Gene Therapy for Neurodegenerative Diseases: Fact Or Fiction?

BRITISH JOURNAL OF PSYCHIATRY 2001), 178, 392^394 EDITORIAL Gene therapy for neurodegenerative diseases: CURRENT GENE THERAPY STRATEGIES FOR fact or fiction? NEURODEGENERATIVE DISEASES JANET E. CARTER and EDWARD H. SCHUCHMAN To date, gene therapy proper in the CNS has been tested only in experimental animal model systems and has included delivering genes encoding neurotrophic factors to inhibit neurodegeneration or sti- mulate regeneration, and the replacement of deficient neurotransmitter proteins or Primary neurodegenerative diseases repre- function in patients with Huntington's dis- metabolic enzymes. sent debilitating and progressive condi- ease and Parkinson's disease, respectively. In an animal model of Parkinson's tions for which no cure is currently The first of these strategies gene therapy) disease, for example, in vivoinvivo andand ex vivoexvivo available and for which therapeutic inter- is discussed further here. approaches to replace dopamine have ventions remain limited to palliative and included direct stereotactic intracerebral symptomatic treatment. Advances in gene injection of viral vectors expressing the transfer technology now present the realis- GETGETTING TING GENES INTO tyrosine hydroxylase gene to striatal neu- tic prospect of delivering therapeutic genes CELLS ^ VECTOR-MEDIATED rons, or transplanting cells fibroblasts or to the brain for neuroprotection, restora- GENE DELIVERY astrocytes)expressing tyrosine hydrox- tion of neuronal function or replacement ylase Horrelou et aletal, 1994: Ridet et aletal,, of deficient proteins as treatments for To date, two approaches to gene delivery 1999). Co-expression of several enzymes these diseases. Thus, although central ner- into somatic cells exist: ex vivoexvivo andand in vivoinvivo.. on the biosynthetic pathway to dopamine vous system CNS)gene therapy presents a Ex vivoExvivo approaches require vector- e.g.e.g. LL-aromatic amino acid decarboxylase number of unique challenges and clinical mediated gene transfer into cells before and tyrosine hydroxylase)from one viral applications remain in their infancy, the transplantation into the target, whereas in vector or coincident expression of the two realisation of this goal is approaching at the context of the CNS in vivoinvivo refers torefersto enzymes from two separate vectors, deliv- an ever-increasing rate. directdirect in situinsitu intracerebral gene delivery. ered at the same time, has also been used to The vectors of choice for both methods of maximise dopamine production. In a related gene transfer are viruses modified to impair strategy, tyrosine hydroxylase has been THERAPEUTIC STRATEGIES ^ their replication after entering cells i.e. expressed virally together with guanosine- OVERVIEW OF APPROACHES replication-replication-deficient).deficient). Five such viral vector 55'' -triphosphate GTP)cyclohydolase I, the systems are currently available, including enzyme necessary for generation of the Broadly speaking, four categories of thera- retrovirus, adenovirus, adeno-associated tetrahydrobiopterin cofactor for tyrosine peutic strategy have become available as a virus, herpes simplex virus and lentivirus, hydroxylase Mandel et aletal, 1998). Al- result of recent advances in genetics and together with a range of artificially con- though interpretation must remain cau- cell biology. The first is gene therapy structed vectors or chimeras that are tious because of the limitations of proper, which describes attempts to deliver hybrids of the above. Parkinsonian animal models, improve- `healthy' genes to a target organ such as All currently available viral vector ments in behaviour and increased dopa- the brain. This category includes the spe- systems have inherent limitations but it is mine synthesis have been reported. cialised field of stem cell transplantation, important to note that innovations in Neuroprotective paradigms for Parkin- which exploits the inherent biology of vector design and purification strategies son's disease, in vivoinvivo andand ex vivoexvivo, have,have organ-specific stem cells to provide a have helped to overcome some of these included delivering genes encoding trophic source of genetically engineered replace- disadvantages. For example, `gutless' adeno- factors such as glial-derived neurotrophic ment cells for the delivery of therapeutic viral vectors, stripped of all structural viral factor and brain-derived neurotrophic fac- genes to localised and widespread regions genes and disguising pathogenic viruses in tor and anti-apoptotic genes such as the of the CNS. The second set of strategies the `coats' of non-virulent strains, help to proto-oncogene Bcl-2 Bilang-Bleuel et aletal,, aims to reduce expression of mutated genes minimise toxicity. Manipulation of specific 