Recombinant Adenovirus: A Gene Transfer Vector for Study and Treatment of CNS Diseases

Recombinant Adenovirus: A Gene Transfer Vector for Study and Treatment of CNS Diseases

EXPERIMENTAL NEUROLOGY ARTICLE NO. 144, 125–130 (1997) EN966398 Recombinant Adenovirus: A Gene Transfer Vector for Study and Treatment of CNS Disea...

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EXPERIMENTAL NEUROLOGY ARTICLE NO.

144, 125–130 (1997)

EN966398

Recombinant Adenovirus: A Gene Transfer Vector for Study and Treatment of CNS Diseases Beverly L. Davidson* and Martha C. Bohn† *Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, Iowa 52242; and †Department of Neurobiology and Anatomy, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642

Gene transfer to the CNS with recombinant adenoviral vectors is a relatively recent event. In initial reports it was clearly demonstrated that adenoviral vectors can transfer genetic material to multiple cell types within the CNS. The relative ease in generating recombinant adenovirus (Ad) led to feasibility studies in the CNS with application to animal models of inherited disease, neurodegenerative diseases (e.g., Parkinson’s and amyotrophic lateral sclerosis), and cerebrovascular disease. In combination with Ad gene transfer to peripheral tissues, these experiments have identified specific limitations and directed further research to improve vector design, formulation, and delivery. r 1997 Academic Press

INTRODUCTION

Initial studies using recombinant adenoviral (Ad) vectors for gene transfer to the CNS described Ad5based vectors with deletions in E1 and, in some cases, a portion of E3. Direct injection of recombinant adenoviruses expressing Escherichia coli b-galactosidase into rodent CNS resulted in gene transfer to oligodendrocytes, astrocytes, neurons, and ependyma (1, 3, 15, 16). Two aspects of this vector system were enthusiastically received. First, the duration of transgene expression following CNS gene transfer is increased relative to recombinant herpesvirus vectors. Second, recombinant adenoviral vectors are relatively simple to generate. These two characteristics make recombinant Ad attractive for use in experimental CNS gene therapy paradigms of gene replacement and for addressing fundamental questions about the role of certain gene products in CNS (dys)function. IMPROVEMENTS IN VECTOR DESIGN

In rodent studies and human clinical trials, the immunologic response to recombinant Ad in liver and lung was quickly realized. Work in immunotolerant and immunocompetent mice enabled researchers to define the role of both humoral and cell-mediated

immunity in inhibiting readministration of the vector or clearing transduced cells. Second-generation Ad5 vectors contained deletions (26) or a point mutation (Ad5ts125) (22, 61) in the E2A region which abolished expression of the DNA-binding protein. In one series of experiments with the ts125-based recombinant viral vectors, cell-mediated responses to adenovirally transduced cells were clearly attenuated (61). However, more recent studies using a similar virus showed no differences in the duration of transgene expression in rodent and canine models (22). Both the humoral and the cell-mediated responses to Ad in brain and peripheral tissues are dependent on the dose of inoculum (10, 41, 42). Strategies to circumvent the humoral immune response to recombinant Ad have included inhibition of CD40–CD40L interactions (62) and prior treatment with IL-12 (63). Although effective in allowing redosing, IL-12 compromises the duration of expression, apparently by augmenting cellmediated responses. Research efforts directed at increasing the efficiency of gene transfer by recombinant Ad may reduce the antigenicity of the inoculum and diminish T cell (64) or B cell (60) activation. These methods, coupled to modified vector backbones, may allow for sustained expression in terminally differentiated cells or the ability to redose in peripheral tissues that are regenerative. Further adenoviral backbone modifications to circumvent expression of viral proteins or to make additional space for larger sized inserts include removal of E4 (less ORF6) in Ad2 vectors (57) or total gutting of all viral sequences in Ad5 except for the inverted terminal repeats and packaging signal (2, 23, 32). An attractive feature of Ad2 recombinant adenovirus developed by Genzyme Corp. is the repositioning of pIX sequences to the right-hand side (28). This greatly reduces the possibility for generation of wild-type virus during routine propagation and amplification. ALTERNATIVE DELIVERY STRATEGIES

Various approaches have been developed to transfer adenoviral vectors to different regions of the CNS

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0014-4886/97 $25.00 Copyright r 1997 by Academic Press All rights of reproduction in any form reserved.

