Dr Ana Lisa Tavares, Anne Lennox, Dr Meriel McEntagart, Dr Carlo Rinaldi: Can patient collaboration shape the future of therapies for rare conditions?

Rare condition research is evolving, and patient communities are
driving the breakthrough. In this special Rare Disease Day
episode, we explore the challenges and opportunities shaping the
future of rare condition therapies. From groundbreaking gene
therapy trials to the power of patient-driven research, our
guests discuss how collaboration between families, clinicians,
researchers, and regulators is paving the way for faster
diagnoses, equitable access to treatments, and innovative
approaches like nucleic acid therapies and CRISPR gene editing.


With insights from Myotubular Trust, we follow the journey of
family-led patient communities and their impact on advancing gene
therapy for myotubular myopathy - showcasing how lived experience
is shaping the future of medicine. However, while patient-driven
initiatives have led to incredible progress, not every family has
the time, resources, or networks to lead these research efforts.
Our guests discuss initiatives like the UK Platform for Nucleic
Acid Therapies (UPNAT), which aims to streamline the development
of innovative treatments and ensure equitable access for everyone
impacted by rare conditions.


Our host Dr Ana Lisa Tavares, Clinical lead for rare disease at
Genomics England, is joined by Meriel McEntagart, Clinical lead
for rare disease technologies at Genomics England, Anne Lennox,
Founder and CEO of Myotubular Trust and Dr Carlo Rinaldi,
Professor of Molecular and Translational Neuroscience at
University of Oxford.


"My dream is in 5 to 10 years time, an individual with a rare
disease is identified in the clinic, perhaps even before symptoms
have manifested. And at that exact time, the day of the diagnosis
becomes also a day of hope, in a way, where immediately the
researcher that sent the genetics lab flags that specific variant
or specific mutations. We know exactly which is the best genetic
therapy to go after."


You can download the transcript, or read it below.


Ana Lisa: Welcome to Behind the Genes.   


[Music plays] 


Anne: What we’ve understood is that the knowledge and experience
of families and patients is even more vital than we’ve all been
going on about for a long time. Because the issue of there being
a liver complication in myotubular myopathy has been hiding in
plain sight all this time, because if you asked any family, they
would tell you, “Yes, my son has had the odd liver result.” 
There were some very serious liver complications but everybody
thought that was a minor issue, but if we are able to engage the
people who live with the disease and the people who observe the
disease at a much more fundamental level we may be able to see
more about what these rare genes are doing. 


[Music plays] 


Ana Lisa: My name is Ana Lisa Tavares, I’m Clinical Lead for Rare
Disease research at Genomics England and your host for this
episode of Behind the Genes. Today I’m joined by Anne Lennox,
Founder and CEO of the Myotubular Trust, Dr Meriel McEntagart, an
NHS consultant and Clinical Lead for Rare Disease Technologies at
Genomics England, and Dr Carlo Rinaldi, Professor of Molecular
and Translational Neuroscience at the University of Oxford. 
 


Today we’ll be hearing about the importance of involving the
patient community, particularly as new rare therapies are
developed, and discussing the forward-facing work that’s
happening that could have potential to unlock novel treatments
for many rare conditions.  If you enjoy today’s episode we’d
love your support. Please like, share and rate us on wherever you
listen to your podcasts. Thank you so much for joining me
today.  Please could you introduce yourselves.  


Anne: I’m Anne Lennox, I’m one of the founders of the Myotubular
Trust, a charity that raises research funds for and supports
families affected by the rare genetic neuromuscular disorder
myotubular myopathy. 


Meriel: I’m Meriel McEntagart, I’m a consultant in clinical
genetics in the NHS and I have a special interest in neurogenic
and neuromuscular conditions. 


Carlo: Hi, I’m Carlo Rinaldi, I’m Professor of Molecular and
Translational Neuroscience at the University of Oxford. I’m a
clinician scientist juggling my time between the clinic and the
lab where we try to understand mechanisms of diseases to develop
treatments for these conditions.  And I’m also here as a
representative of the UK Platform for Nucleic Acid Therapies,
UPNAT. Thanks for your invitation, I’m very pleased to be
here. 


