1 Renal Division, Gene transfer
approaches offer the promise of revolutionizing medicine. In this
review, we focus on the current and future prospects of somatic gene
transfer into the kidney. The advantages and disadvantages of current
vector systems are described, and the ex vivo and in vitro approaches
applicable to the kidney are reviewed. We discuss uses of gene transfer
approaches to dissect the pathogenesis of kidney disease and the future
directions and applications of gene transfer to combat kidney destruction.
somatic gene transfer
HUMAN GENE TRANSFER, once considered a fantasy, is a
clinical reality. Gene transfer approaches offer the promise of
revolutionizing medicine. In this review we focus on the current and
future prospects for gene transfer into the kidney. We will discuss the
concepts of somatic gene transfer and the general considerations of
gene transfer, and we will review the advantages and disadvantages of current vector systems. We will then address the unique
features of the kidney that dictate the selection of a gene transfer
strategy and review ex vivo and in vivo gene delivery approaches
tailored for the kidney. Finally, we will speculate on the future
directions and application of gene transfer systems to combat kidney
transplant rejection and autoimmune, polycystic, malignant, and other
acute glomerular and chronic interstitial kidney diseases.
Approaches: In Vivo and Ex Vivo
ABSTRACT
Top
Abstract
Introduction
Conclusion
References
INTRODUCTION
Top
Abstract
Introduction
Conclusion
References
SOMATIC GENE TRANSFER
Disease Considerations
The vector system is determined by several broad considerations: delivery, expression, safety, and the disease target (e.g., severity, tempo, affected organs). Delivery refers to the ability to introduce the gene product at the site required to impact on disease, the minimal number of cells needed to be transduced, and the effects of unintended targets. Expression entails an assessment of the protein level: Is it sufficient for a desired biological effect? How tightly does it need to be regulated? What duration is required to alter disease? Finally, safety issues include toxicity, e.g., inflammation engendered either by the vector or gene product leading to damage to the transduced organ. For example, toxicity is a particularly important problem for gene therapy in chronic diseases.Vectors
Retroviral, adenoviral, and nonviral vectors are popular systems for experimental gene transfer delivery that have been applied to human trials. An overview of the advantages and disadvantages of these vector systems is summarized in Table 1 and has been detailed in several reviews (2, 10, 49).
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Retroviral vectors. Retroviruses are attractive vectors because they permanently express a foreign gene in cells. When retroviruses infect a cell, their RNA genomes are converted into a DNA by the viral enzyme reverse transcriptase. The viral DNA is efficiently integrated into the host genome where it permanently resides, replicating along with host DNA. This integrated pro-virus steadily produces viral RNA under a strong promoter located at the end of the genome in a long terminal repeat sequence. Thus the retrovirus genome or any foreign gene placed in the retrovirus becomes a permanent part of the host cell genome.
The most common retroviral vector uses the Moloney murine leukemia virus as a base (11, 49). The gene is cloned into a retroviral vector that lacks most viral genes including the gag, pol, and env sequences required for encapsidation. The recombinant plasmid is transfected into a special packaging cell line that harbors an integrated pro-virus. The pro-virus has been crippled so that, although it produces the proteins required to assemble infectious virus, its own RNA cannot be packaged. Instead, RNA transcribed from the transfer vector is packaged into infectious virus particles and released from the cell. This virus "helper-free" stock is used to infect a target cell culture.
