The Neurosciences Institute, which is associated with Good Samaritan Hospital in Los Angeles, sponsored a symposium on Nov. 2-3, 1996 in Rancho Mirage, CA. Dr. Kopyov made his presentation there. I thank Carole Hilton for making this information available to the Parkinsn archives. Neurotransplantation for Parkinson's disease and Huntington's disease Oleg V. Kopyov, PhD, MD INTRODUCTION Neurotransplantation represents a potential for neurodegenerative diseases with a focused region of cell death Its potential is based on the strategy of neuronal replacement with developing fetal neurons, which can establish connections with the remaimng host neurons to restore functionality to the region. This rationale is supported by animal studies which have demonstrated that in models of Huntington's and Parkinson's disease, transplanted fetal tissue integrates with host brain and ameliorates some behavioral deficits. while this approach may provide a new means of treatment for intractable disease, some concerns remain as to the safety of placing partially characterized fetal tissue into the brains of disease patients. The foremost of these concerns along these lines are the risk of tissue overgrowth which might crowd the existing brain tissue, the risk of intraparenchymal infection, and the possibility that the risks of neurosurgery will not be balanced by the benefits of neurotransplantation. Transplantation of fetal tissue for two Parkinson's disease patients has recently demonstrated that neurotransplantation was a safe and feasible procedure for PD patients. The many patients which have now undertaken transplantation for PD have generally demonstrated good outcomes, with enough improvement in movement dysfunctions to outweigh the risks of neurosurgery. Tissue grafts appear to survive well within the brain, and motor deficits are improved in most patients receiving transplants. None of the patients receiving fetal grafts have demonstrated any evidence of graft overgrowth, nor have they become infected as a result of transplantation despite prolonged periods of immunosuppression to prevent graft rejection. The positive results of neurotransplantation for PD have led to consideration of fetal neurotransplantation to ameliorate the symptoms of HD. Transplants of fetal striatum (a region termed the lateral ganglionic eminence; (LGE) placed in the lesioned striatum of adult rats have been shown to survive, integrate with the host, and express markers typical of striatal tissue. Grafts of human fetal striatal precursors placed into rat striatum have demonstrated striatal markers and outgrowth which was constrained to anatomically appropriate regions. These rats demonstrated functional recovery from the strintal lesion as well. Together with the clinical findings that neurotransplantation can be an effective treatment for PD, these animal studies suggest that transplantation may be safely undertaken for HD patients. Given the evidence of potential benefits of neurotransplantation for HD patients, and the lack of any other effective treatment, the Neurosciences Institute has undertaken transplantation for a small number of carefully chosen HD patients. The first three HD transplantation patients have been evaluated up to 44 weeks following surgery. MR images of the transplants demonstrate contained, healthy grafts with no overgrowth and suggest that neurotransplantation is safe for HD patients. METHODS This protocol was approved by the Institutional Review Board of Good Samaritan Hospital, Los Angeles (IRB# 95-04-06). Diagnostic criteria and implementation of this protocol were based on recommendations from the Core Assessment Program for Intracerebral Transplantation for Huntington's Disease (CAPIT- HD). Inclusion and exclusion criteria are presented in Table 1. Bach patient understood and signed an informed consent form, and then entered a baseline evaluation after the diagnosis of HD was confirmed through DNA analysis and MR imaging revealing the presence of atrophied caudate and putamen of a size sufficient to permit the stereotactic implantation of five needle tracks in each hemisphere. The baseline evaluation phase lasted for 3 to 6 months. During this time, patients' neurological status was evaluated by a neurologist utilizing a videotaped motor and functional assessment utilizing the Unified Huntington's Disease Rating Scale (UHDRS). MRI and deoxyglucose PET scans were performed 6 and 12 months after surgery. The MRI images obtained immediately prior to surgery were used to calculate stereotactic coordinates for one needle track in the caudate nucleus and four in the putamen using GammaPlan software (Version 2.01, Flekta, Sweden). RESULTS The clinical neurological outcomes of the patients demonstrated substantial improvement in balance and mobility within two weeks following surgery, as shown by increased ability to walk and