Ana Lisa: Thank you. Meriel, I’d love you to tell us a bit about
your work and how you met Anne, how did this story start? 


Meriel: Thank you. Well prior to being a consultant in clinical
genetics, I spent 2 years as a clinical research fellow in
neuromuscular conditions, and as part of that training I worked
on a project where the gene for myotubular myopathy had just been
identified, and so there was a big international effort to try
and come up with sort of a registry of all the genetic variants
that had been found as well as all the clinical symptoms that the
affected patients had, and then do kind of a correlation of the
particular variant mutation with symptoms.  


I worked when I was training to be a clinical geneticist because
of my interest in neuromuscular conditions so when I eventually
became a consultant at St George’s Hospital I was actually
interviewed by the Professor of Paediatrics and he knew Anne and
her son, when Anne was looking for more information about the
condition he suggested that perhaps I might be a good person for
Anne to talk to. 


Ana Lisa: Thank you. Interesting connections. Anne, can you tell
us your story and how this led you to found the Myotubular
Trust? 


Anne: Yes, thanks Ana-Lisa.  Well, as many families will
tell you when they’re newly diagnosed with a rare disease, you go
from knowing nothing about a condition to being one of the few
deep experts in that condition because there are so few deep
experts. So this happened to us in 2003 when our son, Tom, was
born, and when he was born he was floppy and his Apgar scores,
the scores they do on new-born babies, were pretty poor, and
before long we knew that it was more than just momentary issues
at birth.  And, cutting a very long story short, 5 weeks
later he was diagnosed with this very rare neuromuscular genetic
disorder that we didn’t know we had in the family.  We were
told that this was a very serious diagnosis.   


At that time – more than 20 years ago – over 80% of those boys
didn’t make it to their first birthday and the stark statistic we
had in our head a lot was that only 1% made it past the age of
10. And that has changed due to better ventilator and breathing
equipment, etc, but at the time we expected that he might not
make it to his first birthday.   


We were very lucky, we had Tom longer than one year, we had him
for nearly 4 years, 4 very lovely years where it was tough, but
he was a really lovely member of our family.  Despite being
really weak he managed to be incredibly cheeky and bossy, and he
was a great little brother for his big sister. We were also very
lucky that he was being looked after by Professor Francesco
Muntoni, who is Head of the Paediatric Neuromuscular Service at
Great Ormond Street. And, like Carlo, he is a clinical researcher
and actually that I found to be amazing as a family member
because you knew what was happening out there and Professor
Muntoni, other than living with the reality day to day you want
to know where things are going.   


We began to realise that back then 20 years ago the more common
rare neuromuscular diseases were finally beginning to get some
fundamental research funds, like Duchenne, spinal muscular
atrophy, and Professor Muntoni was very good at explaining to lay
non-scientific parents like us that one day the technologies that
would lead to a cure, that would re-engage proteins for other
conditions and would translate down eventually into the
possibility of replacing myotubularin, which is the protein not
being produced or not being produced enough in myotubular
myopathy. And then we began to understand actually what the
barriers to that would be, that translating developments in more
common, or let’s say more prevalent conditions, would be hard to
do without some translation research being done; you could not
just not lag years behind, you could lag decades behind if you
haven’t done some other work.   


So, I met Wendy Hughes, another mother, of a boy called Zak who
was a few years older than Tom, and these were the days before
social media, and it was amazing to be in contact with another
family going through something similar and we had great
conversations. But then they were also looked after by Professor
Muntoni and we particularly began to develop the idea as 2
families that we might be able to raise some research funds
towards this concept of keeping pace with the scientific
developments.  And then we discovered there was no charity
we could channel those funds through. Even the umbrella body for
neuromuscular diseases who were covering 30 to 40 conditions,
frankly, they just couldn’t trickle their funding down into
investing in every neuromuscular disease, and slowly but surely
it dawned on us that if we did want to make that difference we
were going to have to set up our own charity.  