Although murine-based retroviral vectors are well suited for ex vivo applications, the first generation vectors are limited for direct in vivo gene transfer. The major limitations include the following: 1) the inability to easily purify and concentrate the large amounts of virus often needed for direct in vivo gene transfer applications; 2) sensitivity of virus with amphotropic host range, i.e., infect a wide variety of species; and 3) inability to integrate into quiescent cells. However, second generation vectors are evolving that improve the vector and broaden its application for in vivo delivery. For example, to produce high titers of recombinant Moloney murine leukemia virus particles, a human retroviral packaging cell line (293GPG) capable of incorporating the vesicular stomatitis virus G (VSV-G) protein was generated (56). The resulting VSV-G/retroviral pseudotypes possess the wide host range of VSV and can be highly concentrated without the loss of bioactivity. However, high levels of VSV-G are toxic to cells. Therefore, a transient transfection system was constructed using tetracycline-dependent expression of VSV-G in the 293GPG producer cells controlled by the tet transactivator system. Thus it is now feasible to generate large amounts of extremely high titer (>109 cfu/ml) virus critical for in vivo gene transfer. An additional advantage is that the virus produced from 293GPG cells is more resistant to serum inactivation than amphotropic virus generated from murine cells. Another second generation retroviral vector is the group of lentivirus-based vectors (54). Lentiviruses are a subclass of retroviruses that infect nondividing cells. Thus lentiviral-based vectors broaden the host range by transducing dividing and nondividing cells. In summary, new retroviral vectors and packaging cell lines are being created to circumvent the limitation of the first generation vectors.
Adenoviral vectors. These DNA viruses offer several distinct advantages. They 1) have a wide host range, 2) survive robustly in the circulation (63), 3) are produced at high titer (~1013 particles/ml), and 4) infect nondividing cells. However, there are some limitations. The duration of expression in vivo is largely limited by a T cell response to low levels of adenoviral proteins and transgene (if non-self) produced in the transduced cell (1). Newer versions of the virus with the nonessential E3 deleted (along with E1 portion) allow inserts up to ~8 kb in size. Moreover, an E2 mutant version is less immunogenic. Recent E4 deletion variants accept an additional 3 kb of insert DNA and are even less immunogenic (12). The ideal vector would contain only the cis elements required for packaging, namely, the so-called inverted terminal repeats and the packaging signal, and progress toward the construction of such a vector has been reported recently (6, 15, 34, 41), though the stability of gene expression in vivo is as yet uncertain (24). However, these advances will not circumvent the antibody response to adenoviral proteins that preclude secondary infection with the same serotype but not with a different serotype (44). The nonspecific inflammatory response (that can be produced even by empty virus) may also limit the amount of adenovirus that can be delivered. The reader is referred to a recent review by Anderson (2) for a summary of the use of adeno-associated and other DNA virus-based vectors.
Nonviral vectors. Nonviral vectors are relatively nontoxic and nonimmunogenic and easy to manufacture, but, in general, transduction efficiency in vivo is far less than with adenoviruses (reviewed in Ref. 37). Moreover, duration is usually transient (days), although use of replication origins and nuclear retention signals has extended this period to weeks or months.
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KIDNEY-TARGETED GENE TRANSFER |
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Special Considerations
Because of the structural complexity of the kidney, it is impossible to introduce genes into the multiple cell types using a single method. In principle, there are four routes for transferring genes into the kidney. They include delivery via the 1) renal artery, 2) renal subcapsule site, 3) retrograde from the ureter, or 4) parenchymal injection. These can be delivered singly or in combination, using ex vivo or in vivo approaches. It is conceivable that introduction into the peripheral circulation of cells or vectors could be targeted to the kidney. For example, Pasqualini and Ruoslahti (57) have identified (using a phase display library) sequences that selectively bind to renal vasculature in vivo.In building a database on which kidney cells are transduced by various gene therapy vectors, it should be noted that delivery in a disease context may differ from that in a normal kidney. There are many reasons for this, e.g., multiple distinct populations of dividing cells, active inflammation, and alterations in vascular permeability. Thus it is critical to select the appropriate preclinical disease model for translating this information to design therapeutics.
