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Lancet: Volume 353, Supplement 1 24 April 1999 Topical issues in selected specialties: Neural transplantation for neurodegenerative disorders Cesario V Borlongan, Paul R Sanberg, Thomas B Freeman Lancet 1999; 353 (suppl I): 29-30 Cellular Neurobiology Branch, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland, USA (C V Borlongan PhD); and Department of Neurological Surgery, Department of Pharmacology and Experimental Therapeutics, University of South Florida College of Medicine, Tampa, FL, USA (P R Sanberg DSc, T B Freeman FACS) Correspondence to: Dr Thomas Freeman, Department of Neurological Surgery, University of South Florida College of Medicine, Tampa 33613, USA Neural transplantation has a century-long history, but the modern era of transplantation began in the 1970s. Parkinson's disease (PD) was the first neurodegenerative disorder to be treated with transplant techniques because symptoms are secondary to the loss of a limited number of nigrostriatal dopaminergic neurons. The initial success of levodopa treatment for PD suggested the feasibility of dopamine-replacement therapy by neural transplantation, and the small size of the striatum (or caudate putamen in human beings), which becomes dopamine-denervated in PD, makes it an easily accessible target for transplantation.1 Preclinical studies since the early 1980s showed that tissue grafts of dopamine-rich fetal ventral mesencephalon survive, reinnervate the brain, and improve parkinsonian symptoms in rodents and non-human primates.2 On the basis of encouraging laboratory findings, clinical trials of neural transplantation were started in the late 1980s. Parkinson's disease Several clinical centres have reported preliminary data that transplantation of fetal tissue is beneficial for some PD patients, with some centres obtaining more reproducible results than others. To date, more than 300 PD patients world wide have received neural transplants of embryonic ventral mesencephalic tissue. Of these patients, three have died because of the surgery, and 11 from causes unrelated to the procedure.1 Clinical trials of transplantation of fetal neural tissue were pioneered by Lindvall and colleagues in Sweden. Subsequent trials of unilateral intrastriatal transplants by these investigators showed graft-derived improvements on fluorodopa positron-emission tomography (FD-PET) and in rigidity, hypokinesia, dyskinesia, and the percentage of time in the "off" state for up to 4 years. Patients gradually deteriorated during years 4-7 post transplantation, most probably because of disease progression on the non-transplanted side.3 These promising results obtained in Sweden prompted similar procedures in the USA, France, England, Canada, Spain, Mexico, Japan, Cuba, Poland, Russia, and China. The first histological evidence that clinical benefits directly correlated with survival of grafted fetal dopaminergic neurons was reported in 1995,1,4,5 and came from the brains of two bilaterally transplanted PD patients who died from causes unrelated to surgery. Examination of the grafted tissue in PD patients who displayed improvements clinically and on FD-PET showed that robust graft survival was characterised by variable neuritic outgrowth (2·5-7 mm within the striatum and 11 mm within white-matter tracts) extending towards and forming synaptic connections with the host tissue, but no host sprouting was observed.1,4 The graft reinnervated up to 78% of the target region, producing a morphological picture typical of normal striatal innervation (figure). The grafted cells were spared from the neurodegenerative process. Grafts were metabolically active, could take up, synthesise, and store dopamine, and had intact blood-brain barriers. All grafts survived in the absence of any immunosuppression for at least 1 year. Neural transplantation remains experimental. At best, moderate clinical improvement has been observed. Graft success can be influenced by several technical variables, including donor age, technique of tissue storage, method of graft preparation, number of donors, distribution of graft tissue, site of implantation, whether transplantation is done unilaterally or bilaterally, and concomitant treatment with trophic factors and anti-oxidants.1,6 Clearly, there are numerous ways to improve grafting strategies for the treatment of PD. There are two prospective, randomised, surgical placebo-controlled trials funded by the US National Institutes of Health that are in progress. They are designed to assess the safety, tolerability, and efficacy of fetal nigral transplantation for the treatment of PD. The results of one of them, conducted by the University of Colorado and Columbia Presbyterian Medical Center in New York, are likely to be presented in mid-1999. The second trial, done collaboratively at Mt Sinai Medical Center in New York, the University of South Florida in Tampa, and Rush Presbyterian Medical Center in Chicago, is enrolling its last few patients. There are several technical differences between these studies, and results may therefore vary. However, the designs are appropriate for the assessments of novel cellular therapies and are based on designs for pharmaceutical trials. They include the use of placebo controls. Alternatives to human fetal tissue as a graft source are being developed. Novel cell types have been transplanted in laboratories or in phase I clinical studies. These include porcine cells, differentiated human neuronal cells derived from teratocarcinoma cell-lines, testis-derived Sertoli cells, genetically engineered cells, and human neural stem cells.7-10 Logistical and ethical concerns associated with the use of fetal tissues may be avoided by the use of non-fetal cells. Huntington's disease and stroke Human and porcine embryonic striatal cells have been transplanted in patients with Huntington's disease,10,11 and cells from a human cell-line derived from neuroteratocarcinoma neurons have been implanted in stroke patients.8 The safety of fetal spinal-cord transplants for the treatment of syringomyelia is also being investigated. Data from these trials are limited, anecdotal, and preliminary. Conclusion With neural reconstruction strategies being assessed for the treatment of progressively complex neurological diseases, and with the possibility that the development of cell-lines might soon replace the need for human fetal tissue, neural transplantation could soon evolve into proven therapy. References <SNIP>