br Nonhuman primate models for transplantation
Nonhuman primate models for transplantation therapy: motor and non-motor manifestations of the MPTP lesion Methods that have been used to induce a parkinsonian state in NHPs include 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) administration (Emborg, 2007), 6-hydroxydopamine administration (Ungerstedt, 1968), and transduction with viral vectors to promote expression of specific proteins such as alpha synuclein (Orth et al., 2003; Decressac et al., 2011). Compared to other lesion-based models of PD including rotenone, paraquat, and 6-hydoxydopamine (Tanner et al., 2011), systemic administration of MPTP is most directly linked to human PD and the most common method to phenocopy PD in animal models (Langston et al., 1983; Langston, 1985). MPTP metabolites are taken up by dopamine neurons via the dopamine transporter and then function as an inhibitor to complex I of the mitochondrial respiratory chain in these Ruxolitinib (Schapira et al., 1989). For reasons that remain undetermined, dopamine neurons from the SNc are especially vulnerable to MPTP (Hantraye et al., 1993; Johannessen et al., 1985; German et al., 1992). Thus, the result of MPTP treatment is a neurodegenerative state that is similar to PD. In this section we review the consequences of MPTP induced lesions in rodents (4.1) and NHPs (4.2), including manifestation of both motor and non-motor symptoms.
The baboon as an optimal model for cell-based therapies for PD In this review, we have presented a detailed comparison of NHP biology with respect to the neuroanatomical, neurophysiological, immunological features pertinent to studying the transplantation of iPSC-derived neurons for treatment of PD. NHPs in general, and baboons in particular, offer considerable advantages over rodents as model systems for preclinical studies to optimize the efficacy and safety of a cell-based approach to the treatment of PD. Among NHPs, old world monkeys are particularly valuable for use in neurological transplantation studies because they share critical neuroanatomical commonalities with humans, including physical separation of the nuclei of the striatum (Bove and Perier, 2012), which is the primary target of SNc neurons, and a gyrencephalic brain (Wu et al., 2012). Old world monkeys also demonstrate age-related loss of TH+ neurons in the SNc and a correlated decline of motor and cognitive skills (Emborg et al., 1998). These age-related changes are not observed in new world monkeys (McCormack et al., 2004). Of the old world genera, rhesus macaques (Macaca mulatta) are the most commonly used NHP species in biomedical research, but are in high demand for HIV/AIDS studies. In contrast, the baboon is widely available and is equally homologous to humans at the genomic level as the rhesus, with both possessing genomes with at least 92% sequence identity to the human genome (Caccone and Powell, 1989; Rogers and Hixson, 1997). However, the advantages of NHP models are not without costs. Studies using NHPs typically require greater time to complete than those using rodents. With respect to PD, this includes the time needed to create a stable lesion in the primate using MPTP and the time required to observe a stable recovery post-transplantation. For example, injection of 6-hydroxydopamine directly into the rodent SNc can effectively ablate the SNc within 1–3days (Hokfelt and Ungerstedt, 1973). It is possible to use MPTP to lesion the SNc of a NHP within one week via intracarotid injections (Emborg et al., 2008) or high doses of systemically injected MPTP (Gonzalez et al., 2015). However, such methods often produce unwanted toxicity and highly variable lesions. The use of MPTP to create a stable lesion in NHPs requires administration of low doses over a period of two to three months (Drouot et al., 2004) with regular assessments for a period of six months to a year to ensure there is no spontaneous recovery (Potts et al., 2014). Following cell transplantation into mice, a stable recovery can typically be observed within one month (Gaillard and Jaber, 2011). In NHPs such as the baboon, however, motor activity does not return to baseline until at least six months after transplantation (Hallett et al., 2015). Thus, it could take 14–28months to observe both a stable lesion-induced motor deficit and a stable graft-mediated recovery in baboons.