are used for most of preclinical validation assays (safety, efficacy, toxicology), although areas where large animal models would be of considerable benefit will be considered. In particular, this chapter will explore the challenges of (1) finding an optimal disease model, (2) ensuring cell survival in the context of a xenograft, (3) creating a model to test functional efficacy and (4) ensuring the complex interaction between the cell therapy and the clinical context is taken into consideration (Fig. 1).