So that’s what we eventually did and back in 2006, we founded
what was actually the first charity in Europe dedicated to
myotubular myopathy – luckily, more have come along since – and
we were dedicated to raising research funding. In fact, it wasn’t
our goal to set up another charity but around that time, about a
year in, we happened to go to a meeting where the Head of the
MRC, the Medical Research Council, was giving a talk and he said
that in the last few years the MRC had begun to really realise
that they couldn’t cure everything, that they couldn’t cure the
diseases that would be cured in the next millennium from a top
down perspective. There had to be a trick, there had to be a
bottom up as well, because that was the only way this was going
to happen. And I have to say that that was a really reassuring
moment in time for us to realise that we weren’t just chasing
pipe dreams and trying to do something impossible, that there was
a role for us.   


Ana Lisa: I think it would be really interesting for people to
hear your story and the amazing set-up and fundraising that
you’ve done, and at the same time it would be really good for us
to reflect on how this isn’t feasible for every patient and every
family and how we’re going to need to work cooperatively to move
forwards with rare therapies. 


Anne: When we explored the idea with Professor Muntoni and Meriel
and others about setting up a charity one of the really
reassuring things that Professor Muntoni got across to us was
that this wasn’t about raising the millions and millions it would
take to fund clinical trials but the issue in the rare disease
space was funding the proof of principle work, the work where you
take a scientist’s hypothesis and take it over the line, and the
rarer the disease, the less places there are for a scientist to
take those ideas. And the example he gave us was a piece of
research like that might cost a hundred to a couple of hundred
thousand, if you fund a piece of work like that and if it is
successful, if the scientist’s principle gets proven, then behind
you it’s much easier for the bigger muscle disease charities to
also invest in it. It’s harder for them to spread their money
across all the very rare diseases hypothesis out there, but if
you’ve helped a scientist get over the line they’ll come in
behind you and then they won’t be the ones who fund the tens of
millions that it takes to run a clinical trial.   


If it’s got potential, then that’s where the commercial world
comes in, and that’s where the biotechs come in. So he’d given
the example of if you spent £ten0,000 on a piece of research and
it actually is proven, in behind you will come the bigger
charities that would put in the million that takes it to the next
phase, and in behind them will come the bio-checks that’ll
provide biotechs that’ll provide the tens of
millions.   


And then, you know, a lot of what happens relies on serendipity
as well, we know that, and you could easily run away with the
idea that you made everything happen but you don’t, you stand on
the shoulders of others. And our very first grant application in
our first grant round, which received extraordinary peer review
for how excellent the application was, was a £100,000 project for
a 3-year project that had gene therapy at the core of it by a
researcher called Dr Ana Buj Bello at Généthon in Paris. This
piece of research was so promising that 18 months in she and
another researcher were able to raise $780,000 and, as Professor
Muntoni predicted, from the French muscle disease charity AFM and
the American muscle diseases charity MDA.  And 18 months
into that 3 years it was so promising that a biotech company was
started up with $30 million funding, literally just on her
work.   


So that doesn’t always happen but, as Professor Muntoni
explained, our job was not that $30 million, our job was that
first £100,000, and our job was also to make ourselves known to
the people in the neuromuscular field.  If you have lab
time, if you have research time and you have a choice where
you’re putting it there is a place you can go to for a myotubular
myopathy related grant application, so it’s not just that this
will come to us out of the blue, people will have done prior
work, and our existence makes it worth their while, hopefully, to
have done that prior work. 


Ana Lisa: That’s an amazing story how you’ve set up this charity
and how successful that first application for gene therapy was.
I’d love to hear more about that gene therapy and did it get to
the clinic and to hear that story from you.  Because I think
there are a lot of learnings and it’s really important that the
first patients who are treated, the first families that are
involved, the researchers who start researching in this area, the
first treatments lead the way and we learn for all the other
treatments for all the other rare conditions that we hope and
that together as a community we can share these learnings. 


Anne: Yeah. I sometimes describe it a bit like going out into
space. When you see a rocket going off look at how many people
are behind and the amount of work that’s been done, the degree of
detail that’s managed, and then you go out into space and there
are a whole load of unknowns, and you can’t account for all of
them.  Who knows what’s out there in this sphere.  But
the amount of preparation, it feels similar to me now, looking
back.  We were so idealistic at the beginning.  Our
grant to Dr Buj Bello was 2008 and actually it is a really fast
time in, the first child was dosed in the gene therapy trial in
September 2017. 


Ana Lisa: So, we’re talking less than 1 years. 


