IRD gene editing and looking for disease-causing mutations in families with dominant RP pedigrees

Our first webinar for 2022 was held on Thursday 26th May, and was an update from two of our recent research funding recipients, Professor Alex Hewitt, University of Tasmania and Associate Professor Fred Chen, Lions Eye Institute, Perth.

Primetime for Inherited Retinal Disease Gene Editing, Professor Alex Hewitt

There have been a number of major advances in gene editing technologies. The genetic correction of variants leading to inherited retinal diseases is now readily achievable. This presentation explored the current state of gene editing technology, and discuss the remaining barriers which need to be overcome, before gene editing is ready for primetime!

Looking for disease-causing mutations in families with dominant RP pedigrees, Associate Professor Fred Chen

Autosomal dominant retinitis pigmentosa (adRP) accounts for one third of patients with RP. In a Retina Australia funded project, genetic analysis of 41 families with dominant RP revealed a causative mutation in 32 families whilst 9 remained unresolved using a retinal dystrophy gene panel. The five most frequent genes encountered in families with adRP were PRPF31 (10 families), RHO (7 families), RP1 (4 families), HK1 (3 families) and PRPH2 (2 families). PRPF31 or RP11 has a unique feature in that some individuals carrying a mutation do not manifest retinal disease . In this talk, the reason behind RP11 non penetrance was explored and how this led to the discovery of VP-001 to treat RP11 is discussed.

You can watch a recording of the event here:

