A lesion to the brain is not necessary for a successful neural transplantation. Embryonic Purkinje cells placed on the surface of an uninjured adult cerebellum can develop and migrate into the host molecular layer. Both the Purkinje cells that migrated into the host cerebellum and those that remained in the graft were innervated by collateral sprouting of adult intact climbing fibers.

For focal neurodegenerative diseases or brain tumors, localized delivery of protein or genetic vectors may be sufficient to alleviate symptoms, halt disease progression, or even cure the disease. One may circumvent the limitation imposed by the blood-brain barrier by transplantation of genetically altered cell grafts or focal inoculation of virus or protein. However, permanent gene replacement therapy for diseases affecting the entire brain will require global delivery of genetic vectors. The neurotoxicity of currently available viral vectors and the transient nature (...) of transgene expression invivomust be overcome before their use in human gene therapy becomes clinically applicable. (shrink)

Gene therapy approaches have great promise in the treatment of neurodegenerative disorders and malignant brain tumors. Neuwelt et al. review available viral-mediated gene therapy methods and their blood-brain-barrier (BBB) disruption delivery technique, briefly mentioning nonviral mediated gene therapy methods. This commentary discussed the BBB disruption delivery technique, viral and nonviral mediated gene therapy approaches to Parkinson's disease, and the potential use of antisense oligo to suppress malignant brain tumors.

It is often presumed that effects of neural tissue transplants are due to release of neurotransmitter. In many cases, however, effects attributed to transplants may be related to phenomena such as trophic effects mediated by glial cells or even tissue reactions to injury. Any conclusion regarding causation of graft effects must be based on the control groups or other comparisons used. In human clinical studies, for example, comparing the same subject before and after transplantation allows for many interpretations of the (...) causes of clinical changes. (shrink)

The lesion and transplantation data cited by Sinden et al., when considered in tandem, seem to harbor an internal inconsistency, raising questions of false localization of function. The extrapolation of such data to cognitive impairment and potential treatment strategies in Alzheimer's disease is problematic. Patients with focal basal forebrain lesions (e.g., anterior communicating artery aneurysm rupture) might be a more appropriate target population.

In spite of Stein and Glasier's justifiable conclusion that initial optimism concerning the immediate clinical applicability of neural transplantation was premature, there exists much experimental evidence to support the potential for incorporating this procedure into a therapeutic arsenal in the future. To realize this potential will require continued evolution of our knowledge at multiple levels of the clinical and basic neurosciences.

Research on neural transplantation has great potential societal importance in part because of the expanding proportion of the population that is elderly. Transplantation studies can benefit from the guidance of research on cognitive aging, especially in connection with the assessment of behavioral outcomes. Speech for example, might be explored using avian models.

The responses displayed by an injured or diseased nervous system are complex. Some of the responses may effect a functional reorganization of the affected neural circuitry. Strategies aimed at the restoration of function, whether or not these involve transplantation, need to recognize the innate reactive capacity of the nervous system to damage. More successful strategies will probably incorporate, rather than ignore, the adaptive responses of the compromised neural systems.

Grafting embryonic brain tissue into the brain of patients with visual field loss due to cerebral lesions may become a method to restore visual function. This method is not without risk, however, and will only be considered in cases of complete blindness after bilateral occipital lesions, when other, risk-free neuropsychological methods fail.

Despite some clinical promise, using fetal transplants for degenerative and traumatic brain injury remains controversial and a number of issues need further attention. This response reexamines a number of questions. Issues addressed include: temporal factors relating to neural grafting, the role of behavioral experience in graft outcome, and the relationship of rebuilding of neural circuitry to functional recovery. Also discussed are organization and type of transplanted tissue, the of transplant viability, and whether transplants are really needed to obtain functional recovery (...) after brain damage. (shrink)

The work of Sinden et al. suggests that it may be possible to produce improvement in the areas of brain function by transplanting brain tissue. What appears to be the limiting factor is not the complexity of the mental process under consideration but the discreteness of the lesion which causes the impairment and the appropriateness and accuracy of placement of the grafted tissue.