Anne: Yeah. And in the meantime obviously as a charity we’re also
funding other proof of principle research. One of the founding
principles of the charity was to have a really excellent peer
review process and scientific advisory board so that we wouldn’t
get carried away with excitement about one lab, one research
team, that everything would always come back to peer review and
would be looked at coldly, objectively. I don’t know how many
times I’ve sat in a scientific advisory board meeting with my
fingers crossed hoping that a certain application would get
through because it looked wonderful to me, and then the peer
review comes back and there are things you just don’t know as a
patient organisation. So, yes, in those 9 years we were also
funding other work. 


Ana Lisa: You’ve just given an interesting perspective on sharing
the learnings between the scientists, clinicians, the experts in
a particular condition, if you like, and the families, and I’d be
really interested to hear your views on what’s been learnt about
how families and the patient community can also teach the
clinical and scientific community. 


Anne: So, the first child was dosed in September 2017 and by the
World Muscle Society Conference 2 years later in October 2019 the
biotech had some fantastic results to show. Children who had been
24-hour ventilated were now ventilator-free, which, unless you
know what it’s like to have somebody in front of you who’s
ventilator-dependent, the idea that they could become
ventilator-free is just extraordinary.   


However, one of the things we’ve learnt about gene therapy is
that we are going out into space so there are extraordinary
things to be found, and extraordinary results are possible, as is
evidenced here, but there is so much that we don’t know once we
are dealing with gene therapy. So unfortunately, in May, June and
August of 2020, 3 little boys died on the clinical trial. So we
have a clinical trial where the most extraordinary results are
possible, and the worst results are possible, and both of those
things are down to the gene…  What we discovered and what is
still being uncovered and discovered is that myotubular myopathy
is not just a neuromuscular disorder, it is a disorder of the
liver too, and these children didn’t die of an immune response,
which is what everybody assumes is going to happen in these
trials, they died of liver complications.   


And one of the things that has come out of that, well,
2 sides to that. Number one is that it is extraordinary that
we have found a treatment that makes every single muscle cell in
the body pick up the protein that was missing and produce that
protein, but also what we’ve understood is that the knowledge and
experience of families and patients is even more vital than we’ve
all been going on about for a long time. Because the issue of
there being a liver complication in myotubular myopathy has been
hiding in plain sight all this time, because if you asked any
family they would tell you, “Yes, my son has had the odd liver
result, yes.”   


We could see something that looked like it was not that relevant
because it was outside the big picture of the disease, which was
about breathing and walking and muscles, but actually there was
this thing going on at the same time where the children had liver
complications. There were some very serious liver complications
but everybody thought that was a minor issue but if we are able
to engage the people who live with the disease and the people who
observe the disease at a much more fundamental level we may be
able to see more about what these rare genes are doing. 


Ana Lisa: Yeah, thank you very much for sharing such a moving
story and with such powerful lessons for the whole community
about how we listen to the expertise that families have about
their condition, and also I think the really important point
about how we tackle the research funding so that we’re including
and sharing learnings from the conditions that are initially
studied in greater depth, and we hope that many more conditions
will be better understood and more treatments found and that
actually the learnings from these first gene therapy trials will
really help inform future trials, not just for gene therapies but
also for many other novel therapies that are being
developed. 


[Music plays]


If you're enjoying what you've heard today, and you'd like to
hear some more great tales from the genomics coalface, why don't
you join us on The Road to Genome podcast. Where our host Helen
Bethel, chats to the professionals, experts and patients involved
in genomics today. In our new series, Helen talks to a fantastic
array of guests, including the rapping consultant, clinical
geneticist, Professor Julian Barwell, about Fragile X syndrome,
cancer genomics and a holistic approach to his practice - a
genuine mic-drop of an interview. The Road to Genome is available
wherever you get your podcasts.


[Music plays]


Ana Lisa: Carlo, I would really like to come to you about some of
the initiatives that are happening in the UK, and particularly it
would be really interesting to hear about the UK Platform for
Nucleic Acid Therapies as a sort of shining example of trying to
do something at a national scale across potentially many
different rare conditions.   


