Kidney International, Vol. 65 (2004), pp.
1551–1555
Gene therapy in renal diseases
ENYU IMAI,1 YOSHITSUGU TAKABATAKE, MASAYUKI MIZUI, and YOSHITAKA ISAKA
Division of Nephrology, Department of Internal Medicine, Osaka University Graduate School of Medicine
Gene therapy in renal diseases. Kidney-targeted gene therapy
could be an ideal treatment for renal diseases since the thera-
peutic molecule is limited in the kidney and the systemic effect
may be minimized. The technical development of the gene de-
livery to kidney and the identification of the responsive gene
for a particular disease encourage the challenge to hereditary
diseases. Collagen type IV reassembling was reported to be
succeeded in Alport syndrome model by introduction of ex-
ogenous COL4A5 gene. Many gene therapies are evaluated
in various glomerulonephritis models and unilateral ureteral
obstruction (UUO) model, and favorable results are accumu-
lated. Transplant kidney is an ideal target for gene therapy, by
which ischemia reperfusion, acute rejection and chronic allo-
graft nephropathy can be treated. The importation of the novel
technology, for example hybrid stem cell-gene therapy could
promote the gene therapy of renal diseases toward clinical
application.
Kidney-targeted gene therapy could be an ideal treat-
ment for renal diseases because the effect of therapeu-
tic molecule is limited in the kidney. The harmful effects
to other tissues can presumably be limited. The kidney
is, however, a well-differentiated organ with specialized
compartments, composed of glomerulus, tubule, vascula-
ture, and interstitium. These anatomic compartments are
separated by basement membranes and associated cells.
The glomerular basement membrane (GBM) separates
the blood flow from urine flow and the tubular base-
ment membrane separates urine flow from interstitial
fluid. These barriers make the gene tranfection difficult
because the vectors are hard to pass through the anatomic
barriers. This review discusses the recent progress of gene
therapy for renal diseases by focusing on Alport syn-
drome, glomerulonephritis, and transplantation.
MONOGENIC HEREDITARY RENAL DISEASE
Until 5 years ago, no one believed that the hereditary
renal diseases could be a target of gene therapy. How-
ever, the technical development of the gene delivery and
1 Participant and speaker.
Key words: gene therapy, renal disease, glomerulonephritis.


C 2004 by the International Society of Nephrology
1551
identification of the responsible genes encouraged us to
attempt to treat the hereditary diseases. Understanding
the pathophysiology of the hereditary diseases became
a driving force to promote the development of the gene
therapy.
Alport syndrome is a representative case since the
pathophysiology was recently revealed. The underlying
cause of the disease is a defective structure of the type
IV collagen framework of the GBM [1]. It has been es-
timated that 85% of cases are caused by mutations in
the X chromosomal gene encoding the a5(IV) collagen
chain (COL4A5). Type IV collagen is a triple-helical pro-
tein consisting of three a chains. In fetus, the GBM is
composed of two a1(IV) collagens and one a2(IV) colla-
gen. After birth, these GBMs are replaced with adult-type
GBM composed with a3(IV), a4(IV), and a5(IV) chains.
In Alport syndrome, the defect of a5(IV) chain results
in disassembling the adult-type GBM and embryonic-
type GBM substitutes. However, since the embryonic-
type GBM does not provide sufficient strength against
the mechanical strength as a filter and sufficient resistance
against proteolysis, the consequence is deterioration
of the structure and development of progressive renal
failure.
Alport syndrome is not believed to be an attractive
candidate for gene therapy because it seems to be dif-
ficult to deliver COL4A5 gene selectively to podocytes
by passing the GBM. Heikkila et al [2] developed a new
gene transfer technique, that is, a perfusion of adenoviral
vector for 2 to 12 hours, which allows gene transfer exclu-
sively to glomerular cells. They succeeded in the delivery
of the a5(IV) collagen gene to the glomerular cells by
renal perfusion of adenovirus vector [3]. They further ap-
plied this technique to gene therapy in canine model Al-
port syndrome. The introduced gene for a5(IV) collagen
expressed in the glomeruli and assembled triple-helical
type IV collagen fiber composed of a3(IV), a4(IV), and
a5(IV). Currently, they are continuing experiments to
isolate the clinical application. A major issue remaining is
how the administration of COL4A5 gene can be repeated
in clinical case. Generally, treatment of monogenic hered-
itary diseases is not so attractive from the viewpoint of
industry. Gene therapy might be a less expensive alterna-
tive therapy for rare diseases.
1552 Imai et al: Gene therapy in renal diseases
GLOMERULONEPHRITIS AND
RENAL FIBROSIS
Several experimental gene therapies were reported.