1997; Choi-Lundberg et aletal, 1997). En- and includes the use of antisense oligo- gene sequences i.e. promoters, enhancers) couraging results demonstrate successful nucleotides and ribozymes. The third has been used to confine transgene expres- rescue of degenerating striatal neurons approach is to use positional cloning sion to specific cell types in the brain and and improved behavioural function in strategies to identify mutated genes in- to produce longer-term expression for a animal models. volved in disease, and then to make use comprehensive review of viral vectors, see Gene therapy in animal models for of the identified gene variants for new Hermans & Verhaagen, 1998). Huntington's disease has similarly concen- drug discovery. Finally, transplantation of A number of non-viral gene transfer trated upon protective ex vivoexvivo approaches, non-genetically engineered primary em- methods also have been developed for gene transplanting cells secreting nerve growth bryonic neural tissue has been used in clin- therapy, but at the present time the ineffi- factor NGF)or human ciliary neuro- ical trials, with varying degrees of success, ciency of these methods precludes clinical trophic factor for a review, see Kordower to improve cognitive function and motor application. et aletal, 1999).,1999). 392 Downloaded from https://www.cambridge.org/core. 27 Sep 2021 at 13:40:59, subject to the Cambridge Core terms of use. GENE THERAPY FOR NEURODEGENERATIVE DISEASES Experimental animal models with JANET E.CARTER, MRCPsych, Department of Neuroscience and Section of Old Age Psychiatry,Institute chemically induced lesions of cholinergic of Psychiatry,King's College, London,UK and and Department Department of of Human Human Genetics, Genetics, Mount Mount Sinai Sinai School School of of Medicine, Medicine, basal forebrain neurons have been used to New York; EDWARD H. SCHUCHMAN, PhD,Department of Human Genetics, Mount Sinai School mimic the behavioural and neurodegenera- of Medicine, New York tive changes of Alzheimer's disease. In exex vivovivo approaches, implantation of fibroblasts, Correspondence: Dr Janet Carter,Department of Neuroscience and Old Age Psychiatry,Institute genetically manipulated to produce NGF,NGF, of Psychiatry,De Crespigny Park,Park,London London SE5 8AF,UK.Tel: 020 7848 0707; Fax: 020 7708 0017; e-mail: janet.carter@@iop.kcl.ac.uk into the basal forebrain before lesioning prevented degeneration of cholinergic neu- :First received 26 April 2000, finalfinalrevision revision 27 27 October October 2000, 2000, accepted accepted11December 11December 2000) 2000) rons in an adult primate model Tuszynski et aletal, 1996).,1996). selective cholinergic lesioning Martinez- adult bone marrow demonstrate the ability STEM CELL Serrano & Bjorklund, 1998). to differentiate into astrocytic and neuronal TRANSPLANTATION ^ Significantly, homogeneous clonal phenotypes neuroectodermal origin)when SPECIALISED EX VIVOEXVIVO GENE populations of genetically immortalised transplanted into the non-haematopoietic THERAPY human embryonic NSCs have been shown environment of the rodent brain ± so-called recently to be capable of differentiation inter-germ layer differentiation Kopen et aletal,, Perhaps one of the most remarkable ad- into mature neuronal cell types on trans- 1999; Pittenger et aletal, 1999). Because mesen- vances for the field of CNS gene therapy plantation into adult rat striatum. This sug- chymal stem cells can be isolated readily has been the identification and isolation of gests their potential as vehicles for from a patient's own bone marrow, their neural stem cells NSCs)from embryonic molecular therapies for neurodegenerative use in transplantation would circumvent or foetal neural tissue. On transplantation conditions Rubio et aletal, 2000).,2000). the problem of graft versus host disease. into developing or adult mouse brain, Despite the promise of brain-derived It can be seen that this radical transfor- human embryonic NSCs can migrate over NSCs, there remain reservations about mation in the concepts of stem cell biology distance, integrate into the surrounding their use in transplantation to the mature advances the prospect of achieving the ulti- microenvironment and demonstrate multi- CNS. It may be that the normal adult mate goal for molecular medicine in the potency i.e. an ability to differentiate into brain lacks the appropriate signals to re- CNS: an easily isolated source of multi- regionally appropriate neuronal cells); for alise their proliferative potential or that potent adult human stem cells with high a review, see Scheffler et aletal 1999). It is specific neuropathological conditions may proliferative capacity that can be lineage- these inherent biological features that, on alter the balance of required

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