stand without assistance. The changes in behavioral symptoms such as aggressive or disruptive behavior and depressive episodes were variable, with frequency and intensity decreased in two patients and increased in one. Chorea and dystonia were decreased in all patients. All patients displayed increased ability to function in daily tasks ranging from taking own medications to dressing oneself and preparing meals. When evaluated six months following surgery, these improvements remained steady or increased. Patients will continue to be evaluated for future changes in symptoms. All three patients recovered well from surgery, with no adverse effects noted. Patient profiles are presented in Table 2. The day following surgery, MR images demonstrated four transplantation tracks placed into the putamen and one needle track in the caudate nucleus of each hemisphere, as targeted. In all patients the grafting sites demonstrated minimal edema. Five to six months following surgery, MR images demonstrated no evidence of edema. An intermediate signal intensity was visible in the striatum at the site of the fetal implants This signal was increased in intensity over that observed in the previous postoperative images, which is consistent with fetal tissue growth. Although larger, the bodies of the grafts were constrained within the confines of the striatum such that the contours of the fetal grafts reflected those of the striatum. Narrow streaks of increased signal intensity were apparent extending from the fetal grafts toward the internal capsule, however, suggesting extension of processes from the grafts to the host tissue. In the first patient, new areas of low density were observed within the right caudate nucleus and basal ganglia. These areas exhibited a signal similar to that of cerebrospinal fluid, suggesting that they may represent regions of porencephaly or remote infarct. No discrete changes were observed in the left caudate nucleus of this patient. DISCUSSION The success of neurotransplantation in the treatment of Parkinson's disease, has raised its consideration as an option for Huntington's disease patients. The current study reports on the treatment of three HD patients with neurotransplantation, and describes the morphological outcomes as visualized with MRI. Together with clinical improvements in symptoms and mobility, these results provide evidence that neurotranspiantation is a safe procedure for HD patients. A primary concern with grafting tissue to the brain is unconcontrolled graft overgrowth. None of the three patients receiving intrastriatal neurotransplantation of human fetal LGE exhibited graft overgrowth six months following grafting. This finding agrees with the majority of transplantation studies performed in rats and primates, which have reported constrained growth of fetal allografts. Transplantation of nigral tissue for PD has not been shown to result in graft overgrowth in any patient. The constrained distribution of the fetal LGE grafts in the present HD patients provides support for the safety of striatal neurotransplantation. The grafted tissue did demonstrate a constrained degree of growth within the striatum, which is consistent with the natural growth of fetal tissue during the course of six months. Fine tissue processes were also observed to extend medially from the graft bodies. These processes resemble those observed in animal studies of neurotransplantation. In the rat, grafts of fetal rat LGE and MGE placed in denervated striatum extend processes to appropriate target regions, establishing functional connections. The presence of such extensions emanating from fetal grafts in HD patients suggest that these grafts may be establishing similar connections with previous targets of the degenerated striatum. In one patient, a postsurgery complication became visible on MR images, appearing to be either porencephaly or remote infarct. The patient has not displayed any adverse effects which may be attributable to such a complication, although he has exhibited a lesser degree of improvement than the other two patients. These clinical and morphological outcomes of the first three HD patients to receive fetal striatal neurotranspiantation has demonstrated that there is no uncontrolled overgrowth of the transplanted tissue, and that the potential benefits from the procedure do appear to merit the risks of neurosurgery. These results provide evidence for the safely of neurotransplantation HD patients. The potential of this approach as a treatment for HD will be further pursued, following the same standardized guidelines to select and evaluate future patients. [log in to unmask] That man may last, but never lives, Who much receives, but nothing gives; HomeBoy #Parkinsons Whom none can love, whom none can thank,-- Creation's blot, creation's blank. John Cottingham Thomas Gibbons (1720-1785): When Jesus dwelt.