- Gene therapy and newer therapeutic options have significantly changed the landscape for inherited retinal diseases (IRDs) over the last decade. Previously considered untreatable, IRDs now have testing and treatment options available. - Advances include widespread availability of low-cost genetic testing to identify causal mutations, numerous clinical trials exploring gene therapy and cell therapy, and the first FDA-approved gene therapy treatment. - While challenges remain, such as high costs and limited treatment for advanced disease, the future is promising with prospects for personalized medicine using gene editing and stem cells. Pursuing a career in IRDs offers exciting opportunities as the field continues to rapidly progress.

1. THE AGE OF
MIRACLES
Grand Rounds
10 May 2023
Dr Mohit Chhabra
No financial disclosures

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

5. IS THERE A TREATMENT
OPTION NOW?

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

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

15. HCQ TOXICITY

16. 16-year-old boy,
complain of night
blindness
VA 20/20

19. TOO MUCH
INFORMATION!!

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.

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

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

33. EXPLOSION OF
TRIALS FOR BOTH
IRDs and AMD

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

35. DON’T THINK CELL
THERAPY IS
BEHIND GENE
THERAPY

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

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”

45. 🇮🇳 THANK YOU 🇨🇦