good afternoon everybody i’d like to welcome you all to this first retina australia webinar for 2022.
uh it’s a research update from two of our currently funded grant recipients professor alex hewitt and associate
professor fred chen my name is sally turnbull and i’m the administrative officer for retina
australia and i’ll be the facilitator of this webinar today our first speaker
today is professor alex hewitt who is a principal research fellow at the menzies institute for medical research at the
university of tasmania as well as a principal investigator at the center for eye research australia
his major research interest lies in the ophthalmic applications of stem cell and gene editing technology
alex obtained his phd from flinders university of south australia in 2009
and completed formal ophthalmology training at the royal victorian eye and ear hospital alex led the first report
of viral mediated crispr caste editing in the retina today’s talk is titled prime time for
inherited retinal disease gene editing so i’ll hand over to him now so yeah
thanks a lot for the introduction and um the it’s great to have the opportunity
to talk about some of the research that we’ve been doing uh over the last couple
of years and principally over the last 12 months with the support from retina australia
um in a way i sort of think maybe fred and i should have had our talks around the
other way because the major sort of thrust of our work has been on actually
the uh genetic correction of uh variants that cause inherited retinal
diseases and i think part of fred’s talk at least will be in identifying
a patients who you know the genetic variants in different patients
um so i guess i think uh when i think about sort of the changes that are happening in in
medicine and and that that will affect humanity i find i think that earthrise
you know has to be one of the most inspiring uh photographs for all of humanity um i find it amazing that we
can send a rocket up into space
have that land on an asteroid take a sample from that asteroid and then
travel back to earth with a sample from that asteroid also find it amazing that we can launch
a rocket into space that’s 15 stories high and actually managed to land that
back on earth on a small platform floating in the ocean
and so you have with all these major sort of advances in in physics why hasn’t uh
biology uh caught up and you know why is it why why isn’t it possible for us just to
go in and readily treat all of these inherited eye diseases
and i think in part the part of the sort of answer to that is
the actual complexity of the human genome so your genome is comprised of 3.3
billion nucleotides or letters that make up your genetic code and just to
comprehend the size of you of that genetic code if you imagine expanding
each of the letters that comprise your genetic code up to be the size of a
matchstick and then if you stack each of those matchsticks end on end you would
have enough matchsticks to stretch from the earth to the moon and back to the earth and
then back up to the moon again so certainly you know 3.3 billion nucleotides is a lot
the you can also then sort of think of your genetic code being comprised of one
of four different letters so essentially that means that you could color each of these matchsticks one of four
different colors and all it takes for a disease to manifest is essentially to have one of
those matchsticks either burnt or just discolored so painted
one of the wrong colors and that can happen just in one site
or for some conditions you actually need a handful of different changes uh to occur
so in part the difficulty in uh in understanding or in treating inherited
eye diseases has been in part just due to the complexity and size of the genome
now when we think about potential treatments for different inherited eye diseases i
think it’s important to appreciate that the treatment that will be best is going
to be very dependent upon how far how far advanced different people’s
disease is such that the more advanced it is
treatment such as stem cell replacement and external technology are going to come to the fore
whereas for the gene editing and gene replacement therapies which our team has primarily been
focused on is certainly going to be needed in the earlier stages
of the disease so essentially you’ll need a fair a reasonable amount of healthy remaining
retinal tissue for gene editing to be potentially beneficial
so focusing on gene editing in particular there have been recent advances over the past eight to nine
years and these were essentially spawned from discoveries from emmanuel
scharpenter and jennifer dalner’s laboratory whereby they were looking at the
adaptive immune system of bacteria and they found that there was a unique
protein complex called crispr which stands for clustered
regularly in special palindromic repeats that appeared to be
appearing in the genome of bacteria and they found that you could adapt this
this protein with an rna complex such that it could then be used to
target any specific region in the genome so essentially this protein
is comprised of a protein component as well as an rna
guide and that rna essentially is what’s used to bounce along the genome and once
it finds a match in a particular site in the genome
the protein is activated a bit like scissors and the dna is cut
now cells don’t like uh its dna being cut and if you sort of imagine it as
being a bit like uh the rope for a rock climber obviously if the weight
of the rock liners if the rock climber’s weight is on the rope and you cut the rope they would naturally fall
and similarly if dna in a cell is cut the cell will die
so cells mammalian cells in particular have evolved mechanisms to rapidly repair
the dna if it is cut and essentially rather than
