10/28: Treatment of Retinal Disorders

Question 1

Why don’t I see?

Can neuroscience help?

Answer 1

Colleen M. Cebulla, MD, PhD

Question 2

The Eye is an extension of the Brain.

Answer 2

The retina is part of the brain.

Question 3

Pupil

Answer 3

The hole in the center of the eye that lets light through to the retina.

Question 4

Choroid

Answer 4

supplies blood to the outer retina.

Contains blood vessels.

Question 5

Techniques to diagnose visual

disorders: mostly noninvasive

Answer 5

• Pupil exam
• Fundus photos
• Optical coherence tomography
• Fluorescein angiography
• Visual Field testing
• Electrophysiology (assess signaling)

Question 6

OCT-noninvasive imaging

based on coherence of light

Answer 6

• OCT: light as ultrasound : sound
• Noninvasive
• Micron resolution
• 3 -D

Question 7

Categories of Visual Loss

Answer 7

• Anterior Segment (Cornea, cataract)
• Glaucoma*
• Retina*
• Neuro-ophthalmology*
• Oculoplastics* (eyelid & orbital disease)

*Important for Neuroscientists

Question 8

Keratoprosthesis:

Answer 8

Artificial Cornea

Question 9

the most common cause of irreversible blindness worldwide

Answer 9

Glaucoma

Question 10

What cells are damaged in Glaucoma?

Answer 10

ganglion cells

Question 11

Glaucoma:

What happens…

Answer 11

Aqueous Fluid enters the
front the eye.
In certain people, the fluid drains (out through the angle)
too slowly out of the eye causing the fluid to build up and the pressure to increase.

Glaucoma can occur in low pressure individual, not just high pressure ones, as previously thought.

Question 12

Glaucoma Diagnosis:

A Historical Perspective

Answer 12

Pre 1980’s
• Intraocular pressure (IOP) > 21 =
glaucoma

1980’s to mid 1990’s
• IOP > 21 + visual field (VF) loss =
glaucoma

Mid 1990’s to present
• Glaucomatous optic disc damage = glaucoma

Question 13

IOP

Answer 13

Intraocular pressure

Question 14

Definition of Glaucoma

Answer 14

• A group of disease in which results in optic neuropathy characterized by “cupping” optic nerve rim loss

• Optic nerve damage which
correlate with visual field loss

• How can we study this?

Question 15

Optic Nerve Cup-to-Disc Ratio

Answer 15

….OCT Retina NFL

Question 16

Pathophysiology

Answer 16

• Intraocular Pressure related connective tissue stress and strain
• Blood flow deficiency/nutrient diffusion/ischemia of the laminar and prelaminar tissue
• Auto-immune and inflammatory mechanism
• Genetic Predisposition

Question 17

Types of Glaucoma:

Primary vs Secondary

Answer 17

• Primary is used when no
identifiable cause for the
glaucoma can be identified.
Starts with the eye.. internal causes.

• Secondary is used when an
abnormality can be found.
Like blood vessels invading the wrong areas of the eye.

Question 18

There are many different types of glaucoma.

Answer 18

They can be divided into 5 groups, depending on whether someonre is born with the disease, whether they are open or closed angle, and primary or secondary:

• Primary OAG
• Secondary OAG
• Primary ACG
• Secondary ACG
• Congenital Glaucoma

Question 19

Measuring Intraocular Pressure

Answer 19

lowering interocular pressure is one of the ways glaucoma is treated.

Question 20

Medication

Answer 20

Some people use eye drops to ease glaucoma

Question 21

Surgical Procedures

Answer 21

• Laser Surgery
• Filtering Surgery
• Cyclodestructive Surgery
• Drainage Device Surgery

Question 22

Glaucoma

Answer 22

“Caveman” procedures

Huge need for new animal models and treatments
• Neuroprotection!!

Question 23

Retinal Problems

Answer 23

Many retinal problems are blood vessel problems!
• Hypoxia
• Oxidative stress

Question 24

Dry Macular Degeneration

Answer 24

Drusen

Question 25

Wet Macular Degeneration

Answer 25

Abnormal blood vessel development under the retina that causes leaking of blood in the eye and scar tissue. The worst form of macular degeneration. Treated by applying anti-VEGF medication. Remember that the brain cells hate blood, and the retina is part of the brain.

Question 26

Macular Degeneration

Answer 26

Caused by Abnormalities in the retinal epithelium. Causes loss of photoreceptors and vision loss over time.

Question 27

Diabetic Macular Edema

Answer 27

Capillary dropout is a big problem in diabetes

Question 28

Central Retinal Artery | Occlusion

Answer 28

......

Question 29

Central Retinal Vein Occlusion

Answer 29

......

