Lecture 27 - Preventing and Treating Blindness

Question 1

What are some causes of retinal blindness?

Answer 1

AMD
Diabetic retinopathy
Retinal vascular occlusions
Hereditary retinal disease
Vitreoretinal interface disease
Myopic macular degeneration
Retinal detachment
Trauma

Question 2

What is the most common cause of untreatable blindness in the developed world?

Answer 2

AMD.

Question 3

How many RPE cells is there per photoreceptors?

Answer 3

1 RPE cell per 20-25 photoreceptors.

Question 4

What is the purpose of epithelial transport in the RPE?

Answer 4

Tight junctions, forming the outer blood retinal barrier controlling the supply of nutrient to neurosensory retina, ion homeostasis and elimination of water and metabolites.

Question 5

What does spatial buffering of ions in the RPE do?

Answer 5

Controls the ionic composition of the retina for efficient photo transduction.

Question 6

Why does the photoreceptor outer segment have to be replaced?

Answer 6

POS are exposed to constant photo-oxidative stress and are constantly being renewed by shedding, RPE phagocytosis and digestion.

Question 7

How many people does AMD affect globally?

Answer 7

200 million - 11 million suffering from late AMD with riding prevalence.

Question 8

What is the clinical classIfication of early stage AMD?

Answer 8

A few small druses (>63um, <125 microns)

Question 9

What is the clinical classification of intermediate stage AMD?

Answer 9

Larger and more frequent druses (>125 microns).
Pigmentary changes in RPE with good vision in daylight and bad in low light.

Question 10

What is the clinical classification of late stage AMD?

Answer 10

Dry or geographical atrophy.
Wet or neovascular.

Question 11

What are drusen?

Answer 11

Lipid and protein deposits under the RPE and Bruch’s membrane that accumulate.

Question 12

Describe dry AMD.

Answer 12

Loss of choriocapillaris and RPE.
Secondarily get photoreceptor atrophy.

Question 13

Describe geographical atrophy.

Answer 13

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.

Question 14

Describe the pathogenesis of AMD.

Answer 14

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.

Question 15

Why does the macula degenerate first?

Answer 15

Because it has the highest light exposure, oxygen uptake and blood supply so it is oxidatively susceptible to ROS.

Question 16

Describe complement dysregulation in AMD.

Answer 16

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.

Question 17

What are some AMD genes?

Answer 17

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.

Question 18

Describe hereditary retinal dystrophies.

Answer 18

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.

Question 19

Describe retinitis pigmentosa.

Answer 19

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.

Question 20

Describe macular dystrophies.

Answer 20

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.

Question 21

Describe gene therapy.

Answer 21

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.

Question 22

What is the problem with gene therapy?

Answer 22

> 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.

Question 23

What is some treatment for wet AMD?

Answer 23

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.

Question 24

What are some treatments for dry AMD?

Answer 24

Anti-complement therapies.
Visual cycle modulation.
Neuroprotection.
Cellular treatments for rescue and transplant.

Question 25

Describe complement inhibition.

Answer 25

Block C3B production and C5 converts activity which reduced progression of GA.
Given via monthly injections in the eye.

Question 26

Describe some anti-inflammatory treatments.

Answer 26

Statins
Integrin inhibitors that target macrophages and decrease inflammasome activation.

Question 27

Describe visual cycle modulation.

Answer 27

Disrupting the conversion of retinol to rhodopsin decreases toxic waste products for photoreceptor rescue such as ciliary neurotrophic factors.
Brimondine implants.

Question 28

Describe autologous RPE transplantation.

Answer 28

RPE patch put in and works well in some yes and shows proof of concept.
Does require extensive surgery to harvest the patch and sometimes the patch can be damaged during retrieval.
May be able to use pluripotent stem cells.