The neural transplantation research described by Sinden and colleagues provides part of the rationale for the clinical application of neural transplantation. The authors are asked to clarify their view of the role of the cholinergic system in cognition, to address extrahippocampal damage caused by transient forebrain ischemia, and to consider the effects of delayed neural degeneration in their structure-function analysis.

The concept of structure, operation, and functionality, as they may be understood by clinicians or researchers using neural transplantation techniques, are briefly defined. Following Stein & Glasier, we emphasize that the question of whether an intracerebral graft is really functional should be addressed not only in terms of what such a graft does in a given brain structure, but also in terms of what it does at the level of the organism.

Over the past two decades, research on neural transplantation in animal models of neurodegeneration has provided provocative in sights into the therapeutic use of grafted tissue for various neurological diseases. Although great strides have been made and functional benefits gained in these animal models, much information is still needed with regard to transplantation in human patients. Several factors are unique to human disease, for example, age of the recipient, duration of disease, and drug interaction with grafted cells; these need to (...) be explored before grafting can be considered a safe and effective therapeutic tool. (shrink)

This commentary reviews data supporting circuitry reconstruction, replacement neurotransmitters, and trophic action as mechanisms whereby transplants promote recovery of function. Issue is taken with the thesis of Sinden et al. that adequate data exist to indicate that reconstruction of hippocampal circuitry damaged by hypoxia with CA1 transplants is a confirmed mechanism whereby these transplants produce recovery. Sinden et al.'s and Stein & Glasier's proposal that there is definitive evidence showing that all transplants produce trophic effects is also questioned.

The transplantation of cholinergic neurons into the hippocampal formation has been well characterized. We describe our studies on the effects of cholinergic transplants in the retrosplenial cortex. These transplants were capable of ameliorating spatial navigation deficits in rats with septohippocampal lesions. In addition, we provide evidence for the modulation of transplanted neurons by the host brain.

Complementation and correction of a genetic defect with CNS manifestations lags behind gene therapy for inherited disorders affecting other organ systems because of shortcomings in delivery vehicles and access to the CNS. The effects of improvements in viral and nonviral vectors, coupled with the development of delivery strategies designed to transfer genetic material thoughout the CNS are being investigated by a number of laboratories in efforts to overcome these problems.

Neural cell transplants have been introduced in clinical practice during the last decade with mixed results, encouraged by success with simple animal models. This commentary is a reminder that although the ideas and techniques of transplantation appear simple, the variables involved in host-transplant integration still require further study. The field may benefit from a concerted, multidisciplinary approach.

Grafts of embryonic neural tissue into the brains of adult patients are currently being used to treat Parkinson's disease and are under 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 for nonsurgical, less intrusive therapeutic use. Certain subjective judgments used to select patients who will receive grafts and in assessment of the outcome of graft therapy make it difficult to evaluate the procedure. 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. (shrink)

Stein & Glasier suggest embryonic neural tissue grafts as a potential treatment strategy for Alzheimer's and Parkinson's disease. As an alternative, we suggest that the family of nerve growth factor-related neurotrophins and their trk (tyrosine kinase) receptors underlie cholinergic basal forebrain (CBF) and dopaminergic substantia nigra neuron degeneration in these diseases, respectively. Therefore, treatment approaches for these disorders could utilize neurotrophins.

We concur that basic research on the use of CNS grafts is needed. Two important model systems for functional studies of grafts are ignored by Stein & Glasier. In the first, reproductive function is restored in hypogonadal mice by transplantation of GnRH-synthesizing neurons. In the second, circadian rhythmicity is restored by transplantation of the suprachiasmatic nucleus.

