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Molecular Neuroscience II > 12 - Age Related Macular Degeneration (AMD) and Retinitis Pigmentosa > Flashcards

12 - Age Related Macular Degeneration (AMD) and Retinitis Pigmentosa Flashcards

1
Q

What are the 8 layers of the retina from shallow to deep?

A
  • Vitreous fluid
  • Ganglion cell layer
  • INL (inner nuclear lining)
  • ONL (outer nuclear lining)
  • Photoreceptors
  • RPE (retinal pigment epithelium)
  • Choroid (Bruch membrane)
  • Sclera
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2
Q

What is Stargardt disease?

A

Loss of central acute vision caused by degeneration of macular cones and ABC transporters.

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3
Q

What are the two forms of age related macular degeneration?

A
  • Dry (most common, slow atrophy and loss of vision)

- Wet (10-20%, fast loss of vision)

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4
Q

What is soft drusen?

A

Mineral deposits in macula.

the presence of larger and more numerous drusen in the macula is a common early sign of age-related macular degeneration (AMD).

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5
Q

Why are caucasians more at risk for age related macular degeneration?

A

Lighter eye colour, melanin prevents formation of lipofuscin

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6
Q

What is lipofuscin?

A

Lipofuscin is the name given to finely granular yellow-brown pigment granules composed of lipid-containing residues of lysosomal digestion.

It is considered to be one of the aging or “wear-and-tear” pigments, found in the liver, kidney, heart muscle, retina, adrenals, nerve cells, and ganglion cells.

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7
Q

How does the retinal pigment epithelium differ between the fovea and surrounding regions?

A

It is slightly thicker in the fovea, even though the fovea as a whole is thinner due to lack of ganglion cell layer.

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8
Q

In wet AMD, there is a break in the ____ membrane leading to accumulation of ____ in the retina

A

In wet AMD, there is a break in the ‘Bruch’ membrane leading to accumulation of ‘blood vessels’ in the retina

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9
Q

How do monoclonal antibodes treat Wet AMD?

A

Bind to vascular endothelial growth factor (anti-VEGF) to block blood vessel growth.

Not practical because they need to be injected monthly and the dose is thousands of dollars.

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10
Q

Who was William H. Dobelle?

A

Developed human visual cortex prosthetics

This is an alternative approach to retinal implants.

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11
Q

What is the epiretinal location for implants? Where these implants successful?

A

Implant on ganglion cell layer. Needs CCTV camera on glasses which provides input to implant on retina.

Formulas needed to be added to the signal to mimic physiological processing cascade.

Quite unsuccessful.

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12
Q

What is the most successful location for retinal implant?

A

Subretinal implant

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13
Q

Describe the anatomy of the macula lutea

A
  • 5-6 mm in diameter

- Centre is called the fovea (max number of cones)

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14
Q

What does the ganglion cell layer converge to form?

A

The optic nerve

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15
Q

What is the inner nuclear layer of the retina composed of?

A

Cell bodies of bipolar, horizontal and amacrine cells

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16
Q

What is the outer nuclear layer of the retina composed of?

A

Cell bodies of photoreceptors

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17
Q

What is the retinal pigment epithelium layer of the retina composed of?

A

A monolayer of cells that gives metabolic support to the photoreceptors.

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18
Q

What is the choroid? What are the two innermost layers of the choroid called?

A

The vascular layer of the eye

  • Bruch’s membrane and choriocapillaris are two innermost layers of the choroid
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19
Q

What is Bruch’s membrane?

A

A complex of collagen and elastic layers interposed between the retinal pigment epithelium and choroid

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20
Q

What is the choriocapillaris of the eye?

A

The capillary bed in the inner choroid that provides the metabolic needs of the outer retina

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21
Q

What is the sclera?

A

The hard fibrous outer layer of the eye, usually white.

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22
Q

How does age related macular degeneration (AMD) and Stargardt disease affect vision?

A

Central vision is gradually lost due to predominant degeneration of macular cones

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23
Q

How does retinitis pigmentosa affect vision?

A

Tunnel like vision, where periphery is lost due to the degeneration of rods

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24
Q

What percent of blindness is caused by age related macular degeneration (AMD)?

A

50%

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25
Q

What percent of the population over 80 will develop AMD?

A

60%

26
Q

What are pathological changes seen in patients with dry AMD? (2)

A
  • Extensive soft drusen

- Geographic atrophy of the fovea

27
Q

What are pathological changes seen in patients with acute wet AMD? (1)

A
  • Visible subretinal or intraretinal haemorrhage from the choroidal neovascular membrane (CNV)
28
Q

What is a pathological change seen in patients with end-stage wet AMD?

