Neural Transplantation: BBS Call for Commentators

BBS Special Issue CONTROVERSIES IN NEUROSCIENCE II: Neural Transplantation Below are the abstracts of 3 forthcoming target articles for a special issue on Neural Transplantation that will appear in Behavioral and Brain Sciences (BBS), an international, interdisciplinary journal that provides Open Peer Commentary on important and controversial current research in the biobehavioral and cognitive sciences. This will be the second in a new series called "Controversies in Neuroscience," undertaken in collaboration with Paul Cordo and the RS Dow Neurological Science Institute. Commentators must be current BBS Associates or nominated by a current BBS Associate. To be considered as a commentator on any of these articles, to suggest other appropriate commentators, or for information about how to become a BBS Associate, please send email to: harnad(a)clarity.princeton.edu or harnad(a)pucc.bitnet or write to: BBS, 20 Nassau Street, #240, Princeton NJ 08542 [tel: 609-921-7771] Please specify which article or articles you would like to comment on. (Commentators are allotted 1000 words to comment on one article, 1750 words to comment on two, and a maximum of 2250 words to comment on all three target articles.) To help us put together a balanced list of commentators, please give some indication of the aspects of the topic on which you would bring your areas of expertise to bear if you were selected as a commentator. Within the next week or so, electronic drafts of the full text of each article will be available for inspection by anonymous ftp, archie, gopher or versonica on host princeton.edu directory pub/harnad/BBS according to the instructions that follow after the abstracts. These drafts are for inspection only; please do not prepare a commentary until you are formally invited to do so. 1. NEURAL TRANSPLANTATION AND RECOVERY OF COGNITIVE FUNCTION John D. Sinden, Helen Hodges & Jeffrey A. Gray Filename: bbs.sinden 2. FETAL BRAIN TISSUE GRAFTS AS THERAPY FOR BRAIN DYSFUNCTIONS Donald G. Stein & Marylou M. Glasier Filename: bbs.stein 3. GENE REPLACEMENT THERAPY IN THE CENTRAL NERVOUS SYSTEM Edward A.Neuwelt, Michael A. Pagel, Leslie L. Muldoon & Alfred Geller Filename: bbs.neuwelt --------------------------------------------------------------------- 1. NEURAL TRANSPLANTATION AND RECOVERY OF COGNITIVE FUNCTION John D. Sinden, Helen Hodges & Jeffrey A. Gray Department of Psychology Institute of Psychiatry De Crespigny Park Denmark Hill London SE5 8AF England spjtjds(a)ucl.ac.uk jgray(a)ux.psych.lon.ac.uk KEYWORDS: Cholinergic system, cerebral ischaemia, cognitive function, diffuse versus point-to-point neuronal systems, neural grafts. ABSTRACT: Cognitive deficits were produced in rats using different methods of damaging the brain: chronic ingestion of alcohol, causing widespread damage to diffuse cholinergic and aminergic projection systems; lesions (by local injection of the excitotoxins, ibotenate, quisqualate and AMPA) to the nuclei of origin of the forebrain cholinergic projection system (FCPS), which innervates the neocortex and hippocampal formation; transient cerebral ischaemia, producing focal damage, especially in the CA1 pyramidal cells of the dorsal hippocampus; and lesions (by local injection of the neurotoxin, colchicine) to the granule cells of the dentrate gyrus. Following chronic alcohol or lesions of the FCPS, transplants of cholinergically rich fetal brain tissue into the terminal areas (neocortex or hippocampus) restored performance almost to control levels, with a time-course consistent with growth of the transplants and integration with host tissue; transplants of cholinergically poor fetal tissue (hippocampus) were without effect, as were transplants of cholinergically rich tissue into the region containing the nuclei of origin of the FCPS. Grafts of primary cells enriched in glia and cultured neuroblastoma cells into the terminal areas of the FCPS were equally effective, suggesting that there are multiple mechanisms by which neural transplants can restore cognitive function following diffuse cholinergic damage. In contrast, after ischaemia- or neurotoxin-induced damage to CA1 or dentate granule cells respectively, cholinergically rich fetal transplants into the damaged hippocampal formation were ineffective in restoring performance. However, after ischaemic damage, performance was restored by suspension grafts of CA1 cells but not by transplants containing CA3 pyramidal cells or granule cells; and after colchicine damage, performance was restored by solid grafts containing granule but not CA1 pyramidal cells. Furthermore, electrophysiological evidence has demonstrated functional, graft type-specific host-graft fuctional neuronal connectivity. Thus, restoration of cognitive function by neural transplants is possible after damage to either diffuse (cholinergic) or point-to-point (intrahippocampal) forebrain systems, but the transplant must be appropriate to the damage to be repaired. Since the different types of brain damage studies provide partial analogues of human alcoholic dementia, Alzheimer's disease and heart attack, these results are encouraging with regard to the eventual application of neural transplant surgery to the treatment of cognitive deficits in humans. ----------------------------------------------------------------------- 2. FETAL BRAIN TISSUE GRAFTS AS THERAPY FOR BRAIN DYSFUNCTIONS: SOME PRACTICAL AND THEORETICAL ISSUES Donald G. Stein & Marylou M. Glasier Laboratory of Brain Research and CNS Plasticity