the therapeutic potential of vegf inhibition in diabetic microvascular complications

Am J Cardiovasc Drugs 2007; 7 (6): 393-398LEADING ARTICLE 1175-3277/07/0006-0393/$44.95/0

© 2007 Adis Data Information BV. All rights reserved.

The Therapeutic Potential of VEGF Inhibition inDiabetic Microvascular ComplicationsGemma Tremolada,1 Rosangela Lattanzio,1 Gabriella Mazzolari2 and Gianpaolo Zerbini2

1 Department of Ophthalmology and Visual Sciences, San Raffaele Scientific Institute, Milan, Italy2 Renal Pathophysiology Unit, San Raffaele Scientific Institute, Milan, Italy

During the last few years, the incidence of microvascular complications in diabetes mellitus has rapidlyAbstractincreased as a consequence of both an increase in incidence of type 2 and type 1 diabetes mellitus.

The pathogenesis of diabetic microvascular complications is still largely unknown. Among the manyhypotheses, a dysfunction in angiogenesis has been suggested as a common origin for retinopathy, nephropathy,and neuropathy. Based on this hypothesis, inhibition of vascular endothelial growth factor (VEGF) has beentested as a potential therapeutic approach to prevent and cure diabetic microvascular complications. SeveralVEGF inhibitors are currently under evaluation or are approved for the treatment of wet age-related maculardegeneration and macular edema. These include inhibitors of intracellular transcription of VEGF (e.g.bevasiranib), inhibitors of extracellular VEGF (e.g. pegaptanib), inhibitors of VEGF receptor expression (e.g.aflibercept [VEGF-TRAP]) and inhibitors of the intracellular signaling cascade activating VEGF (e.g. midos-taurin).

According to the existing evidence base, although inhibition of VEGF results in a better outcome in the caseof diabetic retinopathy and also, despite some discrepant results, in the case of diabetic nephropathy, there is nofinal confirmation that VEGF inhibition is a valid approach for diabetic neuropathy. The latter complicationactually, in line with other chronic neuropathies, seems to improve with stimulation of angiogenesis throughincreased expression of VEGF.

Currently, there is no cure for diabetes mellitus, whether insu- nephropathy is characterized in its early phases by an increasedlin-dependent or non-insulin-dependent. The most intensive treat- capillary permeability (not forgetting that the same phenomenonment programs to correct hyperglycemia can delay the incidence could affect the vasa nervorum in the pathogenesis of diabeticof secondary complications, but are labor intensive and limited in neuropathy) has suggested the hypothesis that a common vasculartheir effectiveness. As a consequence, both the incidence and dysfunction could underlie the pathogenesis of the differentprevalence of microvascular complications of diabetes mellitus are microvascular complications of diabetes mellitus. Consequently,constantly increasing. Although there is evidence that diabetic vascular endothelial growth factor (VEGF), and in particular theretinopathy, nephropathy, and neuropathy may have independent isoform VEGF-A, a major modulator of endothelial biology actingpathogeneses, the hypothesis that microvascular complications of as a mitogen, survival factor, modulator of cell shape, cell migra-diabetes mellitus may share a common background, in particular a tion, and vessel permeability, could be directly involved in diabe-diabetes mellitus-induced abnormal vasculogenesis or angio- tic vascular complications.[1]

genesis, has never been ruled out.[1] In this review, we will Although VEGF inhibition, aimed to prevent/cure diabeticrecapitulate the arguments in support or against a role of angio- complications is a relatively new treatment approach, for severalgenesis in the development of diabetic microangiopathy. years it has been used as an effective therapy in the control of

Diabetic retinopathy is characterized by progressive damage of tumor growth. The large number of US FDA clinical trials usingthe endothelium, leading to the proliferation of new serum-leaking VEGF inhibitors for the treatment of cancer only (450 trialscapillaries. The latter fact along with the finding that diabetic currently listed on http://clinicaltrials.gov/ct/gui) clearly demon-