repairing that in a precise manner the cells mechanisms just aim to join
the dna back together as quickly as possible and unfortunately errors can occur when that when that happens
now as was mentioned before our team was the first to actually apply this uh gene
editing technology uh to uh via a viral mechanism to the retina of a
pre-clinical model and and essentially what we showed was that with very high
efficiency you could actually use this machinery to alter the genes expressed in the retina
so that’s all good and well if we want to potentially remove a gene or stop it from functioning well
what about if we actually wanted to correct a specific disease-causing
variant and so on that front there have been some major advances
primarily that started again with this crispr enzyme complex
whereby two groups in the us and in japan appended a different
an additional enzyme onto this crisp endonuclease and essentially that
enabled they also blunted the scissors on one aspect and essentially that enabled the
chemical conversion of of one nuclear tied into another and essentially that
means that you could then convert a blue matchstick into a red matchstick or a black matchstick into a red matchstick
the following year after that major advance a different enzyme was evolved
and appended onto the onto the endonuclease and that essentially facilitates
the conversion of a green matchstick into a black matchstick or a red matchstick into a blue matchstick
however what was alarming with all of this is that it was uh subsequently reported that
as this complex was bouncing through the cell it was inadvertently editing
other sites so it wasn’t just going to the site that you were aiming for it to target it was as it was
transferring around it was having functions on other genes and essentially one way that you could
think about this would be that if the instructions or if the genetic code in the cells
you know the the what you’re hoping to have it say would say cook the lemon cake
if uh if they if there was a spelling mistake that actually whereby the instructions were cool the lemon cake
um obviously if you’re going to aim to send in a a
crispr editor to correct the l uh in cool to to make it a k in cook
what was happening is that you were inadvertently getting other spelling mistakes introduced
so essentially that’s a bit like saying you know cook the chemin cake um so
if that hopefully sort of makes sense um the one sort of big analogy for these crispr
enzymes and the base editor system is essentially it’s a bit like having an
eraser and a pencil combined in one and we had a talented phd student who
based on some insight from david savage’s lab realized that you could essentially hide
that eraser inside the pencil and that um that meant that you it is possible to
that the rather than having it just tagged on one end of the protein and therefore having that enzyme just waving
in the wind so to speak you could essentially bury it inside the protein hide it from other proteins and actually
bring it closer to the dna of function where it could have its function
and so essentially what peter did was actually screen through a range of different variants and essentially he found a
sweet spot as to where you could hide that eraser and then from there he went on and screened a
number of different variants um and with the aim of correcting those genetic
changes and he found that the hiding the eraser inside the pencil
actually increased the efficiency across a range of sites and also
dramatically reduced these off-target effects peter went on to show that you could
that it was possible to uh package all of that system up into an adeno
associated virus um and that could well be important for future therapeutic
delivery and he also went on to show that his engineered crispr system was actually uh
extremely or you know the most efficient platform for the genetic correction of a
individual change that causes usher syndrome so in particular bearing in the
predicate here in 15 gene so essentially going back to that analogy of where the instructions were
to cook the lemon cake essentially it meant that we had adequately corrected
that initial spelling mistake but also avoided the inadvertent off-target effect
so the natural uh question that leads on from all of that work is that well what
about other potential disease causing variants so all of that technology is
good if you just have one of those four specific changes in that particular sweet spot but what about all of the
other range of genetic variants that can cause inherited disease or inherited retinal diseases
and so returning to that crispr ended nuclease complex david liu’s lab in the u.s actually came
up with the novel idea of appending a different enzyme onto a different part
of the crispr complex and also extending that rna template that’s actually used
to guide that protein along the genetic code and essentially that technology
allows the genetic conversion of a green matchstick into any other color
matchstick and similarly a black matte stick into any other color blue matchstick into any other color but a
red matchstick into any other color so essentially they showed that it was possible to
correct the genetic change of essentially any
small genetic change that that causes a range of disease
so the big question now was you know can how does this uh transfer across the
range of of genetic variants that cause inherited eye disease
and so to in an attempt to address this we designed essentially a big pooled
experiment and the the big issue with this technology is that there’s a range of
different combinations that you can have to essentially optimize the system so in
order to get as high editing efficiency as possible it’s necessary to make a
number of tweaks um to that to the rna and protein complex