Gene replacement therapy holds great promise in the treatment of many genetic CNS disorders. This commentary discusses the feasibility of gene replacement therapy in the unique context of the retina, with regard to: (1) the genetics of retinal neoplasia and degeneration, (2) available gene transfer technology, and (3) potential gene delivery vehicles.

The use of aborted fetal tissues in research and therapy has raised exciting possibilities and a host of social, legal and ethical issues. Perhaps the most difficult issue is whether the use of materials from elective abortion can be viewed and weighed separately from the abortion itself, or if in using these tissues there is inherent complicity with the abortion act. Those who oppose FTT claim that there is complicity with the abortion act and liken the use of fetal tissue (...) from abortions to the use of data from the Nazi experiments. Within this lobby are those who claim that the option to donate fetal tissues will make abortion a more attractive alternative for pregnant women, and that there are doctors who will offer fetal tissue donation as a positive incentive to abortion-with the net effect that more abortions will take place. (shrink)

As the debate about research on foetal tissue transplantation progressed, medical scientists learned more about the procedure and its potential for helping persons with degenerative brain disorders such as Parkinson's disease. Increased scientific knowledge significantly influenced the political process, yet it did not by any means resolve the debate. Rather, increased medical evidence served as a lens which focused discourse on particular issues related to foetal research, such as the details of obtaining informed consent, as well as technical matters related (...) to tissue transplantation, for example, that the creation of a tissue bank was unreasonable, and that foetuses of certain ages were required for the procedure. This increased focus changed the character of the debate on foetal tissue transplantation research, and convinced some law-makers that they should encourage financial support for the research despite their anti-abortion political views.The heart of the stalemate on transplantation research lay in rigid attachment to particular arguments, which in turn resulted in the disunity of the participants; this was compounded by the lack of persuasive scientific evidence that foetal tissue transplantation could significantly benefit those with Parkinson's disease. Privately supported clinical studies answered several important clinical questions while the ban on federal support remained in effect, however, and increased scientific knowledge was soon followed by an increasingly clear analysis of the relevant issues. By the time federal support for the research was permitted, the arguments of all of the interest groups had been altered by the findings of privately supported studies.As research continues under the auspices of a somewhat more permissive administration, these refined arguments and attitudes may continue to contribute to a stronger and more clearly defined public policy. (shrink)

Neuwelt et al. have proposed gene-transfer experiments utilizing an animal model that offers many important advantages for investigating the feasibility of gene therapy in the human brain. A variety of tissues concerning the viral vector and mode of delivery of the corrective genes need to be resolved, however, before such therapy is scientifically supportable.

Studies on the snailMelampusreveal that connectivity is crucial to the survival of transplanted ganglia. Transplanted CNS ganglia can innervate targets or induce supernumerary structures. Neuron survival is optimized by the neural incorporation that occurs when a transplanted ganglion is substituted for an excised ganglion. Better provision for the trophic requirements of neurons will improve the success of mammalian fetal transplants.

In contrast to the views put forth by Stein & Glasier, we support the use of inbred strains of rodents in studies of the immunobiology of neural transplants. Inbred strains demonstrate homology of the major histocompatibility complex (MHC). Virtually all experimental work in transplantation immunology is performed using inbred strains, yet very few published studies of immune rejection in intracerebral grafts have used inbred animals.

Three experiments on neural grafting with adult rat hosts are described. Working memory impairments were produced by lesioning the hippocampus or severing its connections with the septum by ablating the fimbria-fornix. The results suggest that the survival and growth of a neural graft, whether an autograft or a xenograft, is not a necessary condition for functional recovery on a task tapping working memory.