Current Data on Kidney Gene Delivery
In vivo. There are many successful distinct in vivo gene transfer vectors, including HVJ liposomes, retroviruses, and adenoviruses. HVJ LIPOSOMES. Tomita (64) has utilized HVJ, a Sendai virus. Plasmid DNA and a nucleoprotein coencapsulated in liposomes were fused to the inactivated Sendai virus. Gene transfer of an SV40 T-antigen reporter gene was conducted by inserting a catheter proximal to the right renal artery with the abdominal aorta clipped distally beneath the left renal artery. Four days after injection of the liposome suspension, SV40 T-antigen was detected immunohistochemically for several days in 15% of glomerular cells, although it was difficult to ascertain whether expression was in endothelial, epithelial, or mesangial cells. However, foreign gene expression was not detected outside of the glomerulus. The success of this gene transfer method was predicated on the ability of the HMG1 nucleoprotein, a high-mobility group 1 nonhistone nuclear protein, to enhance plasmid DNA passage into nuclei (21). The HVJ virus contains a fusogenic protein on its surface and is responsible for neutral pH-mediated cell fusion. This approach was used by Isaka et al. (19) to transfer cDNAs for transforming growth factor- ![]() |
FUTURE APPLICATIONS FOR KIDNEY DISEASE |
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Below are possible applications of gene therapy for treating renal disease. The reader is also referred to several recent reviews (14, 31, 39, 42).
Transplantation
Somatic gene transfer offers a powerful approach for the delivery of a therapeutic molecule into the kidney, or other tissues, to abort transplant rejection. Gene transfer provides distinct advantages over conventional, systemic administration of therapeutics by delivering a therapeutic locally within an organ. Local delivery avoids systemic complications and is economical since lesser amounts of therapeutics are required. The general barriers of gene transfer in medicine include 1) imprecise site-targeted expression, 2) transient expression, and 3) ethical pitfalls. However, these are not barriers for gene transfer in transplantation. Imprecise site (organ) targeting and issues concerning exclusively targeting the kidney do not apply to transplantation, since gene transfer into harvested organs is readily achievable. Furthermore, the second barrier, transient expression, may not necessarily be a problem in transplantation, since short doses of biologics may tolerize, and transplant therapies are initially intense and then are tapered to low doses. Finally, some ethical pitfalls may be dismissed. Problems of vector toxicity to the host are largely avoided by gene transfer into harvested organs.Gene transfer approaches to block kidney transplant rejection remain in the planning stages. Nevertheless, studies in other organ transplants have provided clues to combat rejection applicable to the kidney. Strategies that block T cell activation or destroy T cells are particularly appealing approaches to combat allograft rejection. Since the interaction of antigen-presenting cells and T cells requires adhesion, recognition, and costimulation to activate T cells, gene transfer interfering with any of these steps offers attractive therapeutic approaches. Let us review several examples.
It was initially thought that local delivery of Fas ligand in
genetically engineered syngeneic carrier cells would protect against
rejection. This was based on the concept that upon T cell activation, a
signal induces Fas and Fas ligand on the T cells (51). Since the
interaction of Fas with its ligand induces apoptosis and thus
eliminates T cells, it was reasoned that provision of Fas ligand into
an allograft would introduce a barrier to dampen or eliminate allograft
rejection (3). Although this strategy was claimed to combat islet
allograft rejection (38), this data has been challenged (23). In fact,
recent evidence determined that -cells in the pancreatic islet in
diabetic mice express Fas and Fas ligand and induce apoptosis of islets
(22). In addition, Fas ligand expression on pancreatic
-cells
results in massive neutrophilic infiltration and islet destruction
(23). Furthermore, evidence suggests that engagement of these molecules
is required for insulin-dependent diabetes at least in mice (20). Thus
provision of Fas ligand is harmful and not protective for islet
transplants. However, this is not necessarily the case for other
tissues. For example, although activated kidney parenchymal cells
express Fas and Fas ligand, we have recently provided evidence that,
unlike islets, the expression of Fas and Fas ligand on renal
parenchymal cells destroys T cells but does not induce apoptosis of
renal parenchymal cells in vivo (68). Thus provision of FasL may be suitable for deleting activated T cells in the kidney transplants but
may be lethal for some other organs. Another approach has been to block
the costimulatory pathway required for T cell activation. Without
costimulation, T cells are paralyzed and may enter a state of
anergy. The interaction of CTLA4 expressed by T cells and
B7 proteins displayed on activated macrophages is a potent
costimulation pathway. Masking B7 antigens using a soluble CTLA4-Ig
fusion protein prolonged allogenic and xenogenic engraftment (40).