Question 30

Retinal Detachment:

Answer 30

results in Retinal hypoxia § Prevalent cause of visual loss § 28,000 cases per year § 1/300 lifetime risk § Incidence increases with pseudophakia, aphakia, myopia, and trauma

Question 31

Causes of Vision Loss After Retinal Detachment:

Answer 31

• Photoreceptor cell loss/dysfunction •“Re-wiring” of the retina • Formation of scar tissue (proliferative vitreoretinopathy)

Question 32

``` Scarring: Proliferative Vitreoretinopathy (PVR) ```

Answer 32

* Scar tissue forms around the retina after RD * Leading cause of failure of retinal detachment repair * Severe visual loss

Question 33

Retinal Degenerations: | Retinitis Pigmentosa

Answer 33

* Loss of photoreceptors (first rods, then cones) * Progressive * Night blindness * Tunnel vision * Severe vision loss

Question 34

hypoxia

Answer 34

reduction of oxygen supply to a tissue below physiological levels despite adequate perfusion of the tissue by blood. Insufficient levels of oxygen in blood or tissue.

Question 35

Retinitis Pigmentosa genetics

Answer 35

One of the most common inherited retinal degenerations Can be autosomal dominant, autosomal recessive, or X-linked inheritance

Question 36

Electroretinogram

Answer 36

..... There's a loss of transmission in Retinal Pigmentosa.

Question 37

Novel strategies to treat retinal | degenerations

Answer 37

* Neuroprotective growth factors * Artificial Vision * Stem Cells * Gene therapy

Question 38

CNTF

Answer 38

Neuroprotective Growth Factor CNTF Trials for retinal degeneration Cell Capsules full of CNTF suetered into the eye to release CNTF gradually over time did well at protecting cones from dying. Didn't improve anything, just slowed down degeneration.

Question 39

CNTF: | What it does....

Answer 39

* Reduced loss of photoreceptor density * Improved retinal thickness * Not significant for visual acuity/function * Reversible decrease in sensitivity in high dose early Retinitis Pigmentosa group * Under evaluation for other retinal diseases

Question 40

Artificial Vision?

Answer 40

1. Camera Glasses: Captures image and wirelessly transmits data to implant 2. Microchip placed on the surface of the retina. Retinal implant and processor stimulates retina. 3. Electrical Signals are sent from the retina via the visual pathway (galnglion cells ---> optic nerve, etc.) to vision processing centers in the brain. Not great vision, Can see high contrast objects.

Question 41

Eye Transplant?

Answer 41

* How to reattach 1-2 million axons? | * Analogous to spinal cord injury problems

Question 42

Stem cells for retinal degenerations

Answer 42

- Lack structure - Would they “know where to go?” - Would they integrate with the right cells and function properly within tissues and systems?

Question 43

Press Release: 10/2014

Answer 43

Subretinal injection human embryonic stem cell-derived RPE No immune suppression ``` Out of the 18 study participants •10/18 “significantly better” vision • 1/18 worse • 7/18 stable ``` Expanding to multiple centers Watching for cancers...

Question 44

Leber's Congenital Amaurosis

Answer 44

* Leber's Congenital Amaurosis (LCA) was first described in 1869 by Theodore Leber. * Type of RP * Affects 1 in 80,000 individuals * Autosomal recessive * Severe vision loss at birth or in the first months of life

Question 45

Genetics of LCA

Answer 45

• Over 12 known genes cause various forms of LCA (LCA1 – LCA12). Additional genes exist. • LCA genes encode proteins which are crucial for photoreceptor function and/or survival. • Some proteins associated with LCA are expressed in photoreceptors; others in RPE cells

Question 46

RPE

Answer 46

retinal pigment epithelium

Question 47

Mutations in RPE65

Answer 47

Inherited mutations in the RPE65 gene (LCA2) •Absent or dysfunctional protein Target for gene therapy: •Goal: delivery RPE65 gene into RPE cells •Express normal RPE65 protein •Restore functional Vitamin A metabolism and photoreceptor function

Question 48

Animal Models for LCA2 | RPE65

Answer 48

* RPE65 knockout mice * Briard dog which has inherited mutations in RPE65. * Both these animal models have severe loss in vision but retain some of their photoreceptor cells

Question 49

Results of the Canine Gene Therapy

Answer 49

RPE65 protein expressed in RPE cells Restoration in vision in this eye Durable response with a single injection • recovery of vision> 8 years Good safety profile

Question 50

Gene Therpy Clinical Trials For Leber's Congenital Amaurosis (LCA2)

Answer 50

3 human Phase I clinical trials started in 2008 – (London, Philadelphia) Initial studies on 9 young adults (19–26 yrs old) with LCA2 have been reported. All had significant visual loss, but some remaining photoreceptors.

Question 51

Early Results from the Phase I Trials

Answer 51

In essentially all cases, there was significant improvement in retinal function and visual response. ``` Patients reported • General improvement in vision • Increased sensitivity to light • Ability to get around in dim light • Some cases: ability to read several lines in an eye chart. ``` Importantly, No noticeable toxic effects or immune response

Question 52

More comprehensive and long-term study to fully | evaluate LCA2-RPE65 gene therapy .....

Answer 52

Dose of the AAV-RPE65 Site of injection Single vs multiple injections Long term effect on visual function Determine long term safety Assessment of Rod vs Cone Function Can visual acuity be improved? Evaluate more patients of different ages