394 Tremolada et al.

strate the potential of this therapy. Previous experience derived gistic effect of local hypoxia and different growth factors infrom anti-VEGF treatment in cancer suggests that this therapy regulating VEGF release has been suggested.[4] Cytokines knownmay not be completely safe for organs that are usually affected by to induce VEGF expression are interleukin (IL)-1, and IL-6,[4]

diabetes mellitus. Recent studies[2,3] have indeed shown that pro- whereas IL-10 and IL-13 have a down-regulatory effect.[14] Thy-teinuria and hypertension represent significant adverse effects of roid stimulating hormone, prostaglandin E 2, and adrenocortico-anti-VEGF treatment in nondiabetic patients with neoplastic dis- tropic hormone increase the expression of VEGF messenger RNAeases, probably a consequence of reduced nitric oxide production (mRNA).[12]

by the vasculature. Finally, recent findings suggest that VEGF-A has a neurotro-phic and neuroprotective activity both in vitro and in vivo.[15,16]

Reduced VEGF-A expression, consequent to some VEGF-A pro-1. Vascular Endothelial Growth Factor (VEGF)moter haplotypes, has been implicated in the pathogenesis ofand Neovascularizationamyotrophic lateral sclerosis (ALS).[17]

VEGF is a key regulator of vasculogenesis (i.e. the formation of2. Diabetic Retinopathynew vessels through the differentiation of bone marrow-derived

endothelial progenitor cells) and angiogenesis (i.e. the formationDiabetic retinopathy is presently the most common diabeticof new capillaries from pre-existing vessels through the prolifera-

microvascular complication, being detectable in nearly 50% of thetion of mature endothelial cells)[4] during embryogenesis, fetaldiabetic population at any time and eventually occurring in nearlygrowth, and adult stages. VEGF has also been demonstrated as theall patients with diabetes mellitus.[18,19] This diabetic complicationmost important regulator of blood vessel formation in both healthrepresents the predominant cause of blindness in the industrializedand disease.[4] The human VEGF gene is localized in chromosomeworld. Visual loss results primarily from two specific complica-6p21.3.[5] As a growth factor, VEGF-A is part of a family thattions. Firstly, the appearance of retinal vascular lesions due toincludes placental growth factor (PLGF), VEGF-B, VEGF-C, andretinal hypoxia, leads to a proliferation of new incompetent vesselsVEGF-D (also known as FIGF [c-fos-induced growth factor]), and(proliferative diabetic retinopathy). These new vessels are oftenthe viral VEGF-E.[6,7] Different VEGFs bind to different tyrosinethe cause of vitreous hemorrhage and the resulting fibrosis predis-kinase receptors (VEGFRs).[8-10] VEGF-A binds to VEGFR-2poses to retinal tractional detachment, with subsequent loss of(also known as KDR/Flk-1) and VEGFR-1 (Flt-1) receptors.vision. The second complication, characteristic of every stage ofPLGF and VEGF-B bind to VEGFR-1, VEGF-C and VEGF-Ddiabetic retinopathy, consists of an increased permeability ofbind to VEGFR-2 and VEGFR-3 (Flt4) receptors. Finally, VEGF-retinal vessels with consequent thickening of the central retina, soE binds to VEGFR-2 receptors.called macular edema, resulting in a loss of central vision.VEGFR-1 and VEGFR-2 have extracellular immunoglobulin-

Based on the results of the Diabetic Retinopathy Study[20] laserlike domains along with a single tyrosine kinase transmembranephotocoagulation has become the treatment of choice for diabeticdomain and are expressed in a number of different cells.[11]

retinopathy, even though this practice is sometimes complicatedVEGFR-3[4] is instead predominantly expressed in the endotheli-by adverse effects.[21,22] Subsequent studies, however, have fo-um of lymphatic vessels. Neuropilin-1, a receptor for semaphorinscused on the molecular basis of diabetic retinopathy, with the finalin the nervous system, is also a receptor for the heparin-bindingaim of identifying new pharmacologic therapies.[23]isoforms of VEGF and PLGF.[12] From a structural point of view,