A

A macular scar. Untreated wet AMD will eventually result in a permanent disc shaped macular scar

29
Q

What are 6 risk factors for age related macular degeneration (AMD)?

A
  • Age
  • Ethnicity (white more prone)
  • Smoking
  • Light exposure
  • Hypertension
  • Genetic predisposition
30
Q

Which cells of the retina have microvilli? Why?

A

Retinal pigment epithelia (to project among photoreceptor cells)

31
Q

What part of the retina has taller retinal pigment epithelial cells?

A

The fovea

32
Q

Describe the pathology of dry AMD (2)

A
  • Drusen form under the retina between the RPE and Bruch’s membrane
  • Reticular drusen can occur in the photoreceptor layer
33
Q

Describe the pathology of wet AMD (4)

A
  • Presence of choroidal neovascularization (CNV)
  • CNV forms within the choroid and enters the sub-RPE space through a break in Bruch’s membrane
  • The CNV then proliferates, which can lead to further growth between the retina and RPE layers.
  • Abnormal vascular growth causes leakage of fluid and haemorrhage which can cause image distortion and thickening and elevation of the retina (detected clinically)
34
Q

How does the choroid change with age?

A

The choriocapillaris becomes less dense

35
Q

What type of proteins do drusen in dry AMD contain?

A

Alternative complement pathway proteins

  • The complement system heps antibodies and phagocytic cells to fight infections
  • In each of the three complement pathways (classical, alternative and lectin) there is observed activation of the C3 molecule, initiation of pro-inflammatory reactions and activation of the terminal complement pathway.
36
Q

What is the basic structure of all the complement pathways? (6)

A
  1. Initiation
  2. Formation of C3 convertase
  3. Cleavage of C3
  4. Formation of C5 convertase
  5. Cleavage of C5
  6. Formation of the membrane attack complex
37
Q

How is the complement pathway amplified? How does this contribute to dry AMD?

A

C3 is proteolytically activated to C3b due to C3 cleavage, and forms a new C3 convertase molecule that will cleave more C3, creating a positive feedback loop.

The positive feedback loop leads to an abundance of C3

38
Q

What are the genes of the complement pathway that are connected to AMD?

A
  • CFH (complement factor H, main inhibitor of alternative pathway, polymorphism may cause dry AMD)
  • Complement factor B (CFB)
  • Complement factor I (CFI)
  • Complement component 2 (C2)
  • Complement component 3 (C3)
  • Complement factor H-related protein 3 and 1 (CFHR3 and CFHR1)
  • Polymorphism in promoter of HTRA1 (high temperature requirement A-1 serine peptidase 1)
39
Q

What is the major genetic risk factor for AMD?

A

Polymorphism in the promoter of HTRA1 (high temperature requirement A-1 serine peptidase 1).

  • Risk associated with a twofold increase in expressed HTRA1 protein.
  • This gene encodes a serine peptidase, which in vitro cleaves clusterin, ADAM9 and vitronectin.
  • Clusterin and vitronectin are inhibitory complement proteins that prevent formation of the membrane attack complex.
  • ADAM9 is a metallopeptidase, which acts as an enzyme to release a growth factor, pro-HB-EGF
40
Q

What are five treatments for wet AMD?

A
  • Laser surgery to damage neovasculature
  • Photodynamic therapy, putting light activated drug into blood vessels to produce singlet oxygen and free radicals that destroy abnormal vasculature
  • Monoclonal antibodies against vascular endothelial growth factor (anti-VEGF)
  • Macugen, a vascular endothelial growth factor (VEGF) inhibitor
  • Eylea, an AMD medication that contains chimeric soluble VEGF receptors. Aflibercept (eylea) acts as a decoy protein, which by binding to VEGF and placental growth factor blocks angiogenesis.
41
Q

What is the main treatment for dry AMD? (1)

What are alternative treatments to dry AMD? (6)

A

Main
- Vitamins, antioxidants, omega 3 fatty acids and zinc

Alternative

  • Compstatin, a peptide that is administered by intravitreal injection and which binds to C3 protein of complement pathway. Inhibits binding of C3 molecule to C3b in C3 convertase
  • CFH (complement factor H) injection
  • PEDF (serine protease inhibitor isolated from RPE cells, can cause neurite outgrowth - good)
  • Statins (reduce plasma cholesterol levels)
  • Intravitreal blockade of complement component 3 (C3)
  • MDM2 inhibitors (blockers of E3 ubiquitin-protein ligase, counteracts growth of neovasculature by stimulating P53-mediated regulation of cell cycle. Similar effects observed with low dose radiation.
42
Q

Which method of dry AMD treatment might be useful with other diseases where there is uncontrolled cell proliferation (eg. retinitis pigmentosa)?