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TABLE 1 Delivery Strategies for Ad Gene Transfer to CNS Target

Reference

Parenchymal Direct Across blood–brain barrier By retrograde transport Intraventricular Perivascular

(1, 16, 17, 35) (17) (18, 25) (3, 44, 52) (46, 47)

(Table 1). Most reports have used intraparenchymal, intravitreal, subretinal, or ventricular injection to target the virus to a specific location (1, 3, 14–16, 35, 37, 38, 50). Direct parenchymal injection of Ad leads to infection of surrounding cells, with the volume of transduced cells dependent upon the dose and concentration of virus. Studies have also demonstrated that direct inoculation of peripheral neurons results in retrograde transport and specific expression in the CNS. Studies by Draghia et al. (18) showed that after nasal instillation of Ad, neurons from the anterior olfactory nucleus, locus coeruleus, and area postrema expressed reporter genes. These data suggest retrograde transport of Ad to the olfactory nucleus, followed by transneuronal transport to the locus coeruleus and area postrema. Retrograde transport was also noted following intramuscular injection, with expression of reporter genes in the CNS sensory and motor neurons innervating the inoculated muscle (25). Parenchymal gene transfer can also be accomplished by intravascular delivery. After osmotic blood–brain barrier disruption, intracarotid infusion of adenovirus allows for delivery to cells beyond the vasculature (17, 44, 45). This technique showed high selectivity for astrocytes, since their foot processes cuff microvessels throughout the brain (7). This may be advantageous in gene transfer of a secreted gene product or in instances where partial correction leads to metabolic cooperation with surrounding cells. Delivery to the vascular endothelium of the CNS creates a significant hurdle since a stop-flow situation to allow for increased dwell time is not well tolerated in brain. As an alternative, extravascular delivery has been developed. Direct injection of recombinant Ad into the cisterna magna results in significant levels of gene transfer to the leptomeningeal cells overlying the major arteries, adventitial cells of large vessels, and occasional gene transfer to smooth muscle cells of small vessels (47). This approach may be useful to study vascular responsiveness in models of cerebrovascular disease, but may be limited to Ad vectors expressing diffusible gene products such as nitric oxide. Injection of recombinant Ad into the ventricles results in significant gene transfer to the ependymal cells

and choroid plexus (1, 8, 15, 16). Despite this limited distribution, Ad vectors can express secreted products that enter the CSF and penetrate into brain (8). This would be advantageous for disorders such as MPS VII, in which the missing lysosomal enzyme b-glucuronidase can be taken up by mannose-6-phosphate receptors if supplied exogenously, resulting in phenotypic correction in the absence of gene transfer (38). APPLICATION OF RECOMBINANT ADENOVIRUS TO CNS DISEASE (TABLE 2)

Gene Replacement Therapy The neurologic deficits accompanying some inherited metabolic diseases can be attenuated or ameliorated by dietary restriction or pharmacologic intervention. However, most inborn errors with CNS manifestations remain untreatable. Bone marrow transplantation or administration of recombinant protein can partially correct systemic manifestations of lysosomal storage disorders, with limited effect on brain and retinal pathology (9, 54, 56, 58). For other metabolic disorders of which Lesch–Nyhan syndrome (LNS), the mucopolysaccharidoses, Canavan’s disease, Batten’s disease, and other forms of ceriod lipofuscinosis are examples, CNS disease onset and progression remain untouched by current therapies. Thus, for single gene defects affecting the CNS, gene therapy-based approaches may offer, at the very least, improved quality of life, and at most, a cure. Genetic correction of affected tissues using recombinant Ad5 vectors has been demonstrated in MPS VII and HPRT-deficiency mouse models. Following intravitreal injection of recombinant adenovirus expressing human b-glucuronidase, reduction of storage material and partial recovery of photoreceptor cells was noted (38). The retina pigmented epithelium (RPE) was metabolically corrected, after gene transfer to the corneal endothelium, and expressed recombinant b-glucuronidase as demonstrated by in situ histochemistry. The RPE was completely cleared of storage material 3 weeks post-gene transfer. It is not yet known if the

TABLE 2 Ad Gene Transfer in Animal Models of CNS Disease Reference Inherited disease Mucopolysaccharidoses HPRT deficiency Neurodegenerative disease Parkinson’s disease Alzheimer’s disease Retinal degeneration Ischemia

(38) (50, 65) (14, 53) (11) (5, 38) (8, 27)