However, the clinical application of the gene therapy to
glomerulonephritis and renal fibrosis needs to clear many
hurdles. The long treatment may be necessary for pro-
gressive glomerulonephritis, which makes it difficult to
ascertain the safety of gene therapy.
Glomeruli-targeted antisense oligonucleotides and de-
coy DNA therapies were reported. Akagi et al [4] demon-
strated that administration of the transforming growth
factor-b (TGF-b) antisense oligonucleotides from renal
artery by hemagglutinating virus of Japan (HVJ) lipo-
some method inhibited TGF-b expression in glomeruli
and consequently, the extracellular matrix expansion in
glomeruli was suppressed in anti-Thy1 glomerulinephri-
tis rats [4]. Carl et al [5] also demonstrated suppression
of early growth response gene-1 (Egr-1), a transcrip-
tion factor involved in mesangial proliferation, by
antisense oligonucleotidess prevented Egr-1 and platelet-
derived growth factor (PDGF) expression and eventually
inhibited mesangial proliferation in anti-Thy1 glomeru-
lonephritis.
Double-strand oligonucleotides containing a cis-
element binding for a particular transcription factor act as
a decoy and inhibit transactivation of the particular pro-
moter coding the cis-element. E2F decoy inhibits the cell
proliferation by binding the cis-element of the promoter
regions of dihydropholate reductase, c-myc, cdc2 kinase,
and proliferating cell nuclear antigen (PCNA), while nu-
clear factor-jB (NF-kB) decoy suppresses inflammatory
genes, including interleukin (IL)-1, IL-6, IL-8, intercel-
lular adhesion molecule-1 (ICAM-1), vascular cell ad-
hesion molecule-1 (VCAM), and endothelial leukocyte
adhesion molecule (ELAM). E2F decoy [6] and NF-kB
decoy [7] successfully inhibited the mesangial prolifera-
tion and extracellular matrix expansion in experimental
glomerulonephritis.
Intraparenchymal injection of adenoviral vector cod-
ing IL-10 suppressed proteinuria of focal segmental
glomerulosclerosis in mouse model [8]. 15-Lipoxygenase
(15-LO) is a key molecule to generate leukotriene B 4 .
Munger et al [9] introduced 15-LO gene into the kidney
induced antinephrotoxic serum nephritis, which reduced
urinary protein excretion but did not affect the pathology.
Renal fibrosis, a hallmark of irreversible injury, is
developed by long-term activation of TGF-b signal.
The inhibitory molecules of TGF-b signal are good
candidates for prevention of renal fibrosis. Unilateral
ureteral obstruction (UUO), a model of acute tubuloin-
terstitial fibrosis, was mainly used for experimental gene
therapy, although it caused irreversible change in kidney.
HVJ-liposome–mediated introduction of antisense
oligonucleotides for TGF-b [10] prevented tubulointer-
stitial fibrosis in UUO model. Electroporation-mediated
transduction of DNA enzyme against Egr1 inhibited
interstitial fibrosis in UUO model [11]. Ultrasound-
mediated introduction of plasmid coding Smad-7,
which is an inhibitory Smads suppressing TGF-b signal,
inhibited TGF-b action and suppressed renal fibrosis
in the UUO model [12]. Terada et al [13] also showed
the adenoviral mediated gene transfer of Smad-7 in
combination with electroporation inhibited the renal
fibrosis. Hepatocyte growth factor (HGF) is a multifunc-
tional cytokine, which regulates mitosis, angiogenesis,
morphogenesis, cell movement, and apoptosis [14].
Since HGF acts against TGF-b and recombinant HGF
administration suppresses renal fibrosis in UUO model
[15], HGF gene therapy was examined in UUO model.
Gao et al [16] introduced plasmid coding HGF by HVJ-
liposome method and Yang, Dai, and Lui [17] introduced
hydrodynamic-based gene transfer. Both HGF gene
therapies suppressed renal fibrosis in UUO model. Infil-
tration of activated macrophages into tubulointerstitial
region in renal disease is relevant to the progression
of renal fibrosis. Shimizu et al [17] introduced plasmid-
coding 7ND, a dominant negative-type antagonist against
monocyte chemoattractract protein-1 (MCP-1), into
kidney by hydrodynamic method [18]. 7ND gene therapy
attenuated the interstitial fibrosis in a protein-overload
proteinuria model. Takase et al [19] also showed the
inhibition of the NF-kB by gene therapy of a truncated
IkBa, a dominant-negative type molecule, and reduced
renal fibrosis in protein-overload model.