and it’s not initially clear as to which one would lead to the most effective
designed a template whereby the the repair
template as well as the target sequence was appended to each other and this was
essentially designed for close to 12 000 established disease-causing variants
that cause a range of inherited eye diseases and what was exciting was that we found
that using this approach we could definitely identify
distinct patterns of genetic correction and essentially that allows us to
tease out some important factors that must be considered when designing
these genetic correction therapies
in particular that we found that the the distance between where the scissors
are activating and the length of that repair template is particularly important
so when it comes to the clinical translation of this technology i think
we’re certainly edging closer to the clinic as fred will introduce in the in the next
talk certainly the genetic diagnosis of inherited
diseases is has improved dramatically over the past decade
um it’s now possible for us to design the things and tools that will correct
these genetic changes if they’re well defined and
and in a small section of the genome it’s possible for us to model
these these conditions so such that it’s possible to test this out
in the laboratory before actually applying it to an an individual
and then finally across australia now there’s a range of different improvements that are
happening that will ensure the production of these therapies
um so uh i was certainly grateful to the small army of
phd students and postdoctoral fellows and and other collaborators who’ve
contributed to all of this work um and i think one of the big take-home messages hopefully from
the the talks today um is that there certainly is a small army of people who
are working very hard on on all of this
and finally we’d like to thank all of the funding support that’s contributed to this work
in particular the grants from retina australia and i think that’s it’s really important to highlight the role that
these uh grants do have in leveraging uh ongoing and
bigger funding so i would certainly uh i think um happy to
open the floor now to questions or have a combined uh questions
at the end and if people are shy you’re certainly welcome to put questions into the
the chat okay reeks van clinkin
oh hi g’day g’day alex great presentation um i was just looking recently at a paper by um i think lee et
a couple of years ago that reviewed um a lot of these genetic technologies and some of the issues around getting
them working in practice and i left that um a bit depressed
about all the barriers what’s what’s your feeling in terms of you know those
the practical issues that have to be overcome to actually get this working in a cost-effective way yeah so
um so i think we’re damn close and like you know always with researchers you know
who says forward one step back um i think you know the um so i was saying the uh in terms
of gene editing technology in the eye there has been a trial started for
labour’s congenital amerosis so a rare condition that primarily affects
children the and that that is just the sort of scissor
technique not the uh the actual genetic correction or base editing method
but there are clinical trials about to commence and there’s actually one starting in new zealand uh in a few
months where they’re actually aiming to apply that uh the base editing technique to the liver
um and to correct uh for hyperlipidemia um so i think you know
the barriers that uh rapidly being overcome so i’d be certainly more optimistic than
pessimistic about it that the big issue yo will be i think uh intervening at a
time when patients would actually benefit from the therapy where otherwise they’ll need sort of
other other sort of modalities that would be needed okay so hopefully that answers the
question rick thanks yeah i noticed you’re actually a author on that paper as well a couple
years ago i think again with all these
technologies you you never want to be first in line but you don’t want to miss out um but i think if there’s been anything
good come from the covert vaccine stuff i think it’s the
proof that you know these platforms can be scaled up for therapy
so i’d certainly um be hopeful and voiced that these therapies
could be rolled out in a manner that that won’t break our health care system
thank you so much alex and i think now that we’ve where fred is with us we’ll we’ll go ahead with the
next speaker so associate professor fred chen is an inherited retinal disease specialist at
the lion’s eye institute and royal perth hospital his academic position is at the university of western australia and the
university of melbourne fred conducts several clinical trials in retinal diseases as the principal
investigator and is the head of the ocular tissue engineering laboratory which focuses on translational research
and drug development for genetic eye diseases fred and his group have published over 200 peer-reviewed papers and he serves
on the editorial board of international journals and advisory boards for several pharma companies that develop novel
treatments for retinal diseases he’s currently an investigator for treatment trials and stargardt disease and usher
syndrome today he’s going to be talking about looking for disease-causing mutations
in families with dominant rp pedigrees thanks very much fred thank you sally thanks
for introduction and it’s a pleasure to present on our research funded by
retinal australia i’m going to talk on dominant rp and first first i’m going to touch on
inheritance patterns because there’s uh there are
confusions regarding uh how we call dominant recessive and x-linked
and then i’m going to talk about the genetic testing that were performed in these dominant rp pedigrees