VEGF-A consists of eight exons, whereas the other human VEGF Although VEGF is virtually absent in the normal human reti-genes have a highly conserved seven-exon structure. Alternative na,[24] VEGF immunoreactivity is present in retinas obtained fromsplicing of VEGF-A have been demonstrated giving rise to differ- diabetic patients. VEGF165 is confined to endothelial cells andent transcripts.[13] Human VEGF isoforms include 121, 145, 165, perivascular regions, while VEGF121, 165, 189 are mostly asso-183, 189, and 206 amino acids (VEGF121, VEGF145, VEGF165, ciated with the extravascular components of the inner retina.[25] AllVEGF183, VEGF189, and VEGF206, respectively), all of them three VEGF receptors are expressed in nonvascular areas of thederived from alternative splicings of a single VEGF gene.[4] human retina, but only VEGFR-1 is constitutively expressed inVEGF165 is the predominant isoform of VEGF.[11] Four isoforms retinal microvessels. In diabetic eyes, an increased microvascularof PLGF and two isoforms of VEGF-B have also been de- expression of VEGFR-2 and VEGFR-3 has been demonstrated.[26]

scribed.[13] VEGF synthesis is stimulated by growth factors includ- In this context, an important role in the pathogenesis of diabeticing epidermal growth factor, keratinocyte growth factor, trans- retinopathy has been attributed to growth factors such as VEGF,forming growth factor-β and insulin-like growth factor.[4,14] Syner- basic fibroblast growth factor (bFGF) and insulin-like growth

© 2007 Adis Data Information BV. All rights reserved. Am J Cardiovasc Drugs 2007; 7 (6)

VEGF Inhibition in Diabetic Complications 395

factor (IGF).[27,28] VEGF, in particular the isoform A, is considered Another agent that includes intravitreal administration isthe most important promoter of ocular angiogenesis and increased ranibizumab, a modified humanized monoclonal antibody frag-vascular permeability in diabetic retinopathy.[29-32] In line with ment (Fab-fragment) that, compared with pegabtanib, has thethese findings, the use of antiangiogenic agents aimed at prevent- advantage of inhibiting all isoforms of VEGF-A. Ranibizumab hasing and/or inhibiting the proliferation of new vessels in the retina been recently approved by the FDA for the treatment of wet age-as well as slowing down the progression of macular edema, have related macular degeneration. A preliminary report suggests thatgained acceptance. intravitreal injection of ranibizumab maintained or improved visu-

al acuity and reduced macular edema in diabetic patients.[36]

2.1 Antiangiogenic Agents Additional studies are presently ongoing to assess safety andefficacy of this procedure. More recently, intravitreal injections ofSeveral antiangiogenic agents inhibiting VEGF activity byranibizumab were shown to be more effective than sham injection,different mechanisms of action are presently under clinical evalua-verteporfin photodynamic therapy, or sham photodynamic ther-tion in diabetic patients with different stages of diabetic reti-apy.nopathy. These include inhibitors of intracellular trascription of

More recently, a new intravitreal agent, bevacizumab, pre-VEGF; inhibitors of extracellular VEGF; antagonists of VEGFviously tested and approved for the treatment of colon-rectalreceptor expression and inhibitors of intracellular signaling cas-cancer, has become available to ophthalmologists. Bevacizumab iscade activating VEGF.the full humanized monoclonal antibody of ranibizumab and like

2.1.1 Inhibitors of Intracellular Transcription of VEGF ranibizumab binds all the isoforms of VEGF-A. This drug isInhibitors of intracellular trascription of VEGF, an interfering presently under evaluation for the treatment of ocular neovascu-

RNA, is able to shut down the production of VEGF released from larization, including diabetic retinopathy. Randomized protocolsretinal pigment epithelium cells. Bevasiranib, a small-interfering are still under way, but pilot studies have demonstrated goodRNA therapeutic, has recently been synthesized. This molecule is efficacy in diabetic retinopathy.[37-39]

presently under evaluation in phase III trials for age-related wet Potential drawbacks of the above therapeutic approaches in-macular degeneration (AMD). clude the route of administration, i.e. intravitreal injection implies