Carlo: Thanks, Ana-Lisa. Thanks very much, Anne, for sharing your
fantastic story. I mean, I just want to iterate that as clinician
scientists we do constantly learn from experiences and constantly
learn from you, from the patient community, and this is
absolutely valuable to push the boundary. And I really liked your
vision of a rocket being launched in space and I would imagine
that this is a similar situation here. So, we are facing a major
challenge. So, there is over 7,000 rare diseases in the world and
with improvements of genetic diagnosis this is only increasing.
So, in a way rare diseases is the ultimate frontier of
personalised medicine and this poses incredible
challenges.  


So, you mentioned the bottom-up approach and the top-down
approach and in a way, both are absolutely necessary. So your
story is a fantastic story but also makes me think of all the
other families where they don’t share perhaps the same spirit,
you know, they are in areas of the world that are not as well
connected or informed, where patient community simply cannot be
‘nucleated’, let’s say, around the family. So, there is
definitely an issue of inclusivity and fair
access.   


So, what we’re trying to do at UPNAT, which is the UK Platform
for Nucleic Acid Therapy, is to try to streamline the development
both at preclinical and clinical level of nucleic acid therapies.
So, we’ll start with antisense oligonucleotides just because
those are the molecules of the class of drugs that are most
‘mature’, let’s say, in clinic. So, there are several antisense
oligonucleotides already approved in the clinic, we know that
they are reasonably safe, we understand them quite well, but of
course the aspiration is to then progress into other forms of
gene therapy, including gene editing approaches, for
example.  


And one of the activities that I’m involved, together with
Professor Muntoni, is to try to streamline the regulatory process
of such therapies and in particular curate a registry of, for
example, side effects associated with nucleic acid therapy in the
real world, and you would be surprised that this is something
that is not yet available.  And the point is exactly that,
it’s trying to understand and learn from previous mistakes
perhaps or previous experiences more in
general.   


And this is very much in synergy with other activities in the UK
in the rare disease domain.  I’m thinking of the Rare
Disease Therapy Launchpad, I’m thinking of the Oxford Harrington
Centre, I am thinking of the recently funded MRC CoRE in
Therapeutic Genomics. These are all very synergistic. Our point
is we want to try to amplify the voice of the patient, the voice
of the clinicians working on rare disease, and we want to
systematise. Because of course one of the risks of rare disease
therapies is the fragmentation that we do all these things in
isolation. And I would argue that the UK at the moment leveraging
on the relatively flexible and independent regulatory agencies,
such as the MHRA, on the enormous amount of genetics data
available through Genomics England, and of course the centralised
healthcare system, such as the NHS, is really probably the best
place in the world to do research in the rare disease area, and
probably I’m allowed to say it because I’m a non-UK
native.      


Ana Lisa: Thank you, that’s a brilliant perspective, Carlo, and
across all the different therapeutic initiatives that you’re
involved with. And, Carlo, presumably - we’re all hoping - these
different initiatives will actually lead to ultimately a bigger
scaling as more and more novel therapies that target both our RNA
and DNA and actually are working, I guess further upstream in the
pathway.   


So classically in the past it’s been necessary to work out all
the underlying biology, find a druggable target somewhere in that
pathway and then get a larger enough clinical trial, which can be
nearly impossible with many of the rare and ultra-rare conditions
or even, as you’ve said, the sub-setting down of more common
condition into rarer subtypes that perhaps can be treated in
different ways.  And with the many new different treatments
on the horizon, ASO therapies, as you’ve said, is a place that’s
rapidly expanding, and also crisper gene editing. I’d be really
interested to hear your reflections on how this might scale and
also how it might extend to other new treatments. 


Carlo: Yeah, that’s exactly the right word, ‘scaling up’. I mean,
there will be of course very unique challenges to every single
rare disease but I would argue that with genetic therapies, such
as ASOs or crisper gene editing, the amount of functional work
that you need to do in a lab to prove yourself and the scientific
community that this is the right approach to go for can be
certainly very important but can be less just because you’re
addressing very directly because of the
disease.   


And then there are commonalities to all these approaches and
possibly, you know, a platform approach type of regulatory
approval might serve in that regard. You know, if you are using
the same chemistry of these antisense oligonucleotides and, you
know, similar doses, in a way the amount of work that you need to
produce to again make sure that the approach is indeed a safe
approach and an effective approach might be also
reduced.   


