Paul R. Sanberg

Fetal-Tissue Transplantation for Huntington’s Disease: Preclinical Studies

Huntington’s disease (HD) is a neurodegenerative disorder transmitted by a single autosomal dominant gene. This normally occurring Huntington gene is mutated in HD. This HD mutation involves an unstable DNA segment; the IT15 gene, which is located near the telomere of the short arm of chromosome 4, contains a trinucleotide repeat (CAG) that is expanded (> 36) and unstable (1). Clinically, HD is characterized by constant, uncontrollable choreiform movements of the body coupled with progressive deterioration of the patient’s mental status (2,3), which ultimately leads to death.

Preclinical Basis for Use of NT2N Cells in Neural Transplantation Therapy

This chapter will review laboratory experiments using human neuroteratocarcinoma cells (hNT cells, also called NT2N cells and LBS neurons) in animal models of neurological disorders. Because NT2N cells are originally derived from adult human cancerous tumors engineered to become neuron-like cells, their use for transplantation therapy eliminates logistical problems associated with the use of fetal and embryonic stem cells. This chapter will focus on functional recovery in stroke animals that received NT2N cell grafts. In light of recent studies demonstrating expression of trophic factors by NT2N cells, such trophic factor property of the cells is presented here as a plausible mechanism underlying the behavioral effects of transplanted NT2N cells. An overview on the clinical report of NT2N cell grafts in stroke patients will also be provided.

Rodent Ischemia Models of Embolism and Ligation of the Middle Cerebral Artery

This chapter focuses on two models of cerebral ischemia: embolism and ligation of the middle cerebral artery (MCA). Advantages and disadvantages of MCA embolism and ligation are discussed in relation to establishing an appropriate model of stroke. In addition, the clinical relevance of each technique to the development of experimental treatment strategies is outlined, highlighting recent novel therapeutic modalities, including neural transplantation and intracerebral infusion of neurotrophic factors. Prior to discussing these two treatment strategies, an overview of the current status of pharmacologic intervention for stroke is provided, and we present critical problems (i.e., therapeutic window) inherent in drug therapy that limit its efficacy in the clinic. It is believed that the experimental evidence presented here will encourage further utilization of embolism and ligation models of cerebral ischemia in rodents as suitable animal models of stroke, and more importantly, should caution researchers and clinicians alike about critical scientific issues (i.e., early stage development of treatment strategies for stroke) that warrant validation in the laboratory setting prior to proceeding with clinical interventions.

Neural Transplantation and Huntington’s Disease

Neural transplantation as a treatment modality for patients suffering from neurodegenerative disorders (e.g., Parkinson’s disease [PD]) has produced encouraging results. In recently conducted clinical trials, neural transplantation of human fetal ventral mesencephalic dopamine-secreting cells (the major type of cells that degenerates in PD) into the brains of PD patients has been demonstrated to ameliorate the clinical symptoms of the disease (1,2). Concrete evidence detailing clinical improvement following fetal dopaminergic cell transplantation has been reported previously in PD patients (3,4). For the first time, direct histopathological evidence became available from a transplanted PD patient, who died more than 16 mo posttransplantation of complications unrelated to the transplant procedure. Viable neural grafts were shown to integrate with the host tissue, and thus fetal tissue transplantation has been implicated as directly promoting symptomatic relief to the patient (1,2). In an attempt to circumvent logistical and ethical problems with using human fetal grafts, porcine fetal cells have been directly transplanted in PD patients and positive preliminary results have been reported (5). Other non-neural graft sources that are being examined at the preclinical level include Sertoli cells (6), carotid body cells (7), and kidney cells (8), all of which have been suggested as dopamine-or neurotrophic factor-enriched cells.

Asymmetrical Motor Behavior in Animal Models of Human Diseases

This chapter will address primarily the behavioral characterization of lesion effects in the central nervous system (CNS). Animal models of Parkinson’s (PD) and Huntington’s disease (HD) will be discussed with emphasis on the novel “elevated body swing test” (EBST) in characterizing the behavioral deficits following unilateral CNS lesions. Advantages of the drug-free EBST paradigm over the conventional drug-induced rotational test in unilaterally lesioned rats will be presented. Because basal ganglia dysfunction underlies the pathophysiology of these two clincial disorders, it is appropriate to begin with an introduction of the basal ganglia.