Based on this concept, adenovirus-mediated transduction of CTLA4-Ig
into the cold preserved liver allograft protected the liver from
allograft rejection (55). Thus this gene transfer approach to block T cell activation offers promise for preserving kidney transplant engraftment.
There are many other promising gene delivery approaches to combat
rejection. Gene delivery of sequences encoding allogenic major
histocompatibility complex (MHC) antigens prior to
transplantation may modify foreign determinants and induce tolerance.
For example, fibroblasts transfected with donor-specific class I or II
MHC genes injected into recipients prior to mouse cardiac allogenic transplantation induced immune unresponsiveness (43). In addition, intrathymic administration of autologous plasmid-transfected myoblasts and myotubes bearing donor MHC class I antigens induced donor-specific unresponsiveness to liver grafts in allogeneic responder rats (33). In
addition, cytokines that dampen immune events offer potential gene
transfer opportunities to combat transplant rejection. Gene transfer
with plasmid DNA encoding TGF-1 in vivo prolonged cardiac mouse
allografts from 12 to 25 days without altering systemic immunity (58).
However, transient expression of TGF-
1 may have been responsible for
rejection, since the duration of expression was unclear.
Although the studies highlighted in this section are encouraging, there remain issues concerning the design of better vectors to deliver more consistent and enduring gene transfer to block transplant rejection in the absence of harmful immune events or toxicity.
Autoimmune Kidney Disease
Successful engraftment and protection from autoimmune kidney destruction share a common theme, i.e., tolerance. In either case, the loss of self or tolerance and perception of an invading foreign component sets in motion a series of tissue self-destructive events. Thus the strategies that combat tissue rejection should also offer therapeutic promise to blocking autoimmune kidney diseases. Several in vivo and ex vivo approaches have successfully delivered genes into the kidney; however, gene transfer approaches targeting autoimmune kidney diseases are as yet unrealized. The challenge will be to have sufficient local gene delivery to preserve the entire kidney, although subtotal preservation may also be clinically useful.Polycystic Kidney Disease
The identification of the PKD1 and PKD2 cDNAs (7, 8) might suggest that transduction of the appropriate cDNAs could provide a therapeutic treatment of autosomal dominant polycystic kidney disease (ADPKD). However, this approach is fraught with problems; the genetics of ADPKD, that is, haplotype insufficiency vs. a dominant-negative mechanism, the requirement for highly efficient tubular cyst transduction, and problems of vector capacity and stability, e.g., the open-reading frame for the PKD1 cDNA ofOur data in the Han:SPRD rat model (71) are a first step in gene
therapy approaches for cystic disease. The Han:SPRD rat is an excellent
model for ADPKD, with genetics and histological features resembling
that of the human disease (9, 25, 26). A replication-deficient
adenovirus carrying a -galactosidase reporter was introduced into
the renal artery. Of note, some of the cysts stained blue and were
entirely blue, suggesting that adenovirus had reached the cyst lumen.
Moreover, some interstitial cells, in addition to vascular staining
noted in normal animals, were also positive. One explanation for these
findings is that vascular permeability/integrity in cystic kidneys is
compromised compared with normal kidneys. In very recent studies, we
have shown that pelvic (retrograde) injection into cystic kidneys leads to substantial interstitial expression, with the highest density of
-galactosidase cells in areas of greatest disease activity (63). An
occasional blue cyst was also noted. This procedure is remarkably
straightforward, in contrast to the intra-arterial injection method.
These studies underscore the importance of assessing gene delivery in
the context of pathology.