RECOMBINANT ADENOVIRUS AS GENE TRANSFER VECTOR

storage material remains cleared throughout the animal’s shortened life span, although adenovirus-mediated b-galactosidase gene transfer to RPE results in transgene expression for many months (6, 37). In HPRT-deficient mice, a model for LNS, levels of purine pools in brain are reduced compared to normal (30). HPRT-deficient mice can be further depleted of purine pools by inhibition of a second purine salvage enzyme, adenine phosphoribosyltransferase (59). Recombinant Ad5 expressing rat HPRT restores purine pools when delivered to the striatum in this genetic biochemical animal model of Lesch–Nyhan syndrome. Gene transfer resulted in HPRT mRNA and protein expression with marked improvements in IMP (5-fold), AMP (2-fold), and GMP (1.5-fold) levels (50). Recombinant Ad5 expressing rat HPRT has also been delivered to the brain of nonhuman primates (16). In an animal sacrificed 1 week following gene transfer, 1.6and 4.4-fold increases in AMP and GMP levels were noted (16). Notably, the presence of preexisting anti-Ad antibodies did not preclude infection and expression of rat HPRT. Follow-up MRI and PET evaluation in animals monitored for several months post-gene transfer demonstrated that the acute inflammatory reaction resolved in less than 1 month, suggesting that recombinant Ad may be useful as a gene transfer vector for human brain (B. L. Davidson, unpublished observation). Neuroprotection in Stroke and Chronic Neurodegenerative Disease The use of gene therapy to provide neuroprotective gene products has relevance to many diseases of, and injuries to, the CNS. Recent studies have used herpes simplex virus (HSV)-based vectors or anti-sense oligonucleotides to dissect the role of anti-apopotic proteins, receptors, the glucose transporter, and neurotrophic factors in protecting or augmenting injury following ischemic events in adult rodent CNS (33, 34, 39, 40, 43, 48). Adenoviral vectors expressing the interleukin-1 receptor antagonist (IL-1ra) protein have confirmed a role for IL-1 in exacerbating injury after middle cerebral artery occlusion (8, 51). In studies where animals were pretreated with recombinant Ad5 expressing IL1ra prior to middle cerebral artery occlusion, a 64% decrease in stroke size was noted. IL-1ra expressed from Ad was also protective in a rat model of CNS ischemia in neonates (27). A similar degree of protection following MCA occlusion was reported following injecting of an HSV amplicon vector harboring the anti-apototic gene bcl 2 (39). Direct gene transfer for treatment of chronic neurodegenerative disease has taken several approaches. One approach is to augment levels of neurotransmitter receptors. The levels of neurotransmitter receptors in the CNS are known to decline during aging and in

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neurodegenerative disease, such as Parkinson’s disease. A recent report has shown that adenoviral vectors can increase expression of the dopamine D2 receptor in striatum, resulting in an increased level of [3H]spiperone binding (29). Restoration of neurotransmitter levels may also allow for treatment of neurodegenerative disease. In rat models of Parkinson’s, this has been accomplished by gene transfer of the cDNA encoding tyrosine hydroxylase (TH) into striatum. TH converts tyrosine to L-dopa which is subsequently converted to dopamine by aromatic acid decarboxylase (AADC). L-Dopa and dopamine production can be enhanced by codelivery of TH and AADC genes or the gene for GTP-cyclohydrolase 1, an enzyme required for synthesis of the tetrahydrobiopterin cofactor for TH (4). These strategies have been effective in reducing behavioral deficients in rat and monkey models of Parkinson’s for adeno-associated virus and HSV vectors (22, 31; M. During and B. L. Davidson, unpublished observation). An ex vivo method of Ad gene transfer of TH to neural progenitor cells also modified behavior in this model (53). Others have developed recombinant adenoviral vectors to inhibit the neurodegenerative process and possibly stimulate regeneration. Significant improvements in animal behavior and dopamine cell survival have been reported following ex vivo and in vivo gene transfer of neurotrophic factor genes in rat models of Parkinson’s disease (14, 19, 20, 24, 36, 66). In one study, rats were injected intrastriatally with Fluorogold to identify a subpopulation of dopaminergic neurons in the substantia nigra. One week prior to inducing neurodegeneration by 6-hydroxydopamine, rats were injected near the substantia nigra with recombinant Ad expressing GDNF. Transduced cells produced nanogram quantities of GDNF in situ. This resulted in substantial neuroprotection, with greater than 80% survival of Fluorogold-labeled neurons 6 weeks later, compared to only 30% labeled neurons remaining in controls (14). Studies have also shown that NGF expressed from Ad can protect against neuronal atrophy in a rat model of Alzheimer’s disease (11). A recombinant Ad5 vector expressing NGF was injected into the nucleus basalis magnocellularis of aged rats. Three weeks later, the cell soma area of cholinergic neurons was significantly increased. Similar to rescue of biochemical and pathological phenotypes in animal models of inherited disease, these recent studies with first-generation adenoviral vectors, such as AdGDNF and AdNGF, demonstrate the experimental and therapeutic potential of Ad. CNS Malignancies Direct intratumoral Ad injection and delivery of Ad after osmotic disruption of the blood–brain barrier has resulted in decreases in tumor volume (12, 13, 45, 49, 52). Gene transfer with Ad containing the gene for

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HSV-1 thymidine kinase results in improved cell killing over retroviral vectors. Increased killing is a direct result of higher levels of expression, resulting in increased conversion of the drug ganciclovir to a toxic metabolite (55). These exciting results in animal models of primary and metastatic brain tumors have led to initiation of clinical trials for treatment of glioblastoma (21). CONCLUSION

For most disorders, recombinant Ad for gene treatment of CNS disease in humans is not yet feasible. Only recently have studies shown efficacy in animal models of neurologic disease (LNS, MPS VII, Parkinson’s). Recent and continued improvements in vector backbones and formulation of purified viral products can be coupled to optimized delivery methods to boost efficiency and efficacy. Nevertheless, these vectors should be exploited as tools for gene transfer to brain for study of mechanisms underlying specific disease processes.

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ACKNOWLEDGMENTS B.L.D. and M.C.B. receive partial support from the NIH (HD 33531, NS 34568; NS31957). B.L.D. is a fellow of the Roy J. Carver Charitable Trust. The authors acknowledge Deb Gilmere for secretarial assistance.

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