NEURONAL TRANSPLANTATION AND ITS IMPLICATIONS IN PARKINSONS DISEASE - PowerPoint PPT Presentation

NEURONAL TRANSPLANTATION AND ITS IMPLICATIONS IN PARKINSON’S DISEASE 1. INTRODUCTION 2. ESSENTIAL ELEMENTS OF NEURONAL TRANSPLANTATION 3. CELL TYPES AND METHODS OF NEURONAL TRANSPLANTATION 4. NEURONAL TRANSPLANTATION IN ANIMAL MODELS OF PD 5. NEURONAL TRANSPLANTATION IN PD PATIENTS

Neuronal Transplantation 1. Most neurons must carry their function for an entire life – as they are not replaced if damaged by lesion or neuro- degenerative disorders 2. Cell replacement technique represents one of the advanced methods by which one can ameliorate dysfunction of the lesioned or damaged brain 3. It has clinical implication in neurodegenerative disorder for which there is no adequate medical treatments

Essential Elements of Neuronal Transplantation 1. DONOR AGE - embryonic tissue from active stage of embryogenesis ( Histogenesis – Cell migration – Differentiation – Maturation – Axon elongation and synaptogenesis) CNS Tissue In situ Histogenesis Suspension grafts Hippocampus E13 - P18 E15 - E16 Cortex E14 - E22 E15 - E20 Cerebellum E14 - P13 E13 - E15 (Developmental windows that are used for suspension grafts) 2. HOST AGE - influences survival and fiber outgrowth of graft 3. VASCULARIZATION - important factor determining graft survival

Neuronal Histogenesis Within the Rat CNS 4. IMMUNOLOGIC FACTORS - brain is an immunologic privilege site which leads to delayed immune response to the graft 5. TARGET ACCESS - Appropriate target area and denervation influence graft survival and growth Nigrostriatal pathway Neural graft Neurons in the Brain

Cell Types and Methods of Transplantation 1. Neuronal graft should always be placed at the terminal area and not at the site of cellular origin Forebrain cholinergic pathway Nigrostriatal pathway Target area CORTEX CORTEX Target area HIPPO HIPPO MS MS BAS BAS DBN DBN Site of Cellular Origin Site of Cellular Origin Methods of Neuronal Transplantation: 1. Transplantation of embryonic tissues 2. Transplantation of Genetically modified cells 3. Transplantation of Polymer-encapsulated cells

Cell Types and Methods of Transplantation 1. Transplantation of embryonic tissues: a) solid tissue pieces b) cell suspension Advantages : a) good graft survival b) regulated release Disadvantages : a) ethical issues b) limited availability of fetal tissue Rat Brain Human Brain

Cell Types and Methods of Transplantation 2. Genetically modified cells: a) immortalized cells b) primary cells Essential genes/DNA: a) Growth factor (NGF) – cells genetically modified to produce NGF can prevent degeneration of cholinergic neurons following fimbria-fornix lesion b) affected neurotransmitter/modulator enzymes – cells genetically modified to produce TH/L-DOPA can ameliorate behavioral deficits in animal models of PD Disadvantages : a) unregulated secretion b) poor survival of graft

Cell Types and Methods of Transplantation 3. Polymer-encapsulated cells: comprise of a selective barrier that allows free transport of low but not high molecular weight molecules. Encapsulated PC12 cells can ameliorate behavioral deficits in animal models of PD. Advantages : a) use of unmatched tissue b) without danger of tumor formation c) can be retrieved in case of detrimental effects Disadvantages : a) unregulated secretion

Neuronal Transplantation and PD - loss of dopaminergic neurons of the substantia nigra projecting to striatum - characterized by akinesia, rigidity, tremor and postural abnormalities - phamacological treatments: administration of L-DOPA or the use certain drugs (e.g., bromocriptine) in conjunction with L-DOPA - this treatment has limited long-term success and does not prevent ongoing neuronal degeneration Affected in PD

Neuronal Transplantation in Animal Models of PD 1) unilateral lesion of the nigrostriatal pathway with 6-hydroxydopamine Lesion-induced changes - loss of dopaminergic cells along with a drug-induced stereotypical rotational behavior Transplantation - nigral tissue – promotes recovery of the drug-induced rotational Contralateral Ipsilateral behavior and sensorimotor deficits for 2-7 months - medullary chromaffin cells, fibroblast genetically modified to produce TH and polymer encapsulated PC12 or GDNF producing cells – promotes only partial recovery - mouse embryonic stem cells – significantly ameliorates drug-induced rotational behavior for up to 5-9 weeks following lesion 2) bilateral lesion of the nigrostriatal pathways with MPTP Lesion-induced changes - loss of dopaminergic cells along with behavioral changes such as tremor, freezing and difficulty in movements Transplantation - nigral tissue – produces significant recovery in behavior until 7-8 months - medullary chromaffin cells and polymer encapsulated PC12 cells – promotes only partial recovery

Neuronal Transplantation in PD Patients 1. Transplantation with adrenal medullary cells The first clinical trials were undertaken in early 1980s in Sweden with only minimal benefits Madrazo et al. (1987) placed the grafts in contact with the CSF and reported improvement in motor and cognitive function for at least 1 year This was replicated by other groups in about 390 patients Autopsy results revealed either few or no surviving cells within the graft High mortality and morbidity outweigh the modest and transient improvements

Neuronal Transplantation in PD Patients 2. Transplantation with embryonic ventral mesencephalic mesencephalic cells cells 2. Transplantation with embryonic ventral Open label studies showed that grafted dopaminergic neurons can survive and mature and can alleviate the debilitating tremors associated with the disease. The first double-blind placebo controlled trial (placebo control = 20 and transplants = 20) showed some improvements in UPDRS score for one year in younger (<60 yrs) but not older group of patients. (C.R. Freed et al., 2001) Transplanted cells survived but, dystonia and dyskinesias recurred after 1st year in 15% of the patients. The second double-blind trial in 34 PD patients (placebo control = 11 and transplants with one or four donors = 23) showed only limited benefit on clinical outcomes despite good graft survival. (C.W. Olanow et al., 2003) Dyskinesias were present in a significant number of transplanted patients

18 F-Fluorodopa Uptake in the brains of PD patients with or without Transplantation Change in 18 F-Fluorodopa Uptake in the Brains of Patients with Parkinson's Disease after Transplantation, as Shown in Fluorodopa PET C.R. Freed et al., 2001, N. Eng. J. Med. 344: 710-719.

Dopaminergic Neurons in Transplanted PD Patients Surviving Dopaminergic neurons in PD patients treated with transplantation C.R. Freed et al., 2001, N. Eng. J. Med. 344: 710-719.

18 F-Fluorodopa Uptake in the brains of PD patients with or without Transplantation PET images of striatal fluorodopa uptake at baseline, 1 year, and 2 years in patients receiving transplantation with one donor per side (a), four donors per side (b), or a placebo procedure (c). C. W. Olanow et al., Ann Neurol. (2003) 54, 403-414

Dopaminergic Neurons in Transplanted PD Patients TH-immunostained sections through the striatum of patients receiving transplantation with one donor per side (A, B), four donors per side (C, D), and placebo (E, F) CD45 immunostaining, a measure of activated microglia and immune reactivity, in the one donor (A, B), four donors (C, D), and placebo (E, F) groups. Note that CD45 staining is increased in the one and four donor groups compared with placebo. These show some immune rejection in transplanted groups and may account for the clinical deterioration C. W. Olanow et al ., Ann Neurol. (2003) 54, 403-414