Lecture 27 - Preventing and Treating Blindness Flashcards
What are some causes of retinal blindness?
AMD
Diabetic retinopathy
Retinal vascular occlusions
Hereditary retinal disease
Vitreoretinal interface disease
Myopic macular degeneration
Retinal detachment
Trauma
What is the most common cause of untreatable blindness in the developed world?
AMD.
How many RPE cells is there per photoreceptors?
1 RPE cell per 20-25 photoreceptors.
What is the purpose of epithelial transport in the RPE?
Tight junctions, forming the outer blood retinal barrier controlling the supply of nutrient to neurosensory retina, ion homeostasis and elimination of water and metabolites.
What does spatial buffering of ions in the RPE do?
Controls the ionic composition of the retina for efficient photo transduction.
Why does the photoreceptor outer segment have to be replaced?
POS are exposed to constant photo-oxidative stress and are constantly being renewed by shedding, RPE phagocytosis and digestion.
How many people does AMD affect globally?
200 million - 11 million suffering from late AMD with riding prevalence.
What is the clinical classIfication of early stage AMD?
A few small druses (>63um, <125 microns)
What is the clinical classification of intermediate stage AMD?
Larger and more frequent druses (>125 microns).
Pigmentary changes in RPE with good vision in daylight and bad in low light.
What is the clinical classification of late stage AMD?
Dry or geographical atrophy.
Wet or neovascular.
What are drusen?
Lipid and protein deposits under the RPE and Bruch’s membrane that accumulate.
Describe dry AMD.
Loss of choriocapillaris and RPE.
Secondarily get photoreceptor atrophy.
Describe geographical atrophy.
Pleomorphic
Faster progression in some subtypes
Extrafoveal and multifocal GA faster than central.
2 in 3 unable to drive within 2 years.
1 in 5 registered blind at 6 years.
Describe the pathogenesis of AMD.
Age and oxidative stress lead to mitochondrial DNA damage leading to impaired RPE phagocytosis and autophagy.
This leads to RPE cell dysfunction, accumulation of lipofuscin and alternate complement activation and druses build up.
This leads to RPE cell death and an angiogenic response.
Why does the macula degenerate first?
Because it has the highest light exposure, oxygen uptake and blood supply so it is oxidatively susceptible to ROS.
Describe complement dysregulation in AMD.
Variants in the complement system genes, including CFH, CFI, C3 and C9 are strongly associated in AMD pathogenesis.
C3 and C5 complement proteins accumulate in the druses and the sub-RPE space in AMD.
What are some AMD genes?
37 genes.
Mutations in CFI, CFH, C3 and C9.
Most common risk factor is a mutation in FH - a T-C substitution in exon 9 of the CFH gene on 1q.
Describe hereditary retinal dystrophies.
Single gene defect dystrophies = 1:3000.
Over 200 genes identified to date involving a huge variety of cellular pathways and mechanisms.
20% gene defects unidentified.
Describe retinitis pigmentosa.
Night blindness then progressive field constriction followed by central vision loss in late stages.
Symptoms begin to show in late teens/early twenties.
Primarily rod defects but cones rely on rod function to survive so if rod cells die so do cones.
Can be isolated to the eyes or syndromic.
Inherited as AR, AD or X-linked.
Describe macular dystrophies.
Stargardt disease as an example which is AR and has a build up of abnormal phototransduction products in RPE which in turn leads to RPE and photoreceptor loss caused by ABCA4 gene.
Describe gene therapy.
Corrects simple loss of function in monogenetic diseases, works best with a later onset and known family history.
RPE 65 gene defect that causes a rare form of early onset recessive RP is available as a licensed therapy called luxturna. Uses AAV virus vector injected subretinally to transfect RPE cells with a wt RPE65 gene.
What is the problem with gene therapy?
> 50% of all cases the gene defect is unknown so can’t be targeted.
Several defects are not correctable and gene therapy can’t improve function where the cell is dead.
What is some treatment for wet AMD?
Vascular endothelial growth factor (VEGF) stimulates new vascular growth in the retina. Anti-VEGF agents prevent further choroidal new vessel growth, causing vasoconstriction and reduced vascular leak.
Examples are ranibizumab, bevacizumab and farcimab.
Not 100% effective and don’t remove the scar.
What are some treatments for dry AMD?
Anti-complement therapies.
Visual cycle modulation.
Neuroprotection.
Cellular treatments for rescue and transplant.
