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Neural transplantation for neurodegenerative disorders

1999; Elsevier BV; Volume: 353; Linguagem: Inglês

10.1016/s0140-6736(99)90229-5

1474-547X

Cesar V. Borlongan, Paul R. Sanberg, Thomas B. Freeman,

Neurological disorders and treatments

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.1Freeman TB Olanow WC Hauser RA et al.Human fetal tissue transplantation.in: Germano IM Neurosurgical treatment of movement disorders. American Association of Neurological Surgeons, Park Ridge1998: 177-192Google Scholar 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.2Lindvall O Prospects of transplantation in human neurodegenerative diseases.Trends Neurosci. 1991; 14: 376-384Summary Full Text PDF PubMed Scopus (119) Google Scholar On the basis of encouraging laboratory findings, clinical trials of neural transplantation were started in the late 1980s. 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.1Freeman TB Olanow WC Hauser RA et al.Human fetal tissue transplantation.in: Germano IM Neurosurgical treatment of movement disorders. American Association of Neurological Surgeons, Park Ridge1998: 177-192Google Scholar 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.3Wenning GK Odin P Morrish P et al.Short-and long-term survival and function of unilateral intrastriatal dopaminergic grafts in Parkinson's disease.Ann Neurol. 1997; 42: 95-107Crossref PubMed Scopus (319) Google Scholar 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 1995,1Freeman TB Olanow WC Hauser RA et al.Human fetal tissue transplantation.in: Germano IM Neurosurgical treatment of movement disorders. American Association of Neurological Surgeons, Park Ridge1998: 177-192Google Scholar, 4Kordower JH Freeman TB Chen E-Y et al.Fetal nigral grafts survive and mediate clinical benefit in a patient with Parkinson's disease.Movt Dis. 1998; 13: 383-393Crossref PubMed Scopus (232) Google Scholar, 5Hauser RA Freman TB Snow BJ et al.Long-term evaluation of bilateral fetal nigral transplantation in Parkinson's disease.Arch Neurol. 1999; 56: 179-187Crossref PubMed Scopus (300) Google Scholar 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.1Freeman TB Olanow WC Hauser RA et al.Human fetal tissue transplantation.in: Germano IM Neurosurgical treatment of movement disorders. American Association of Neurological Surgeons, Park Ridge1998: 177-192Google Scholar, 4Kordower JH Freeman TB Chen E-Y et al.Fetal nigral grafts survive and mediate clinical benefit in a patient with Parkinson's disease.Movt Dis. 1998; 13: 383-393Crossref PubMed Scopus (232) Google Scholar 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.1Freeman TB Olanow WC Hauser RA et al.Human fetal tissue transplantation.in: Germano IM Neurosurgical treatment of movement disorders. American Association of Neurological Surgeons, Park Ridge1998: 177-192Google Scholar, 6Hoffer BJ Olson L Treatment strategies for neurodegenerative diseases based on trophic factors and cell transplantation techniques.J Neural Transm. 1997; 49: 1-10Google Scholar 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.7Flax JD Aurora S Yang C et al.Engraftable human neural stem cells respond to developmental cues, replace neurons, and express foreign genes.Nat Biotechnol. 1998; 16: 1033-1039Crossref PubMed Scopus (668) Google Scholar, 8Brustle O Choudhary K Karram K et al.Chimeric brains generated by intraventricular transplantation of fetal human brain cells into embryonic rats.Nat Biotechnol. 1995; 11: 1040-1044Google Scholar, 9Borlongan CV Tajima Y Trojanowski JQ Lee VM Sanberg PR Transplantation of cryopreserved human embryonal carcinoma-derived neurons (NT2N cells) promotes functional recovery in ischemic rats.Exp Neurol. 1998; 149: 310-321Crossref PubMed Scopus (276) Google Scholar, 10Isacson O Breakefield XO Benefits and risks of hosting animal cells in the human brain.Nat Med. 1997; 9: 964-969Crossref Scopus (64) Google Scholar Logistical and ethical concerns associated with the use of fetal tissues may be avoided by the use of non-fetal cells. Human and porcine embryonic striatal cells have been transplanted in patients with Huntington's disease,10Isacson O Breakefield XO Benefits and risks of hosting animal cells in the human brain.Nat Med. 1997; 9: 964-969Crossref Scopus (64) Google Scholar, 11Philpott LM Kopyov OV Lee AJ et al.Neuropsychological functioning following fetal striatal transplantation in Huntington's chorea: three case presentations.Cell Transplant. 1997; 6: 203-212Crossref PubMed Scopus (114) Google Scholar and cells from a human cell-line derived from neuroteratocarcinoma neurons have been implanted in stroke patients.8Brustle O Choudhary K Karram K et al.Chimeric brains generated by intraventricular transplantation of fetal human brain cells into embryonic rats.Nat Biotechnol. 1995; 11: 1040-1044Google Scholar 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. 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.