2. TOPICS FOR DISCUSSION
• Basics and Approach to IRDs
• Review of gene therapy in retinal diseases
• Newer therapeutic options for IRDs
• How the landscape of inherited retinal degeneration has shifted
3. BASICS OF IRDs
• Inherited retinal diseases:
• Phenotypically diverse – typically affect structure and function of outer retina
• Various genetic mutations
• Overall rare but an important class of diseases
• Most common cause of visual impairment in children and young adults
• 20-25% blindness in working age population due to IRDs
• Prevalence higher in India than the western world
• Prevalence higher in rural and tribal populations compared to urban (possibly due
to more consanguinity)
4. • Why are IRDs challenging?
• Vast heterogeneity
• Difficult to characterize
• Challenging to diagnose correctly by a clinician who is not an IRD expert
• Families are often bewildered by the progressive vision loss and are
concerned about whether and when blindness will develop.
• Patients are always anxious about progression and understandably always
have the same question in all annual visits.
BASICS OF IRDs
6. • Medical history is vital (as always)
• Age of onset
• Symptom complex at onset
• Progressive or stationary?
• If available: previous ophthalmological records: especially BCVA, VF
• Whether the vision loss is:
• Peripheral/ night blindness – rod predominant disease
• Central/ photophobia/ hemeralopia – cone predominant disease
APPROACH TO IRDs
7. APPROACH TO IRDs
• Family history, especially history of consanguinity
• Try to develop an inheritance pattern using a 3-generation-pedigree
chart
• Systemic disorders in family: e.g. DM in mother/ hearing loss in sister
can point to mitochondrial inheritance
• Consanguinity – associated with AR disorders
• VERY IMPORTANT to ask for associated systemic features– associated
syndromic conditions
• Usher syndrome – hearing loss
• Bardet-Biedl syndrome – obesity, polydactyly, mental retardation, nyctalopia
8. • Important to rule out acquired conditions that can mimic IRDs
clinically
• Vitamin A deficiency
• Toxicity to drugs such as phenothiazines, hydroxychloroquine, pentosan
polysulfate
• Autoimmune or carcinoma related retinopathy
• Diffuse uveitis/ infections/ arterial occlusions
APPROACH TO IRDs
9. • Importance of a good history and review of previous records cannot
be overemphasized.
APPROACH TO IRDs
A case of
deferoxamine toxicity
in a patient with
Sickle Cell on
transfusion therapy
10. ELECTROPHYSIOLOGY
• Identify site of damage
• Pin-point the cell type involved in the degenerative process
• Non-invasive, important when fundus image doesn’t correspond with vision
• Include:
• Full-field ERG
• Multi-focal ERG
• Pattern ERG
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14. Basics of ERG
• In Pattern ERG P50/ positive peak – indicates macular function
• N95/ negative deflection – indicates ganglion cell function
• However, PERG is affected by refractive errors and media opacities
• Spatial localization of defects is better with mfERG
20. GENETIC TESTING
• Foundation of the age of miracles
• Landscape has changed drastically in the last decade
• BEFORE: difficult to access, prohibitively expensive, only test a few genes at
a time using standard techniques, results did not affect clinical care
• NOW: Accessible, from free to inexpensive, option of whole-gene-
sequencing, results have a HUGE bearing on treatment options
• Free if patients undergo testing by the Province. Very inexpensive and
much faster if using private providers.
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26. • Important to know important aspects of the Visual Cycle
• E.g. RPE65 gene converts all-trans-retinyl ester into 11-cis-retinol
• So RPE65 deficiency causes retinyl esters to accumulate causing recessive
blinding disorder – LCA
• Mechanisms of gene therapy
• Augmentation – Recessive disease
• Suppression – Dominant disease
• Addition – Subretinal delivery of growth factors
• Optogenetics – Neuromodulation
• Why RPE is a favorable target?