I would say that there are also challenges on other aspects of
course, as you were saying, Ana-Lisa. Certainly the typical or
standard randomised placebo control trial that is the standard
and ultimate trial that we use in a clinical setting to prove
that a molecule is better than a placebo is many times in the
context of rare diseases simply not possible, so we need to think
of other ways to prove that a drug is safe and is
effective.  


This is something that we all collectively as a scientific
community are trying to address, and the alliance with the
regulatory agencies, such as the MHRA, and you said that you have
found your interaction with the MHRA very positive, and I can
tell you exactly the same. So we are all trying to go for the
same goal, effectively, so trying to find a way to systematise,
platformise these sort of approaches. And I guess starting with
antisense oligonucleotides is really the right place to go
because it’s a class of drugs that we have known for a long time,
and we know it can work. 


Ana Lisa: Meriel, can you tell us a little about the National
Genomic Research Library at Genomics England and how this could
link with initiatives to find many more patients as new
treatments become available for rare and ultra-rare
conditions? 


Meriel: Yes, I think what’s wonderful now is actually that what
we’re really trying to do is give everybody the opportunity to
have their rare condition specifically diagnosed at the molecular
level, and the way in which that is being done is by offering
whole genome sequencing in the NHS currently in England but to
all patients with rare diseases.   


And so, it’s about trying to establish their diagnosis. And as
well as that, even if the diagnosis isn’t definitely made at the
first pass when the clinical scientists look at the data, because
the whole genome has been sequenced, actually all that
information about their genome, if they consent, can then be put
into the National Genomics Research Library.  And that is a
fantastic resource for national and international researchers who
get approved to work in this trusted research environment to make
new disease gene discoveries and identify these diagnoses for
patients. 


What’s also offered by Genomics England as well is when the
National Genomics Library data results in a new publication, the
discovery of a new gene or perhaps a new molecular mechanism that
causes a disease we already know about, that feeds back into the
diagnostic discovery pathway within Genomics England back onto
the diagnostic side of all the data.   


So, patients who may have had genetic testing previously using
whole genome sequencing where they’ve, if you like, had their
sequencing done before the diagnosis was sort of known about,
will also be picked up. And so, what this is really doing is
trying to kind of give this really equal platform for everybody
having testing to all have the same opportunity to have their
diagnosis made, either on the diagnostic side or with
research. 


Ana Lisa: So, sort of on a cohort-wide scale as new discoveries
are made and published you can go back and find those patients
that may actually have that diagnosis and get it back to them,
which is brilliant. 


Meriel: Exactly. And this speeds up the whole process of getting
these diagnoses back to people. So on a regular basis in the NHS,
we will get feedback from the Diagnostic Discovery Pathway about
“Here’s some patients who you requested whole genome sequencing
from a number of years ago and actually now we think we know what
the particular molecular condition is.”  And so, it’s key of
course for our patients with rare conditions to make that
molecular diagnosis because then we’re able to have them
identified for our colleagues who are doing this ground-breaking
research trying to bring therapies for these rare
conditions. 


Ana Lisa: Thank you. And I hope that, as currently, if a novel
genetic mechanism, as you’ve just described, is identified that
could explain a rare condition that those patients can be found
and they can receive that diagnosis, even many years later, and
hopefully as novel treatments become available and say there’s a
chance to individualise ASO therapies, for example, to start
with, that one could also go and look for patients with
particular variants that could be amenable potentially to that
treatment. And that’s really sort of exciting that one could look
for those patients across England, irrespective of which clinic
they’re under, which specialist they’re under, and I think that
could be really powerful as new treatments develop. I suppose,
Meriel, if somebody comes to see you now in clinic are things
different? 


Meriel: Well, I think one of the things for me when patients come
to clinic now is we might have an idea about what we think their
condition is, maybe even we think it’s a specific gene. And we
can offer whole genome sequencing and so it’s not just the way we
used to do things before by looking just at the coding regions of
the gene, we can find more unusual ways in which the gene can be
perturbed using whole genome sequencing.  But let’s say we
don’t make the diagnosis. I encourage my patients, if they’re
comfortable with it, to join the National Genomics Research
Library, because really it’s been incredibly productive seeing
the new genetic discoveries that are coming out of that, but as
well I say to them, even if we don’t get the diagnosis the first
time round when we look at the data, actually this is a constant
cycle of relooking at their data, either if they’re in the NGRL
or as well on the Diagnostic Discovery Pathway side of the
service that’s run by Genomics England. So yeah, I feel like it’s
a very big difference; they don’t have to keep coming every year
and saying, “Is there a new test?” because actually they’ve had
an excellent test, it’s just developing our skills to really
analyse it well. 