Neural transplantation as a recovery strategy for neuro-degenerative diseases in humans has used mainly grafting following acute denervation strategies in young adult hosts. Our work in aged mice and rats demonstrates an age-related increase in susceptibility to oxidative damage from neurotoxins, a remarkably poor recovery of C57BL/6 mice from MPTP insult with transplantation and growth factors, even at 12 months of age, and diminished plasticity of host neurons. We believe that extrapolation of data from young adult animal models to aged (...) humans without thorough investigation of transplantation and host response in aged recipients is scientifically and ethically inappropriate. (shrink)

The use of neural transplantation to alleviate cognitive deficits is still in its infancy. We have an inadequate understanding of the deficits induced by different types of brain damage and their homologies in animal models against which to assess graft-induced recovery, and of the ways in which graft growth and function are influenced by factors within the host brain and the environment in which the host is operating. Further, use of fetal tissue may only be a transitory phase in the (...) search for appropriate donor sources. Nevertheless, findings from our laboratory and elsewhere have made a prima facie case for successful cognitive reconstruction by graft methods. (shrink)

The spinal cord provides an alternative model for nerve tissue grafting experiments. Anatomo-functional correlations are easier to make here than in any other region of the CNS because of a direct implication of spinal cord neurons in sensorimotor activities. Lesions can be easily performed to isolate spinal cord neurons from descending inputs. The anatomy of descending monoaminergic systems is well defined and these systems offer a favourable paradigm for lesion-graft experiments.

It is well established that neural grafts can exert functional effects on the host animal by a multiplicity of different mechanisms – by diffuse release of trophic molecules, neurohormones, and deficient neurotransmitters, as well as by growth and reformation of neural circuits. Our challenge is to understand how these different mechanisms complement each other.

The transition from research to patient following advances in transplantation research is likely to be disappointing unless it includes a better understanding of critically relevant characteristics of the neurological disorder and improvements in the animal models, particularly the behavioral features. The appropriateness of the model has less to do with the species than with how the species is used.

In 1989, in the wake of the first operations to transplant fetal tissue into the brains of sufferers from Parkinson's Disease, the UK Code of Practice governing the use of the fetus for research was overhauled by an eminent committee under the chairmanship of the Reverend Dr John Polkinghorne. The Polkinghorne Report has, however, attracted remarkably little comment or analysis. This paper is believed to be the first to subject it to sustained ethical and legal scrutiny. The author concludes that, (...) although the committee's recommendations meet the major objections to the Code of Practice, the report is nevertheless vulnerable to criticism in its treatment of at least three issues: the moral status of the fetus; paternal consent to fetal use, and the ethical inter-relation of fetal use and abortion. (shrink)

A major problem in developing an effective gene therapy for the nervous system lies in understanding the principles that maintain or turn off the expression of genes following their transfer into the CNS.

Neural fetal tissue transplantation offers promise as a treatment for devasting neurologic conditions such as Parkinson's disease. Two types of issues arise from this procedure: those associated with the use of fetuses, and those associated with the use of neural tissue. The former issues have been examined in many forums; the latter have not. This paper reviews issues and arguments raised by the use of fetal tissue in general, but focuses on the implications of the use of neural tissue for (...) basic concepts of personnood and personal identity. (shrink)

Despite reports of recovery of function after neural transplantation, the biological interactions between transplanted neurons and the host brain that are necessary to mediate recovery are unclear at present. One source of confusion is in the variety of models and protocols used in these studies. It is suggested that multisite experimentation using standard protocols, models, and recovery criteria would be helpful in moving neural transplantation from the laboratory to the clinic.

Cholinergic-rich grafts have been shown to be effective in restoring maze-learning deficits in rats with lesions of the forebrain cholinergic projection system. However, the relevance of those studies to developing novel therapies for Alzheimer's disease is questioned.

In addition to the scientific and medical issues surrounding the use of fetal tissue transplants, the ethical implications should be considered. Two major ethical issues are relevant. The first of these is whether this experimental procedure can be justified on the basis of potential benefit to the patient. The second is whether the use of tissue obtained from intentionally aborted fetuses can be justified in the context of historical and existing guidelines for the protection of human subjects. The separation of (...) ethical decisions from medical practice and scientific research is necessary to prevent the exploitation of innocent human life. (shrink)