Skeletal muscle targeted gene therapy for renal dis-
eases is more practical and less invasive because it pro-
vides high efficiency and long-lasting gene expression
compared with kidney [20]. However, the risk of the sys-
temic delivery is concerned about side effect on other
organs. Inhibitory molecules against TGF-b were stud-
ied for muscle gene therapy. Isaka et al [21] transduced
plasmid for decorin, a natural inhibitor against TGF-b,
into muscle cell by HVJ-liposome method. The decorin
provided from muscle inhibited TGF-b expression and
ameliorated glomerulosclerosis. Gene therapy of the arti-
ficial soluble receptor for TGF-b [22] and that for PDGF-
B [23] targeted muscle also inhibited glomerulosclerosis
in anti-Thy1 glomerulonephritis.
Genetically modified macrophage-like cell is devel-
oped for treatment of anti-GBM glomerulonephritis.
Yokoo et al [24] differentiated bone marrow cells into
CD11b+ CD18+ cells, which migrate into inflamed
glomeruli. They transfected IL-1 receptor antagonist ex
vivo by venous injection. The macrophage expressing IL-
1 receptor antagonist migrated into inflamed glomeruli
and ameliorated the glomerulonephritis. Furthermore,
they reconstituted bone marrow with transplantation of
the anti-inflammatory stem cells expressing IL-1 receptor
antagonist constitutively [25]. Glomerulonephritis was
 Imai et al: Gene therapy in renal diseases
then induced in these mice. Renal function and histology
were preserved in the mice whose bone marrow was
reconstituted with IL-1 receptor antagonist–producing
cells. The survival rate after a second challenge with
nephrotoxic antibody was significantly improved in the
IL-1 receptor antagonist chimera. These results suggest
that reconstitution of bone marrow for continuous supply
of anti-inflammatory cells may be a novel strategy for the
treatment of chronic inflammation.
TRANSPLANTATION
Reduction of ischemia-reperfusion injury has been
challenged by gene therapy. Noiri et al [26] intracardia-
cally injected antisense for inducible nitric oxide syn-
thase (iNOS) in rats. The rats were protected from the
subsequently inflicted ischemic renal injury. This study
showed the direct evidence of the toxic effect of iNOS
in ischemic insult of kidney. Haller et al [27] injected
ICAM-1 antisense oligonucleotides with lipofectin into
vein 6 hours before renal artery occlusion. They showed
the improvement of the ischemia-induced infiltration of
granulocytes and macrophages, and less cortical renal
damage and renal function. Furuichi et al [28] injected
plasmid coding 7ND into skeletal muscle 7 days before
ischemia. The 7ND gene therapy inhibited acute tubular
necrosis in mouse model in concomitant with reduction
of macrophage infiltration. However, these gene modifi-
cations were prophylactic therapeutics.
Acute rejection occurs as a consequence of T-cell acti-
vation. In the process of interaction of T-cell and antigen-
presenting cell (APC), the engagement of T-cell receptor
and alloantigens presented by major histocompatibility
complex (MHC) molecules is essential but also needs cos-
timulatory signals. The interaction of CD28 with B7 is the
most important one. A chimeric fusion protein, cytotoxic
T-lymphocyte antigen-4 Ig (CTLA4Ig), binds to B7 but
blocks the signal. Tomasoni et al [29] injected adenoviral
vector coding CTLA4Ig gene into renal artery of Brown
Norway rat kidney ex vivo. Then, they transplanted the
kidney to a Lewis rat, which normally rejects the Brown
Norway rat kidney and abolishes the renal function in
10 days. The CTLA4Ig gene transfected to transplanted
kidney improved graft survival more than 50 days by in-
hibiting the T-cell activation.
Induction of immunologic tolerance to alloantigens is
a major goal in the field of transplantation. Graft toler-
ance may be induced by apoptosis of alloreactive T cells.
Fas antigen-Fas ligand interaction triggers the apoptosis
in activated T cells. Adenoviral vector–mediated FasL
gene transfer to the transplanted kidney prolonged the
graft survival [30, 31]. Suppression of Th1 cytokines and
up-regulation of Th2 cytokines are often observed in the
setting of tolerance induction. Overexpression of Th2 cy-
tokines, IL-10 and IL-4, may induce the tolerance. IL-4
1553
gene overexpression prolonged the renal survival [32]. In
contrast, there is no report to show that IL-10 gene ther-
apy prolongs the survival of the renal allograft, although
cardiac and liver allografts were reported to improve the
survival [33, 34].
Allo-MHC is the main target for alloimmune re-
sponse, exposure of these donor MHC antigens through
hematopoietic stem cells could serve as a strategy for in-
ducing antigen-specific tolerance. DNA-mediated gene
transfer of MHC classes I and II molecules to recipi-
ent bone marrow cells prolong the survival of cardiac
allograft [35]. Kohn et al [36] demonstrated that efficient
transduction and expression of a retrovirally transduced
MHC class I gene [H-2K(b)] in bone marrow–derived
cells, resulting in the life-long expression of the retrovi-
ral gene product on the surface of bone marrow–derived
hematopoietic lineages including Sca-1(+), lineage neg-
ative, hematopoietic progenitors. T cells from the mice
receiving MHC-transduced bone marrow were unable to
reject H-2K(b) mismatched skin graft. They acquired the
tolerance but were able to respond to third-party controls.