Ana Lisa: Yes, and our knowledge, the technology and the skills
keep evolving, certainly.  And I think one of the things
that I’m sort of hearing from this conversation is that balance
of hope and realism, Carlo we were talking about earlier how you
need all the pieces of the puzzle to be lined up - so the
regulatory agency, the clinicians, all the preclinical work has
to have been done, monitoring afterwards for side effects - every
piece of the puzzle has to be lined up for a new treatment to
make it to a patient.   


And, Anne, I’d like to come back to you because we’ve talked
about this before, how one balances these messages of optimism
and hope which are needed for bringing everybody together as a
community to crack some of these very difficult challenges
highlighted by treatments for rare and ultra-rare conditions and
at the same time the need for realism, a balance
conversation. 


Anne: Yeah, that was one of our big learnings through the gene
therapy trial and other trials we’ve had in the condition. As a
rare disease charity, you do everything. You know, my title is
CEO, but I tell people that’s Chief Everything Officer because
there’s only a few of you and you do everything. So, you go and
you lead the London Hope Walk and you also are a layperson on the
Scientific Advisory Board and you also send out the emails about
grants... And so, you could easily as a small rare disease
charity conflate different communication messages because you’re
in a certain mode.  And so we have been from the early days
in the mode of raising hope for people to say, “Look, we can make
a difference as a patient community, we could raise funds, we
might be able to move things forward, you’ve got the power to
make a difference if you want to.” That’s one set of hope. 
And it’s not dreamlike hope, we’re linked to the reality of there
are great breakthroughs.  So, you know, in the world of
spinal muscular atrophy these clinical trials have led somewhere
very quickly, so we’re not selling false hope, we’re talking
about the difference we can make.   


But then as soon as you flip into “There’s a clinical trial being
run” that’s a completely different type of communication and you
cannot conflate that message with the previous message.  And
we always say to everybody, “We’re your team, we’re a family,
we’re a team, we all help each other.  When you are
considering joining a clinical trial your team is the clinical
trial team.   


The other team does other things for you but the people you need
to work with and ask hard questions of and listen hard to, that’s
your clinical trial team led by the principal investigator
because then you’re in that with them. And, you know, the reality
of the fact that many, many clinical trials don’t work as we wish
they would be and the decision you make for your child, your
baby, your little one, to join a clinical trial… because that’s
what it comes down to in our disease, has to be made with that
team, not the team that’s selling you a fundraising event. It’s
worth reminding rare disease patient organisations we’re wearing
different hats and the hope and the realism are different tracks
you have to go down.   


But at the same time as being realistic you also have to keep
remembering that there is still grounds for hope, we are moving
forward. And 21 years ago, when Tom was born the idea that you
would be able to get all of the muscles in the body to switch
back on – putting it in lay terms – seemed like a bit dream.
Well, that is what has happened in the gene therapy clinical
trial, we just have to now make it safer and understand more
about what we’re dealing with. So, the 2 things, the hope and the
realism, do exist side by side. 


Ana Lisa: I think that perfectly encapsulates a lot of the
messages around rare disease therapies where there’s such hope
that novel treatments will really target directly the DNA or RNA
to potentially correct the problem across many different rare
conditions and therefore actually making treatments one day
suddenly available to a much, much bigger population of people
with rare conditions than we could’ve dreamt of 20 years ago
or perhaps now, and at the same time this massive need to work
cooperatively to all make this as fair, as equitable. Not
everybody is going to have the opportunity to fundraise massively
to be an expert about their condition, and the importance of
sharing these learnings and also really, really listening to the
patient community and really, as Carlo was saying, keeping track
of side effects, having registries/databases to share these is
going to be incredibly important. 


