The contribution made by OCT imaging (Optical Coherence Tomography) as a tool in essential therapeutic management:

OCT is an integral part of the tracking of this pathology in that it has now become almost inseparable from the therapeutic decision. Although at the initial stage of exudative AMD diagnosis complete exploration is necessary (fluorescein and indocyanine green angiography) to avoid missing a different diagnosis, OCT is now the essential para-clinical examination for regular monitoring, coupled with clinical examination (visual acuity and ocular fundus).

First put on the market in 1995, the OCT Time Domain technique has benefited from constant developments since the first generation, successively with the OCT2 version and then the OCT3 version, which is revolutionary in clinics, with resolution of 8 to 10μm.

In 2007, further technological progress was made with the arrival of the OCT Spectral Domain which on the one hand shortens measurement acquisition times, and therefore examination time for the patient and on the other, and above all, offers increased resolution. It is now of the order of 3 μm (very high resolution, 3D OCT) (Fig. 3). The latter is now taking over from OCT Time Domain, particularly since it can be coupled on the same machine with the angiography technique.

Fig. 3: Development of OCT.

Over this past decade OCT has revolutionised retinal imaging and more OCT advances are already available, derived from a principle of astronomy: adaptive optics, this time enabling a cellular approach, visualising the cones.

OCT now enables a better understanding of the physiopathogeny of AMD. It is, moreover, used for anatomical classification of neovessels, according to their location in terms of the Pigment Epithelium (PE):

• Pre-epithelial neovessels in front of the PE, also known as visible or classical, the rapid evolution of which is well known, compared to
• Sub-epithelial neovessels, behind the PE, also known as hidden, and which are the most frequent.

Finally, in the majority of cases, this examination removes the need for the injection of fluorescein (possible allergy which is sometimes serious) during monitoring (active or inactive nature of neovessels). Over these past few years this has therefore led to a reduction in the number of AGF (Angiopoietin-Related Growth Factor) - such as for diabetic macular oedema - even though the latter are still used for the initial examination and in the monitoring of particular cases of exudative AMD.

Prevention by micro-nutrition

In 2001, the AREDS study showed for the first time that antioxidant supplements reduce the risk of the development of early forms (Age- Related Maculopathy) into advanced form (AMD). Indeed, they reduce by 25% the risk of AMD progression in its neovascular form and by 27% the loss of visual acuity.

The precise qualitative and quantitative composition of these supplements was, however, disputed over the following years, specifically with the importance of Omega 3 (unsaturated fatty acids) and of the carotenoids that compose the macular pigment, as well as the place of ß carotene, which is not recommended in the case of a history of smoking. The aim of the randomised, multi-centre AREDS II study, which is currently on-going, is to re-evaluate this initial composition. Whilst awaiting the results (in a few years time), the AREDS I study is still today's reference, adapted to current knowledge.

Concerning polyunsaturated fatty acids: this group contains in particular the group of Omega 6 (role in inflammation, thrombosis and vasoconstriction) and Omega 3 (anti-inflammatory, anti-aggregating and hypolipemiating). The latter are mainly linoleic acid which is the precursor to EPA and DHA, Ω 3 present in rapeseed oil, walnuts and oily fish.

Current knowledge indicates:

• The importance of the Ω3-Ω6 ratio in nutritional intake
• The reduction of the risk of AMD with a reduction of Ω6
• The probable protective role played by Ω3 for AMD found in several studies (AREDS I ; San Giovanni et al., 2009; Chong et al., 2009)
• Finally, the relationship between the density of the macular pigment (probable protector) and the plasmatic rate of Ω3 (Delyfer et al., ARVO 2010)

The NAT-2 prospective, randomised, double-blind study aims to evaluate the protective role of DHA v. placebo on the AMD risk for the second eye. The results, and those of AREDS II will be of major importance in adapting micro-nutritional supplements.

Concerning carotenoids: Lutein and zeaxanthin are xanthophyll pigments specific to the macular region and give it its yellow colour, at the basis of its initial description in 1782 given as “macula lutea”, that is to say yellow spot. In the foveola the zeaxanthin/lutein density ratio is 2 in the physiological state.

Several studies attempt to show the protective role of these pigments on the risk of AMD occurrence, the latter acting as a natural filter of blue light as well as having a probable antioxidant, even antiinflammatory role, as has been recently found in vitro. They are obtained through diet (courgettes, broccoli, spinach…) as well as being integrated into the food supplements currently on the market in association with the initial formula of AREDS I. Nevertheless, doses to be used, as well as the precise indications, are yet to be defined.