Another molecule AGN 211745 (Sirna 027), able to inhibit the an invasive procedure with some important adverse effects such asexpression of VEGF receptor on the surface of endothelial cells by endophthalmitis, retinal detachment, elevation of eye pressure,interfering with mRNA transcription[33] is also being tested at and cataract. Clinical trials demonstrated a low incidence of thesepresent in phase II trials for AMD. complications, but the risk may be higher in chronic diseases (such

as chronic macular edema in diabetic retinopathy) requiring re-2.1.2 Inhibitors of Extracellular VEGFpeated injections as a consequence of the short duration of actionAnother strategy that is showing important and promisingof these agents.[40,41] Systemic complications such as thromboem-clinical results in the treatment of diabetic retinopathy is thebolic events and hypertension have also been reported.[42]

inhibition of extracellular VEGF. Pegaptanib, an RNA aptamerwith extremely high affinity for the human VEGF165 peptide, is 2.1.3 Antagonists of VEGF Receptor Expressionpresently under evaluation in the US and Europe. Pegaptanib, by Another way to block VEGF is the so-called VEGF-TRAPbinding the VEGF165 peptide prevents VEGF receptor activation. (aflibercept) acting like a receptor trap by binding all the isoformsIntravitreal pegaptanib has been approved by the FDA for the of extracellular VEGF. VEGF-TRAP is a fusion protein consistingtreatment of all types of neovascular AMD. Some clinical trials are of immunoglobulin domains of both VEGF-1 and -2 fused to anpresently testing the hypothesis that pegaptanib might be active Fc-fragment of human IgG. This molecule in under evaluation foralso in diabetic macular edema and proliferative diabetic reti- wet AMD.[43]

nopathy. In particular, in a phase II trial, the patients treated with2.1.4 Inhibitors of Intracellular Signaling Cascadepegaptanib injections showed a better visual acuity and a reduction

of the macular edema compared with controls.[34] Moreover, in a The last anti-VEGF approach is represented by the inhibitors ofretrospective analysis, it was also demonstrated that most of the intracellular signaling cascade activating VEGF. These inhibitorsindividuals with retinal neovascularization assigned to pegaptanib of VEGF are small molecule tyrosine kinase inhibitors (TKIs) thatshowed an early regression of the neovascularization, suggesting a block signal transduction following VEGF binding to its receptors.direct effect of pegaptanib in retinal neovascularization in diabetic Several TKIs have been through phase I/II trials in cancer and maypatients.[35] Phase III studies are presently under way to verify the in future be seen as potential therapy for diabetic retinopathy. Thelong-term efficacy and safety of this drug. future potential for TKIs in diabetes mellitus is concerning more if



they could be delivered orally for systemic action. Whilst attempt- receptors.[55,56] In particular, in the kidney, VEGF is expressed anding to control retinopathy, the TKIs may exacerbate the risk of secreted by podocytes and glomerular endothelial cells representneuropathy in the diabetic population. Similarly, there is a concern its specific binding site.[57,58] Because of this peculiar anatomicthat peripheral vascular ischaemia and wound healing may be setting, it has been hypothesized that VEGF may play a role in theadversely affected.[44-47] regulation of glomerular permeability and glomerular endothelial

cell growth.[59] Recent studies have demonstrated that VEGFMidostaurin (PKC 412) is the only TKI presently under evalua-secretion and the expression of its receptors (in particulartion for the treatment of macular edema. This molecule is adminis-VEGFR-2) are upregulated by high ambient glucose concentra-tered orally. A number of adverse effects, probably as a result oftions in kidneys of diabetic rats.[60,61]the non-selective inhibition of tyrosine kinase, have been ascribed