This approach could be a promising strategy to induce
tolerance in transplant kidney.
HGF is known as a renotropic growth factor and pro-
tects tubular cells from toxic and ischemia/reperfusion
injury [14]. In the early phase of kidney transplantation,
when the transplanted kidney is exposed to insults by
ischemia/reperfusion and high dose of immunosuppres-
sant, HGF may afford protection against the acute re-
nal injury and may enhance regeneration. After adding a
calcineurin inhibitor, the short-term outcome of survival
rate of transplant kidney improved significantly. How-
ever, chronic allograft nephropathy remains as an impor-
tant issue to be resolved. Chronic allograft nephropathy is
characterized by the deterioration of renal allograft func-
tion and is associated with typical morphologic change,
such as glomerulosclerosis, arterial intimal thickness and
smooth muscle cell proliferation, tubular atrophy, and
interstitial fibrosis. Azuma et al [37] demonstrated that
only 4 weeks of HGF injection into penile vein improved
the graft survival in rat chronic allograft nephropathy
model, in which Fisher 344 rat kidneys were transplanted
to Lewis rats, whose own kidneys were removed. Half of
control rats died in 32 weeks, while no graft loss occurred
in HGF-treated rats. Tubular cell death was significantly
suppressed in HGF-treated allograft in concomitant with
the significant improvement of morphologic change. The
early change including tubular necrosis and macrophage
infiltration was reduced and the late change of interstitial
fibrosis was also blocked by HGF treatment. These results
strongly suggest that the HGF treatment may provide a
new therapy for transplant organs. We are currently per-
formed HGF gene therapy as a preclinical study for pre-
serving transplant kidney. HGF gene was introduced into
pig kidney ex vivo by electroporation and transplanted
1554 Imai et al: Gene therapy in renal diseases
to the same pig and then removed the other one. The
kidney-introduced HGF gene significantly reduced inter-
stitial fibrosis (unpublished data). Interestingly, the graft-
versus-host disease (GVHD) is suppressed by skeletal
muscle gene therapy with HGF [38] in conjunction
with interferon-c (IFN-c) and tumor necrosis factor-a
(TNF-a) expression in the intestine and liver, and de-
creasing the serum IL-12 and prolonging the survival,
suggesting HGF may modulate the immune system to
induce the tolerance.
CONCLUSION
The ethical issue of gene therapy limited its application
to incurable and life-threatening diseases, like advanced
cancer, human immunodeficiency virus (HIV) infection
and lethal inherited diseases. In the field of cardiovascu-
lar diseases, however, a gene therapy for severe ischemic
limb diseases shows prominent impact on the improve-
ment of the quality of life by induction of angiogene-
sis. This success built up a consensus of the application
of gene therapy to nonlethal diseases with low activi-
ties of daily living. The innovative therapy for halting the
progress of chronic renal failure is anticipated from the
patient. The consideration of the risk and benefit through
lifelong activities of daily living and expanding medical
expense for treatment of the end-stage renal disease may
permit the clinical application of gene therapy for pro-
gressive kidney diseases. Assurance of safety is, of course,
the major hurdle of the gene therapy for chronic kidney
diseases as well.
In contrast, kidney transplantation is an ideal target
for gene therapy. At least three strategies are envisioned,
which are reduction of ischemia/reperfusion injury, inhi-
bition of acute rejection. and induction of tolerance. The
clinical application of gene therapy to transplant kidney is
promising. Furthermore, the application of gene therapy
to xenotransplantation is also expected.
Gene repair is the ultimate purpose of gene therapy.
The targeting gene repair has several advantages over
the gene augmentation or gene silencing. As the repair
within a cell only needs to occur in the homologous re-
combination once. It is not necessary to construct the ex-
pression vector system and relatively easy to synthesize
a large amount of the therapeutic small DNA molecules.
In addition, the gene expression is regulated by its own
promoter. Small fragment homologous replacement [39]
and RNA/DNA chimeric oligonucleotides [40] are possi-
ble for use in gene repair of the monogenic diseases.
The importation of the novel technology for gene ma-
nipulation such as stem cells technology must be essential
for development of hybrid cell-gene therapy. The hurdle
is still high to clinically introduce the gene therapy in re-
nal diseases except renal cancer. We are, however, very
optimistic for clinical application of the gene therapy of
renal diseases in future.
Reprint requests to Enyu Imai, Suita 565–0871, Osaka, Japan.
E-mail: imai@medone.med.osaka-u.ac.jp
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