Renal Cancer
The clinically challenging problem in renal cancer is largely that of metastatic disease. Nevertheless, it is worth reviewing all the gene therapy modalities that might impact on the treatment of cancer. Several options exist: 1) a gene correction strategy (e.g., replacement of an intracellularly acting tumor suppressor gene would likely require 100% of tumor cells transduced), unless there were a bystander effect, as recently suggested for p53; 2) introduction of an agent that would cause cell differentiation, acting intracellularly or extracellularly; 3) cytotoxic therapy, e.g., with HSV-TK, the herpes simplex virus-thymidine kinase gene, which has a bystander effect, i.e., the ability to kill neighboring nontransduced cells; 4) anti-angiogenic therapies; and 5) immunotherapy. All of these options are useful for the treatment of local disease. For localized renal cell carcinoma, nephrectomy is a reasonable choice; therefore, gene therapy would have to be even more beneficial, which is a difficult goal. For the treatment of metastatic disease by gene therapy, "immunotherapy" and anti-angiogenics are rational approaches, perhaps in combination with other modalities. In addition, since renal cancer is sensitive to systemic IL-2 and to natural and recombinant interferon, this approach merits consideration. Recent work has focused on the reintroduction of renal cells transduced ex vivo with the GM-CSF gene to elicit an immune response to tumor antigens (60). Other treatment modalities would include anti-angiogenic therapy or cytoprotective gene therapy. Studies from our laboratory in a xenograft renal cancer model point to the efficacy of endostatin, an anti-angiogenic protein, for renal cancer (M. Dhanabal, R. Ramchandran, and V. P. Sukhatme, unpublished data). Such a molecule could, in principle, be delivered to the vascular bed of a tumor via a suitably targeted vector. Regarding cytoprotective gene therapy, a multidrug resistance gene could be transferred into bone marrow or gut epithelial cells, allowing more vigorous chemotherapy or reducing toxicity of current regimes. Thus various gene therapy-based options exist for the treatment of renal and other cancers.Acute Glomerular Disease
The notion of utilizing gene therapy (perhaps delivered as antisense oligonucleotides) to counter the action of various inflammatory, proliferative, or profibrotic cytokines in acute glomerulonephritides is not unreasonable. The rapidly progressive glomerulonephritides may provide a suitable first setting since disease progression is rapid, thereby making the efficacy of therapy easy to judge. It is possible that retroviral vectors may be particularly advantageous in this context, since they selectively transduce dividing cells. Moreover, gene therapy to muscle or liver (72), with the aim of creating a transient source of circulating protein, could also be useful in glomerular disease. Border and colleagues (18) have utilized the HVJ system in skeletal muscle to deliver a cDNA for decorin, a proteoglycan known to bind TGF-Chronic Interstitial Disease
Glomerular and/or interstitial fibrosis is the hallmark of chronic renal failure, with the degree of interstitial fibrosis correlating with long-term renal prognosis irrespective of initiating insult. Approaches, including gene transfer, for blocking fibrosis have been recently reviewed (61). Long-term therapy would be needed. There are many patients (Miscellaneous
Applications "outside of the kidney" of interest to nephrologists include vascular access, and in particular, the problem of graft stenosis (62), and genes such as EPO expressed from liver, e.g., utilizing adenovirus or muscle (13, 16, 50, 59, 65, 66) as a "depot" source. Even without the ability to regulate gene expression quantitatively, gene therapy for the anemia of chronic disease could be used to raise the baseline hematocrit in an end-stage renal disease patient to a level in the high twenties, with fine tuning accomplished by EPO protein injections. Primary hyperoxaluria is another kidney disease in which therapy would be directed to the liver. Cloning of the relevant genes would clearly be a first step. Moreover, techniques to obtain long-term expression from the liver would also need to be perfected, unless repeated transduction were contemplated. ![]() |
CONCLUSION |
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There are numerous hurdles to tackle before gene transfer for the treatment of kidney disease is a clinical reality. Constructing databases for vectors and gene transfer methods for the normal and diseased kidney are critical first steps.
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FOOTNOTES |
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Address for reprint requests: V. R. Kelley, Harvard Institutes of Medicine, 77 Ave. Louis Pasteur, Boston, MA 02115.
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