and then i’m going to talk about treatment for prpf31 which is one form of dominant rp
so where do our patients come from there are two sources of patients
my patients are enrolled into what we call the ward study which is western australian rental degeneration study
majority of these patients are from our states and i have the impression that it’s about
fifty percent of all the ird patients in the states are in this registry there’s also the australian
inherited retinal disease registry led by john derose it’s a national registry and they’ve
they suspect that they’ve captured about a quarter of all the australian r d patients
i talked on this webinar two years ago in may 2020 and at that stage i
presented how our water study was tracking it and we recruited 800 patients
up to 2020 and in the last couple years we’ve recruited more so there’s now over
a thousand 150 patients not all of these patients are
uh or have inherited rental disease there were 684 so just over half have
inherited rental diseases as of may this year about 300 have road coin dystrophy or we
commonly call it rp 294 were typical rp so these are bone speakers with so attenuation pale discs
some of them have asymmetrical rp five of them called sector rp and they’d had
typical features of corrodoremia there are also patients who have female
carriers and we know they have carrier status because of the the way the thunders look
uh eight of them were female carriers for corollary and 17 were for x-linked rp so that’s rpgr
and rp2 so i’m going to focus on
dominant rp now when we define this it seems quite straightforward for most clinicians what’s x-linked recessive
dominance there’s a group of patients where we don’t know which one it is so we call
them simplex because they’re the only person in the family who has the disease
there’s also mitochondrial diseases which i’m not going to talk about but but these are inherited through the mother to all the children and only
females can pass it on it doesn’t typically cause rp they cause a mitochondrial retinopathy which can be
confused with rp kss is kansai syndrome which is a condition with the motility disorder so
problem with moving the eye plus retinopathy so i want to talk about that group i’ll focus on x-linked recessive
dominant and the simplex so as you can see uh quite a large proportion of patients
are the only person in their family uh affected by this condition that’s 42
percent so so what what determines this kind of
inheritance well we have to look back to to understand what what the gene is gene i
tend to use the example of lego blocks uh we we
we have about 29 000 genes on the dna
and each one of this gene is a bit like the instruction booklet in the lego box it tells you what to do with these
blocks and you can make a little pattern or little toy out of it we have two copies of every
instruction book one from the mum and one from the dad except for those who those uh instructions on the sex
chromosomes of x and y’s the cells uses both copies
to make uh protein so these are like the lego blocks that are built these can be enzymes
growth factors receptors structural proteins and many other things
when there’s a faulty uh copy of the gene uh due to
uh errors in the code or missing codes altogether
there can be lots of function because the protein is not made or the
protein doesn’t work when it’s made alternatively it can lead to production
of a protein that is altered in this function which then inhibits other proteins
made from the normal copy it can also lead to excessive production or hyperactivity of
the protein so enzymes can be more active for example or they could be more of the
growth factors produced rather than less so there are three three things that can
can result from faulty copy of the gene the simplest
inheritance to understand is actually the x-linked inheritance so males have only one copy of the x chromosome and
one copy of the y chromosome females are two copies but only one of these is is functioning
at any one time so males will manifest disease when the gene on the x chromosomes faulty because
there’s no backup the females will manifest retinal disease when most of the retinal cells inactivate the normal
x chromosome we still don’t know really how how female manifest is diseases there’s this
research been done here and in melbourne looking at why do carriers manifest disease
in some people so we do see corrodoremi carriers and rgp
rpgr carriers who are severely affected by the condition
and others are not affected at all here’s a family tree that’s rather
complicated but you can see the females are drawn with the dots inside so they’re carriers and the males the boxes
here are the affected male individuals so only
only the females can pass the disease on to affected
males males can only pass the condition onto female
members recessive inheritance is generally
due to two faulty genes and the combined severity of these two
mutations would determine the severity of the disease so if you have two severe mutations you get a severe disease two
mile mutations you get mild or even no disease manifesting they have one severe one mild you get moderate disease so the
condition can manifest in many different ways based on the severity of the disease but the inheritance is pretty
straightforward so here you have both parents who are carriers who are not affected by the
condition but their children has a one in four chance of inheriting both 40 copies
the most complex of all is actually the the dominant pedigree so these mutations can lead to loss of function gain a
function or dominant negative effects so
when there’s the loss of function it means that 50 percent of what’s produced is not enough in the
eye often we find these mutations in proteins in genes that codes for