to this compound. Inhibitors of protein kinase C (PKC), such as Results of a study published a few years ago point to theruboxistaurin are also under evaluation for the treatment of diabe- involvement of angiogenesis in the development of glomerulartic retinopathy. PKC, and particularly its β isoform, has been alterations that characterizes diabetic nephropathy.[62] This studylinked to diabetic microvascular diseases. PKC-β activation (in- demonstrated that increased glomerular filtration surface in earlyduced by hyperglycemia) seems to be involved in excess retinal stages of diabetic nephropathy is associated with the formation ofvascular permeability and neovascularization in diabetic ani- new glomerular capillaries, a phenomenon also observed in diabe-mals.[48,49] PKC activation results in intracellular activation of tic retinopathy. In line with this hypothesis is the evidence thatVEGF. Inhibition of PKC has been suggested to be of use in the inhibition of VEGF has a beneficial effect in the pathogenesis oftreatment of diabetic retinopathy both for macular edema and for diabetic nephropathy.[63-65] In particular, tumstatin, a VEGF inhib-retinal neovascularization. itor derived from type IV collagen, reduced in vivo glomerular

hypertrophy, hyperfiltration, and albuminuria in streptozotocin-A recent study[50] demonstrated that ruboxistaurin was wellinduced diabetic mice. Tumstatin treatment also resulted not onlytolerated and reduced the risk of visual loss but did not prevent thein significant inhibition of glomerular matrix expansion and ofprogression of moderately severe to very severe nonproliferativemonocyte/macrophage accumulation, but also in the normalizationdiabetic retinopathy. More recently, another study demonstratedof glomerular nephrin expression, a podocyte protein crucial forthat administration of ruboxistaurine ameliorated diabetes mel-maintaining the glomerular filtration barrier.[66] Altogether theselitus-induced retinal hemodynamic abnormalities in patients with-findings suggest that inhibitors of VEGF may represent a validout retinopathy or with very mild diabetic retinopathy.[51] Furtherpharmacologic alternative in the prevention and cure of diabeticstudies are presently ongoing to verify safety and efficacy of thisnephropathy. However, not all the reports have so far confirmeddrug in the treatment of diabetic retinopathy. Whether VEGFthe beneficial renal effect of VEGF inhibition[67] in animal modelsinhibition either as a single therapy or in associated with laser-of diabetes mellitus.therapy will become the leading treatment for diabetic retinopathy

will be hopefully clarified in the next few years by the severalongoing clinical studies. 4. Diabetic Neuropathy

The term diabetic neuropathy encompasses a heterogeneous3. Diabetic Nephropathygroup of diabetes mellitus-induced neurologic disorders present-

Diabetic nephropathy is the most common cause of end-stage ing a wide range of dysfunctions. Diabetic neuropathy is one of therenal disease and the strongest predictor of premature death and most common long-term complications of diabetes mellitus, andcardiovascular disease in Europe and the US. Although good represents a significant cause of morbidity and mortality.[68] A roleglycemic and pressure control can slow the progression of the for angiogenesis in the pathogenesis of diabetic neuropathy iscomplication, we have no tools to definitely cure or prevent it. The made possible by the evidence that VEGF and the VEGF receptorsneed for more advanced therapeutic approaches to diabetic ne- VEGFR-1 and VEGFR-2 are expressed by both neurons andphropathy is becoming imperative particularly taking into consid- peripheral nerves.[69,70]

eration the evidence that patients affected by this complication are At difference with other microvascular complications of diabe-presently the fastest-growing group of recipients of dialysis and tes mellitus, there is presently no proof that VEGF inhibition maytransplantation.[52-54] be of use in the prevention or treatment of diabetic neuropathy. In

A number of renal cells, including mesangial cells, glomerular animal models VEGF gene transfer was shown to have a directendothelial cells, podocytes, vascular smooth muscle cells, proxi- neuroprotective effect in neurodegenerative disorders,[71] as wellmal and distal tubular cells actively express VEGF and VEGF as in diabetic neuropathy.[72,73] In line with these observations it


VEGF Inhibition in Diabetic Complications 397

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the therapeutic potential of vegf inhibition in diabetic microvascular complications

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