ARTICLE IN PRESS Extensive neuroprotection by choroid plexus transplants in excitotoxin lesioned monkeys Dwaine F. Emerich, a, * Christopher G. Thanos, a Moses Goddard, a Stephen J.M. Skinner, b Marilyn S. Geany, b William J. Bell, a Briannan Bintz, a Patricia Schneider, a Yaping Chu, c Rangasamy Suresh Babu, c Cesario V. Borlongan, d Kim Boekelheide, e Susan Hall, e Bronwyn Bryant, e and Jeffrey H. Kordower c a LCT BioPharma, 4 Richmond Square, Providence, RI 02906, USA b Living Cell Technologies NZ Ltd., Auckland, New Zealand c Dept. Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA d Neurol/Inst Mol Med and Genetics/School of Graduate Studies, Medical College Georgia; Research and Affiliations Service Line, Augusta VAMC, Augusta, GA 30904, USA e Department of Pathology and Laboratory Medicine, Brown University, Providence, RI 02912, USA Received 10 January 2006; revised 4 April 2006; accepted 7 April 2006 Huntington’s disease (HD) results from degeneration of striatal neurons. Choroid plexus (CP) cells secrete neurotrophic factors, and CP trans- plants are neuroprotective in rat models of HD. To determine if similar neuroprotective effects could be obtained in primates, porcine CP was encapsulated in alginate capsules. PCR confirmed that the CP cells expressed transthyretin and immunocytochemistry demonstrated typi- cal ZO-1 and tubulin staining. In vitro, CP conditioned media enhanced the survival and preserved neurite number and length on serum deprived neurons. Cynomolgus primates were transplanted with CP- loaded capsules into the caudate and putamen followed by quinolinic acid (QA) lesions 1 week later. Control monkeys received empty capsules plus QA. Choroid plexus transplants significantly protected striatal neurons as revealed by stereological counts of NeuN-positive neurons (8% loss vs. 43% in controls) and striatum volume (10% decrease vs. 40% in controls). These data indicate that CP transplants might be useful for preventing the degeneration of neurons in HD. D 2006 Elsevier Inc. All rights reserved. Keywords: Choroid plexus; CNS transplantation; Alginate; Encapsulation; Neuroprotection Introduction Huntington’s disease (HD) is a devastating autosomal dominant neurodegenerative disorder that usually begins in midlife and is characterized by an intractable course of mental deterioration and progressive motor abnormalities that invariably results in death (Greenamyre and Shoulson, 1994). There are no effective treat- ments. Although medications may reduce the severity of chorea or diminish the behavioral symptoms, they do not increase patient survival or substantially improve quality of life (Shoulson, 1981). Unlike many other neurodegenerative diseases, the polyglutamine expression in HD permits an unequivocal diagnosis of HD early in life, even in utero (Conneally et al., 1984; The Huntington’s Disease Collaborative Research Group, 1993). The ability to identify presymptomatic individuals provides the opportunity to design interventions that could intercede far before the develop- ment of substantial neurodegeneration and the expression of behavioral changes. Accordingly, if therapies can be devised that preserve the structural and functional integrity of the striatum, they could potently forestall the onset and pace of functional decline in HD patients. Recent studies have demonstrated that intracerebral delivery of neurotrophic factors preserves multiple populations of striatal neurons, including GABAergic neurons in animal models of HD (Alberch et al., 2004; Araujo and Hilt, 1997, 1998; Davies and Beardsall, 1992; de Almeida et al., 2001; Emerich et al., 1996, 1997; Gratacos et al., 2001; Kells et al., 2004; McBride et al., 2003; Menei et al., 2000; Mittoux et al., 2000; Perez-Navarro et al., 1996, 1999, 2000). One intriguing means of delivering neurotrophic factors to the brain to potentially obviate the neurodegeneration that occurs with diseases such as HD is to transplant neurotrophic factor secreting cells into the region of cell loss. One source of transplantable cells is the choroid plexus (CP). In addition to its well-delineated role in CSF production and maintenance of extracellular fluid concen- trations throughout the brain, the CP secretes numerous endoge- nous neurotrophic factors with therapeutic potential (Chodobski and Szmydynger-Chodobska, 2001; Emerich et al., 2005; Stopa 0969-9961/$ - see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.nbd.2006.04.014 * Corresponding author. E-mail address: ed3fjm@aol.com (D.F. Emerich). Available online on ScienceDirect (www.sciencedirect.com). www.elsevier.com/locate/ynbdi YNBDI-01258; No. of pages: 10; 4C: 5, 7 DTD 5 Neurobiology of Disease xx (2006) xxx – xxx