proteins that can be used all throughout the body but yet the eyes are neither organ the only organ that’s affected
so for most parts of the body 50 is enough but for the eye it’s not enough
there are also mutations that cause increased function for example if there’s duplication of
the gene or if the enzyme activity is increased it can be toxic prps1 is one
example of that and then the mutations that are causing inhibitory effects for example prp h2 when the mutation can
cause one copy to make a protein which then binds
the healthy copies protein which is normal and then that has an inhibitory effect on the healthy copies uh product
protein so here where it gets very complicated so a simplex case where there’s only one
person affecting the family can be due to recessive gene can be due to excelling stream can be a dominant gene
so we can’t assume when there’s only one person in the family that this is recessive condition which is what people
tend to assume it is a dominant gene occurs uh in this situation when the parent patient is
adopted so we have no access to parental information when there’s a de novo mutation or when the parents are non-penetrant
then there are also situations where the dominant disease can present with a recessive pattern
and where a recessive disease can present as a pseudo-dominant pattern
i will explain a little bit more socio-recessive you can see this pedigree where neither
parents are affected but there’s one two children affected here so you assume this is recessive but
without further information you don’t really know that because here the mother father is actually affected but we may
not know that because if the fathers are young he men have never manifested the disease
so you don’t really know prior information and and if we do genetic testing we
might find that this patient is a non-penetrant carrier and in fact there’s two other non-penetrant carriers
so you can have a dominant disease which looks like a recessive pedigree
here’s a pseudo-dominant pedigree you have the mother affected two trillion factor you think this is dominance pretty
straightforward but then when you do the genetic testing you realize actually
the father is a carrier of a mutation and this is often comes up when you have the siblings with very different
manifestation because one of the copy of the mutation
is from the father one’s from the mother but the mother has two copies and they could be mild and severe so you get
different manifestation of this so so a dominant pedigree doesn’t always means it’s a dominant disease
so in our retinal australia grant we we found 57 families with what we
presume was dominant inheritance based on history so this is the key point just because the history tells us
dominant doesn’t mean this is a dominant gene proband’s a current age of 50 and range
from 11 to 89 synthetic onsets from about 25 years of age but that’s a huge
range we have 41 pedigrees with preliminary results
10 are still pending analysis at molecular vision laboratory in the us and six patients have not provided dna
and so there’s always a proportion of patients who are not willing or not wanting to know their genetic diagnosis
and we leave them as as they are and at some stage they may change their
mind or that you know their children want wants counseling regarding their
risk of passing on the condition then they might come back to ask for genetic analysis
there were three other families who presented with simplex or pseudo-recessive inheritance who were found to have dominant mutation so here
are the the combined here the the results from the dominant families
uh when we get the report back you know you send a dna off you get a report that says it’s positive likely positive or
inclusive 60 63 of the report says
have have a result that’s likely positive apology but quite a number of
them have inconclusive results if you just send the dna as a swap to
these companies you you’re stuck there with inconclusive result in 37 in fact even the 63
is not that conclusive because you really need to test this the variance in other members of the
family in the affected and the non-affected family to be absolutely sure
so further analysis needs to be performed on not just the 37 but also those 63
percent with further analysis we were able to solve seven additional families in this
inconclusive basket
um to assume undergoing further testing of suspected causative gene which was
listed as inconclusive and we’re left with six families which we have no idea still what the genetic
course is and they’re clearly dominant inheritance with the rp
so here we have 63 percent who have positive results based on just a report alone but that requires
confirmation on segregation analysis so that’s two extra samples of dna to be sent off for analysis
and then with the australian id registry teams help expertise in this and further testing
for large deletions which wasn’t covered in the previous panels we managed to solve another 22 so we’re
now with 85 of the families solved here are the breakdown of the various
families so the by far the most common is rp11 and there are 10 families in wa
which affects 52 individuals and i’ve examined 30 of them it’s actually very
difficult to examine all the family affected family members and the reasons are either they’ve passed away
obviously we can’t examine them or their history of
we get told about these individuals but there’s just no access to these people or they don’t want to come in for examination
reduction is second most common it causes rp4 we have 30 affected
individuals in these pedigrees and then there’s rp1 uh four families 16
affected individuals hk1 which is hexokinase one uh three families separate families all with the same
mutation but they’re not related and prph2 are two families and then you