• RPE is a single cell layer
• So disorders where photoreceptors damage is secondary to genetic RPE problems
give better results with gene therapy
GENE THERAPY
27. • Viral vectors
• Ideally good transduction effects, low immunogenicity, no mutagenesis, cell specific tropism but
with ability to target both dividing and non-dividing cells, unlimited cloning capacity while having
low cytotoxicity
• Adeno, adeno-associated (AAVs), Retro, Lentiviruses
• AAVs most promising right now
• MAIN DISADVANTAGE – Low packaging capacity (e.g. ABCA4 for Stargadt is too large for AAV4)
• Non-Viral vectors
• Nanoparticles, Liposomes, naked DNA
• Many unresolved issues so not preferred
GENE DELIVERY SYSTEMS
28. VARIANTS OF GENE THERAPY
• Optogenetics
• “Conventional” gene therapy cannot overcome lack of photoreceptors which
is usually the case in advanced IRDs
• AAV vectors deliver Rhodopsin and Melanopsin to functional bipolar and
ganglion cells – activated by light – trigger nerve impulse
• Sounds incredible but opsins have very low efficiency in non native cells
• AON
• Antisense oligonucleotide (ASO) therapy
• Uses much smaller molecules so BIG ADVANTAGE: intravitreal route possible
• CRISPR/CAS-9 Therapy: gene editing
• Trying to overcome a major hurdle: Current therapies ARE USELESS IN
AUTOSOMAL DOMINANT DISORDERS
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31. LUXTURNA
• Voretigene Neparvovec (VN)
• First USFDA gene therapy in 2017
• For Biallelic LCA (LCA type 2 – rarer, more severe)
• Supposed to be a one-time treatment
• Why? – Because RPE cells are non-dividing, so delivered genome remains
stable
34. CELL THERAPY
• Cell replacement therapy aims at replacing damaged host cells with transplanted
donor cells
• Mutation independent and can work even when the cells are completely lost
• Potential For RPE transplantation as a viable therapy came from studies noting
improvement in visual acuity following the transplantation of autologous RPE
• Again, why RPE is so attractive? - The RPE cells grow readily in laboratory
cultures and unlike other cell types within the retina, RPE cells do not require
synaptic connections for their functions
37. OUTLINE OF STUDY
• The optogenetic vector, AAV vector encoding the light-sensing channel
rhodopsin protein ChrimsonR fused to the red fluorescent protein
tdTomato, was administered by a single intravitreal injection into the
worse-seeing eye to target mainly foveal retinal ganglion cells.
• The fusion protein tdTomato was included to increase the expression of
ChrimsonR in the cell membrane.
• 58 y old male. LP vision. RP for 40 years
• 15 visits over 84 months
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40. LOTS OF CHALLENGES
• Gene therapy requires viable PR cells and hence will not be effective in advanced
stages of IRDs with severe PR degeneration
• Gene therapy is gene specific and treatment for each gene has to go through all
the steps of drug development
• VERY expensive – 450,000 USD per injection at the US
• Limited cargo capacity
• Complications inherent to the method of delivery of the product
• Potential presence/ development of antibodies
• Cell therapy requires systemic immunosuppression for prolonged periods
41. IMPORTANT DATA TO BE COLLECTED
• 10 years ago – different landscape - patients counselled but not much
hope, plus expensive gene testing
• Now, important to counsel regarding inexpensive and timely nature of gene
testing
• Important to inform about ongoing trials
• Important to form/ add to a database and registry.
• Even general ophthalmologists and practitioners should be aware that IRDs
in 2023 are different than before and warrant testing and possible therapy.
42. FUTURE PROSPECTS/ CONCLUSION
• If the 20th century belonged to major surgical breakthroughs in anterior and
posterior segments, the 21st century belongs to breakthroughs in gene testing,
therapies and treatment of diseases previously considered untreatable.
• The landscape has changed vastly over the last decade
• Future will involve gene therapy at early stages to preserve function.
• Stem cells harvested from skin biopsies or blood will provide easier access
compared to embryonic stem cells
• Next era will be an era of personalized medicine: combination of gene editing
(e.g CRISPR) and stem cells. Maybe everyone gets a unique gene ID (like PHIN).
43. FOR OUR RESIDENTS
• Even within the niche of retina specialists, there is a growing demand
of IRD experts
• Very few IRD specialists globally, mostly in the US
• Exciting opportunities in the form of fellowships in IRD and a practice
that will become more and more rewarding as time goes on.
44. A famous quote (though overused) fits the
description of future opportunities in a
career dealing with IRDs very appropriately –
“I skate to where the puck is going to be, not
to where it has been”