Institute of Animal Behavior Rutgers University Newark, NJ 07102 stein(a)draco.rutgers.edu KEYWORDS: Brain damage; functional recovery; grafts; neural grafts; neural transplants ABSTRACT: Grafting embryonic neural tissue into the brains of adult patients is currently being used to treat Parkinson's disease and is being given serious consideration as therapy for a variety of other degenerative and traumatic disorders. This target article evaluates the use of transplants to promote recovery from brain injury and highlights the kinds of questions and problems that must be addressed before this form of therapy is routinely applied. It has been argued that neural transplantation can promote functional recovery through the replacement of damaged nerve cells, the reestablishment of specific nerve pathways lost as a result of injury, the release of specific neurotransmitters, or the production of factors that promote neuronal growth. The latter two mechanisms, which need not rely on anatomical connections to the host brain, are open to examination through nonsurgical, less intrusive therapy. Subjective judgments in selecting which patients will receive grafts and in assessing the outcome of graft therapy make evaluation of the procedure methodologically difficult. In addition, little long-term assessment of transplant efficacy and effect has been done in nonhuman primates. Carefully controlled human studies, with multiple testing paradigms, are also needed to establish the efficacy of transplant therapy. ----------------------------------------------------------------------- 3. GENE REPLACEMENT THERAPY IN THE CENTRAL NERVOUS SYSTEM: VIRAL VECTOR MEDIATED THERAPY OF GLOBAL NEURODEGENERATIVE DISEASE Edward A.Neuwelt, Michael A. Pagel, Leslie L. Muldoon Oregon Health Sciences University, Portland OR 97201 Alred Geller Children's Hospital Boston, MA 02115 KEYWORDS: adenovirus; blood-brain barrier; gene therapy; herpes virus; pHexosaminidase ABSTRACT: This target article describes the current state of global gene replacement in the brain through the use of viral vectors and it assesses possible solutions to some of the many problems inherent in gene therapy for the central nervous system (CNS). Gene replacement therapy is a way to generate normal human proteins in deficient cells, making cures possible for certain genetically inherited enzyme deficiences, metabolic diseases, and cancers. The two major issues to be addressed are the delivery of genetic material to the brain and the expression of recombinant genetic material in CNS target cells. Focal inoculation of recombinant virions or other genetic vectors has limitations when there is global brain disease. A new blood-brain-barrier (BBB) disruption technique, in which hypertonic mannitol transiently shrinks the BBB endothelium, allows the passage of high molecular weight compounds and even viruses. CNS gene therapy will require a viral vector system that allows long-term, nontoxic gene expression in neurons or glial cells. Retroviral vectors have limitations in CNS gene replacement, although they are suitable for expressing recombinant genes in intracerebral grafts, or toxic genes in brain tumors. Mutant neurotropic viruses with reduced neurotoxicity (e.g., defective herpes simplex virus type 1 [HSV-1], the HSV-1 amplicon vector system we have developed, or adenovirus mutants) have potential for direct treatment of neurons. Injecting these vectors into rodent brains can lead to the stable expression of foreign genetic material in postmitotic neuronal cells. We discuss our BBB disruption delivery technique, our defective HSV-1 aplicon vector system, and our feline model for the neuronal lysosomal storage disorder Gm2-gangliosidosis (Sandhoff disease), which may prove to be a useful model system for CNS gene therapy. ---------------------------------------------------------------------- To help you decide whether you would be an appropriate commentator for this article, electronic drafts are retrievable by anonymous ftp from princeton.edu according to the instructions below (the filenames are bbs.sinden bbs.stein and bbs.neuwelt). Please do not prepare a commentary on these drafts. Just let us know, after having inspected them, what relevant expertise you feel you would bring to bear on what aspect of each article. ------------------------------------------------------------- To retrieve a file by ftp from a Unix/Internet site, type either: ftp princeton.edu or ftp 128.112.128.1 When you are asked for your login, type: anonymous Enter password as per instructions (make sure to include the specified @), and then change directories with: cd /pub/harnad/BBS To show the available files, type: ls Next, retrieve the file you want with (for example): get bbs.sinden When you have the file(s) you want, type: quit In case of doubt or difficulty, consult your system manager. A more elaborate version of these instructions for the U.K. is available on request (thanks to Brian Josephson). The files are also retrievable through archie, gopher, veronica, etc. ---------- Where the above procedures are not available (e.g. from Bitnet or other networks), there are two fileservers: ftpmail(a)decwrl.dec.com and bitftp(a)pucc.bitnet that will do the transfer for you. To one or the other of them, send the following one line message: help for instructions (which will be similar to the above, but will be in the form of a series of lines in an email message that ftpmail or bitftp will then execute for you). -------------------------------------------------------------