can see a scatter of other genes that only occurs in one family rp9 ip65
and you know rp65 is a recessive disease but it can also cause dominant disease
sag typically is a recessive disease as well but it can also cause dominant rp
and similarly some of these other ones uh can be recessive more dominant but this is all
dominant rp so with focusing down on prpf31 we have
ten of these seven presented with the dominant pedigree so it was straightforward to know this was dominant disease but three had simplex
pseudo-recessive pedigree and the reason was that either they were adopted
or there was non-penetrance in the family so when the parents had it but wasn’t manifesting the disease
seven of them were found on the panel as positive or likely positive but three were inconclusive and
we had to search for the mutation of deletion by doing further testing
and three of these seven uh three of the ten families had members in the family who were carriers carriers of the
mutation by not manifesting rp and it’s been reported that less than
five percent of these mutation carriers don’t have the disease you can look in the eye very carefully
do electrophysiology and they’re normal they don’t have the disease and yet they have the mutation in the eye cells
and and and the way it happens is because the healthy copy of the prp of 31
can compensate the reduction in the faulty copy function by
overproducing a pip 31 protein and because of this
this understanding and then and also our understanding of how this gene is
regulated we were able to develop a treatment for pip31 we targeted
c not three which is another gene that suppresses prp-31 so if we can
suppress the negative regulator that will allow more of the pip 31 on the healthy copy to be produced and this
will then overcome the deficiency so two years ago i presented this timeline
we had the war study present started in 2015 there was a collaboration between leia
murdoch university between myself and sue fletcher we had phd students working on this
which led to the discovery of this invention then the collaboration with pyc
to further progress in pre-clinical studies and that today indicates the talk two
years ago we had a plan to get this drug
through the the pipeline to get fda approval looking at
rabbit monkey studies large animal studies and
and the plan for clinical trial this year so this is the timeline now
in 2022 so we’re almost there at the completion of the uh the pre-clinical testing
uh the sprinkle trial is planned for next year uh once we submit the fda for approval
it can then be used in human what we’ll do prior to that also is the natural history study so there are
several sites in the us and hopefully in australia as well
looking at prpf natural history
so that’s the update on the most common dominant rp gene in australia i presume
similar situation is found in other states and i need to acknowledge lion’s
institute uwa madong university and specifically red australia for funding this project to allow us to identify
these patients uh pyc therapeutics for their help with the pre-clinical studies
and all the various funding bodies and donations our team of scientists and fellows in uh working on these cells and
recruiting patients the studies and jade for organizing all the meetings
between myself and my team john derose team id registry is
is critical and indispensable in our work because without them
a lot of these families will still not be solved and you know we’ll still be able to diagnose
many of the families who had inconclusive results from the initial panel
and uh clinic staff in looking at these patients and the referring clinicians optometrist thank you
thank you so much fred that was great and so exciting to hear about these new developments and the the upcoming
clinical trial um so we’ve got an opportunity to have some more questions from people um i
think alex is still around um so uh if you’ve got any questions for either alex
or fred just raise your hand um you can also use alt y on the keyboard
if that’s more convenient for you and we’ll just
wait to hear from people has anyone got a question
i was going to ask a question actually fred i just wanted to get an idea you talked about a panel of genes that
you’re testing for how many how many different genes are in the panel because obviously you’ve shown us
some there but were there a whole lot more that didn’t appear in that yeah so it varies between depending on when we
test the gene so in the very early phases we’re talking about like only 50 genes
but now the the oregon gene panel has 988 genes and they also look at copy
number variations as well in addition to that and even with 988 genes being looked for
i don’t think the rate of finding positive result is is going to increase
because the majority of the new genes that’s added to the panel it is not actually related to rpgs
amazing what sort of timeline is there on the the clinical trial that’s starting how
how long will the do you think that that process will take
in general these trials are last several years they are also phase one two and three so
the different trials for different purposes phase one trials tend to last one to two years looking for toxicity
and tolerability and many drugs are knocked out that state so if they cause any side effect
that’s you know not anticipated because they didn’t see any monkeys then it goes no further
and those that pass first phase one will go into phase two sometimes they combine phase two three
uh which can last another couple of years for each patient for rare diseases because it takes
longer to recruit you can imagine you’re trying to find this patient it may take two years to find all the patients and