A

MDM2 inhibitors

These are blockers of mouse double minute 2 homolog (AKA E3 ubiquitin-protein ligase). MDM2 is an inhibitor of the p53 (AKA tumor suppressor p53, which inhibits cell growth and proliferation) transcriptional activation.

43
Q

What is retinitis pigmentosa (RP)?

A

The term given to a set of hereditary retinal diseases that feature degeneration of rod and cone photoreceptors

44
Q

What is the worldwide prevalence of retinitis pigmentosa?

A

1 in 4000

45
Q

What are the three ways that retinitis pigmentosa can be inherited?

A

The disease can be inherited as

  • an autosomal-dominant (about 30–40% of cases),
  • autosomal-recessive (50–60%), or
  • X-linked (5–15%) trait.

More than 100 genes are implicated so far.

46
Q

In retinitis pigmentosa, which degenerate first, rods or cones?

A

The rods are degenerating first which results in tunnel-like vision. Patients typically lose night vision in adolescence, side vision in young adulthood, and central vision in later life.

47
Q

What are three pathological changes associated with retinitis pigmentosa?

A
  • Loss of photoreceptors
  • Accumulation of intraretinal deposits
  • Attenuated arterioles
48
Q

Why is retinitis pigmentosa often diagnosed late?

A

Patients can lose 90% of cones in the fovea before having a reduction in visual acuity

49
Q

How is retinitis pigmentosa nutritionally treated? (4)

A

Slow disease progression

  • Vitamin A palmitate (15,000 IU)
  • Omega-3 rich fish
  • Reduce vitamin E intake, but not too much.
  • High DHA from fish good!
50
Q

What are two non-nutritional retinitis pigmentosa treatments? (5)

A
  • Calcium channel antagonists
  • Gene therapy
  • Biochemical pathway intervention
  • Transplantation
  • Implanted electrical devices
51
Q

How can retinitis pigmentosa be treated by gene therapy?

A

Autosomal recessive: supplementation of dysfunctional gene

Autosomal dominant: Gene delivery and RNA interference or transcriptional repression of mutated gene

52
Q

How can gene suppression of autosomal dominant retinitis pigmentosa be done? (4)

A
  • Zing finger artificial transcription factors
  • Zinc finger nucleases cause a double stranded break leading to correction of the mutation through recombination
  • miRNA and shRNA degradation of the endogenous target transcript while sparing introduced resistant mRNA (altered sequence)
  • Catalytic cleavage of the target transcript by ribozymes
53
Q

How can light sensitivity be restored in retinitis pigmentosa patients?

A

Adeno-associated virus carrying Natronomonas pharaonis halorhodopsin (eNpHR) applied in the retina

54
Q

What is a null mutant of peripherin-2 mouse (rds mouse)?

A

A neurodegeneration model for retinitis pigmentosa.

Peripherin-2 is required for the generation of photoreceptor outer segment discs. The neurodegeneration is slow.

Transplanted rod photoreceptor precursor cells express peripherin-2 and the expression is maintained more than 10 weeks (restored function).

55
Q

Describe how transplantation can treat retinitis pigmentosa

A

Transplanting rod photoreceptor precursor cells (P1-postnatal day 1) into the outer nuclear layer (ONL) can restore some visual function.

56
Q

How is progress of the artificial retina measured? What is a method that is being developed?

A

Measured by electrode count

Methods to transmit optical signal directly to the visual cortex are being developed.

57
Q

What are three types of visual eye prosthetics?

A
  • Epiretinal (outside of retina/eye)
  • Subretinal (between RPE layer and bipolar cells, best implant)
  • Suprachoroidal (behind choroidal vessels)
58
Q

Which type of retinal implant requires an external camera?

A

Epiretinal chip

59
Q

What is a MPDA?

A

Micro-photodiode array, it converts incoming light into electric signal in an intensity-dependent manner. The light signal can be amplified and processed.

Used in subretinal implants.

60
Q

Where are subretinal implants placed?

A

In the fundus of the eye, new retinal vessels can grow over top the chip.

61
Q

What type of results are achieved with subretinal implants?

A
  • Implant is well tolerated
  • Patients could locate bright objects on dark table, discern patterns and name certain objects, also discern shades of grey
62
Q

What is choroideremia?

A

An X-linked recessive disease that leads to blindness, due to mutations in the CHM gene. Can be treated by gene delivery.

Molecular Neuroscience II (7 decks)

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