The revolution of Anti-VEGF (Anti-Vascular Endothelial Growth Factor)

Obtaining of the marketing licence for Anti-VEGF (2007 in France, whereas FDA approval in the USA was obtained at the end of 2004 for Pegaptanib) was a major turning point in the treatment of AMD. For the first time, in 2006, studies (MARINA, ANCHOR and PIER) showed an improvement in possible visual acuity for hidden and visible neovessels. The Anti-VEGF (Vascular Endothelial Growth Factor) molecule is delivered by intravitreous injections (IVT) (Fig. 4) according to different injection rates: monthly, as circumstances arise or “treat and extend” for reinjections. The PRN treatment programme consists of injecting on request during monthly monitoring after an induction of 3 IVT at 1 month intervals. The “treat and extend” treatment programme is similar but Spaide et al. suggest spacing monitoring in the absence of any neovessel activity (successively postponing checks by two weeks). This programme may be an alternative in case of difficulties in following the programme for certain patients.

Fig. 4: Intra-vitreous injection (IVT).

The PrONTO study (Prospective OCT imaging of Patients with Neovascular AMD Treated with intraOcular Ranibizumab Study), which is a prospective, single centre, non-randomised study involving forty patients, has proved that strict monthly monitoring associated with injections on demand (PRN) was just as efficient as the systematic monthly injections of the pivotal MARINA and ANCHOR studies, with 5.6 IVT at 12 months and 9.9 IVT at 24 months.

A consensus is now appearing with an initial treatment or induction period of 3 IVT at intervals of 1 month, combined with monthly monitoring comprising a visual acuity examination, an ocular fundus examination and an OCT before taking the decision to reinject according to the active (exudative) nature, or not, of the neo-vessels.

In case of initial non-response or tachyphylaxia (exhaustion of response), association with dynamic phototherapy (PDT) using Visudyne is suggested, whilst awaiting the arrival of other molecules and combined treatments.

Therapeutic prospects

Numerous molecules are at the pre-clinical development stage or in the early stages of clinical trials. It is therefore difficult to provide an exhaustive view. We present below the main current research routes, according to their target in the cascade of complex angiogenesis, which has not yet been completely elucidated.

The prevention of AMD involves:

• The combat against oxidative stress and the instillation of prodrug OT551 (OMEGA study, phase II completed, failure in the progress of geographic atrophy is perhaps linked to the method used to deliver therapy).
• High intake of Omega-3 protects against the risk of Age-related macular degeneration (ALIENOR study) and is correlated to the density of the macular pigment (PIVAMOSA study).
• The reduction of “waste products” in the cells of the pigment epithelium (toxic fluorophores and lipofuscin) through the administration of:

• Fenretinide (received orally, phase II on-going)
• 13-cis retinoic acid, another modulator of the visual cycle

Targeting the inflammation that is implicated in the pathogeny, using anti-inflammatory agents:

• anti-inflammatory and antiangiogenic effects of corticosteroids for the Iluvien implant (fluocinolone acetonide, in IVT, phase II for geographic atrophy, moreover currently being FDA approved for diabetic oedema),
• inhibition of the complement cascade: POT-4 and rhCFHp which target complement C3, the ARC1905 Aptamer, directed against complement C5.

Limit the cellular loss of photoreceptors using neurotrophic agents in atrophic AMD:

• CNTF (Ciliary Neurotrophic Factor, in IVT prolonged release mechanism, phase II completed, also being evaluated in pigmentary retinitis)
• Biodegradable brimonidine implants, in phase II.

Limit the action of VEGF, a major inducer of angiogenesis, by direct action or by blocking its receptor:

• inhibition of the intracellular signal for the production of VEGF (sirolimus, everolimus)
• intracellular inhibition of the activity of tyrosine kinases (pazopanib, TG100801, vatalanib, AG013958 and AL39324)
• trap of VEGF receptors = VEGF-Trap (phase III, VIEW study)

Increase the natural antiangiogenic action of PEDF (Pigment Epithelial Derived Factor) by IVT or peri-ocular injection of Ad-PEDF 11D which causes local production of PEDF.

Limit the migration and grouping of the endothelial cells of the future neovessel:

• by specific integrin antagonists involved in ocular angiogenesis (JSM6427, Volociximab)
• by blocking the PDGF (Platelet-Derived Growth Factor) (Aptamer E10030 in IVT and in phase II, which ensure the recruitment, growth and survival of pericytes.)
• by inhibiting the grouping of the microtubules forming the neovessels (Fosbretabulin and Combretastatin, phase II)

Conclusion

The first decade of the 21st century has been marked by a major turning point in the treatment of AMD. The arrival of Anti-VEGF has improved the visual acuity of our patients for the first time in the history of this disease, in its exudative form. The next decade is just as promising and will no doubt be the decade of combined, multi-target treatments, gene therapy and better treatment of atrophic AMD.

References