16.2.2  Impact of Genetics

In view of recent advances in medical genetics of AMD and related diseases by genome-wide association studies, it is advantageous to consider other drugs and other routes. About 70% of the risk of developing AMD is accounted for by alleles in several complement cascade genes and the LOC387715/HTRA1 locus, and imply a role of the innate immune system in AMD etiology. A more thorough understanding of the workings of the innate immune system in the eye and at the blood-retina barrier is important. Meta-analyses predict additional risk alleles. Other risk factors were discovered in epidemiological studies and include diet, smoking, light exposure, blue irides, drinking, and others. It remains to be determined what initiates the disease process in AMD, and it is possible that any number of putative causative events start the disease. We need to know more about the precipitating events in AMD, and how the body normally protects itself from these insults. Such information might generate better drugs.

Better knowledge of the VEGF-mediated pathways that cause neovascularization may provide alternative potential therapies. New drugs may prove useful that block: (1) the interaction of VEGF with its receptor, (2) the formation of VEGF or promote its inactivation or breakdown, (3) the formation of its receptor, and (4) the action of the receptor’s signaling pathway.

16.3  Better Tools for Delivery and Treatment

Given this current state of knowledge, nonetheless, it is equally clear that we need better tools and approaches to deliver a drug to its correct target. We recognize the need for effective, convenient, safe, and inexpensive drug delivery. No matter how potent a new drug might be, its delivery is a concern. Delivery to an inappropriate target can be life threatening. Ultimately it comes down to simple arithmetic: What is the balance between minimizing side-effects of a drug and maximizing the duration of time for which the correct dose of drug is delivered to the target cell?

16.3.1  Barriers to Success

Regardless of the type of drug, each takes a perilous journey to its subcellular target. These include but are not limited to – (1) physical barriers such as fascia, membranes, linings, or blood vessel walls, (2) voluminous gaps or interstitial and intracellular spaces that result in dilution, (3) convection, pressure, and flow barriers such as solvent flow including blood, aqueous, and lymph flow, which can force drugs away from the target cell, (4) binding of the drug to extracellular matrices such that charge-charge or hydrophobic interactions bind or entangle the drug, (5) enzymatic activities that metabolize the drug, (6) compartmentalization, sequestration, and