another two years for the last passion to finish so you’re talking about four years from starting another year for results so that’s five
years just for phase two and then after phase two you’ve got phase three phase three depending on the
design for drug therapy usually again two years like intravitreal injections or usually two years for gene therapy
it’s usually five years plus a running of one year so they’ll get treated in one eye another year
later get treated in the other eye and then follow for five years so that’s six years for each patient
and if you looking for rare diseases it depends on how quickly they can recruit for rare patients and
it may take several years to recruit that and how many patients do you need to to
make a a reasonable number it depends on the purpose so again for early phase for
toxicity yes maybe a handful low dose handful high dose
to see whether there’s any side effects so you could be looking at 10 to 15 or
20. whereas for larger trials for gene therapy trials we’re talking
usually about 50 patients it’ll be worldwide of course because
it’s very hard to find 50 rare disease patients and
at different you know they’ll be randomized in one eye
usually not treated in both eyes the delay in giving the treatment
in those who are randomized to sham will give them some idea whether that that treatment is better than placebo
sally there’s a question in the chat um if we have family members that haven’t sent in dna is it too late for
them to do so ah never too late
never too late the dna lasts basically forever uh so we we generally don’t need to
collect dna unless you know we had to test it many many times and we used up the material but those who haven’t sent
dna yeah they’re very welcome to send in there’s another question here um from
kelly is there any research currently being undertaken for punctate in a choro choroidopathy
so that’s an inflammatory disease uh there may be genetic association but
uh we we we’re not working on any inflammatory the genetic basis of
inflammatory disease at this stage but certainly you know that that’s an interesting topic
there are researchers who are looking at genetic british positions to pick
a disease response to treatments or non-responders or different manifestations of that any further
questions does anyone have if there aren’t
i might say thank you very much to our speakers and hand over to leighton boyd the chairman of retina australia just to
say thank you well on behalf of retina australia i mean
we’re very lucky here in australia i mean us as patients people with
inherited eye diseases we can be unlucky in one way that we have our various um conditions
but we’re in a very fortunate situation that we have lots of teams and
certainly alex and fred are two people that have had a long association with
retina australia they’ve presented numerous times themselves and and
various members of their team us in retina australia we
we welcome all the the donations from all of our
um our donors obviously and our members but this has enabled
um alex and fred in this case to to put together and do some
special work on behalf of us as patients the collaboration across
this country is amazing and as an organization
um our aim is to to bring it all together as often as we can
and to help us to find a treatment and cure eventually for for us all
so thanks thanks to both of you today it always amazes me when i hear these
presentations how such a very very difficult um topic of
trying to explain so people like us as lay people can understand it the analogies that were
given unfortunately rosaries here and could explain to me all these graphics and the
the cakes and all the the rockets and all the other things and it’s it’s just
makes things easier for us to understand we are grateful for your time we’re
grateful for your work and your teams and uh i thank you all
on behalf of all of us here uh we can do a virtual round of applause and uh thank you for
your time thanks so much leighton just on that can i just
do a sales pitch um people like alex and fred um can only
do their work and we help contribute a little bit and and they do get bigger grants from nh and mrc and all other
sources and and and we as an organization try to do what we can to help them out
the money that we give is you seed funding as an organization and we’ve given over six million dollars
since retina australia started giving our grants which is i think astounding and and amazing for all these
people online today and and people that aren’t online we’re so grateful about
and on june 21 uh this year we will be running our our
giving day last year on the same day that coincides with the winter solstice
we’re having our giving day now we’ll launch that on june 10 this year
and all donations given on that day and after june 10 will be matched by our
match donors last year we we raised around 78 000 in 24 hours
which is an amazing effort and i just would like everybody online here today and all your
friends and email list and your contact list let people know that this day is on on
june 21 again this year and we encourage you all to give and that will enable us
as a board to make decisions and to fund more applicants more researchers
in in the next years ahead so thanks again to everyone and i hand back to you celine
thanks so much leighton so that’s the end of the webinar thank you so much to both of our presenters for your time and
the wonderful presentations and thank you all for coming along this afternoon and have the rest enjoy the rest of the
day thanks so much bye

Past Webinars

October 2024

Cell therapy, genetic research and a patient’s perspective

May 2024

Research Update Event – Geographic atrophy and AMD

October 2023

Vision Loss Priority Setting Partnership and an Introduction to Stem Cell & Gene Therapies

VIEW ALL about Past webinars