[Music plays] 


Ana Lisa:  Anne, can you tell us a little about your
reflections on equity from the patient community
perspective? 


Anne: Well I mentioned serendipity early and one of the aspects
of serendipity that played into our favour for setting up the
Myotubular Trust was that by hook or by crook Wendy Hughes, who
set up the charity with me, and I were both able to devote time
at that period of our lives to setting up a charity. When my
husband, Andrew, and I were told that Tom would more than likely
die before his first birthday, one of the decisions we made as a
family was that he would never not be with a parent, we would
always have someone around, and that kind of meant someone had to
give up a full-time job and that was me.  We thought, “If
Tom has a few scarce months on the planet, we’ll be with him.”
And then when Tom lived to be nearly 4, as a family we got used
to living on one salary and we were very lucky that we could pay
the mortgage that way and run our family that way and eventually
that meant I had the time to run the charity.   


That doesn’t happen that easily, that’s a tall order,
particularly when you have somebody in the family who has such
high needs. And one of the things that I have often thought about
is that in the rare disease space we could do with a different
funding model for rare disease charities, we could, in an ideal
world I have this nirvana that I imagine where there’s a fund
that you can apply to that is contributed to by the people who
make profits out of finding rare disease cures - so the
pharmaceutical companies and the biotechs - and there’s a fund
that they contribute to and that if you have a rare disease and
you are willing to set up an organisation that supports families,
that raises research funds, that provides a way of hearing the
patient voice, then you could apply to that for running cost
funds and then you’d be able to run this charity. And then you
wouldn’t have to rely on whether you live in an area where people
will raise money for you or…  We were very lucky that we
came across a few great benefactors who would give us money for
running the charity, which is actually how we fund
it.   


All the research money we raise goes 100% into research, not a
penny of it goes towards running costs because we have
serendipitously found people who will be benefactors for the
charity, but we’re relying on a lot of good luck for that kind of
model to work. And when you look at how much profit is made from
developing rare disease treatments and cures – which is fine
because that’s what puts the passion and that gets people working
on it – then why not have an advance fund to run rare disease
charities? One of my nirvana dreams. 


Ana Lisa: It’s good to dream. Indeed, my hope is that there will
be some amazing shining examples that lead the way that open
doors, make things possible, prove that something can work and
how and that then that will enable many other treatments for many
additional rare conditions to be added in so that if you’ve
learnt how this particular treatment modality works for this rare
condition and there was funding behind it and everything else
that’s needed that then you can, the learning from that, I’m
going to use the word ‘tweak’, which sounds minor and could be
very major but actually the concept that you can then tweak all
those learnings and findings so that that same type of treatment
modality could be adapted to treat somebody else with a different
rare condition in a different location would be absolutely
incredible and really powerful, given that if something like 85%
of rare conditions affect less than one in a million people it’s
not going to be feasible to use the same strategies that have
been used in the past for very common
conditions.   


One of the other big barriers is the cost of developing treatment
for ultra-rare conditions.  Where it’s a small number of
patients that you have and therefore all the challenges that come
with monitoring, checking for efficacy, monitoring safety and
ultimately funding the challenges are much greater, however if
some of these treatment modalities are also going to be used to
treat common conditions it might be that actually there’s a lot
more cross-talk between the nano-rare, ultra-rare, rare and
common conditions and that we can share a lot of that learning.
I’d love to hear from each of you where you hope we will be for
rare disease and rare therapies. 


Carlo: Well my dream is that in 5 to 10 years’ time an individual
with a rare disease is identified in the clinic, perhaps even
before symptoms have manifested, and at that exact time the day
of the diagnosis becomes also a day of hope in a way where
immediately the researcher, the centre, genetics lab, flags that
there are the specific mutations, we know exactly which is the
best genetic therapy to go after, antisense oligonucleotides as
opposed to CRISPR editing, and a path forward, both at the
preclinical and clinical level, to demonstrate and to cure these
patients eventually is already laid out in front of the
patient.  So, transforming the day of their diagnosis as a
day of hope, this is my dream with the next ten years. 


Ana Lisa: Thank you, that’s a wonderful dream. Meriel, can I come
to you? 


Meriel: Yes, I think I just want to echo Carlo.  We’ve had
great developments and progress with getting whole genome
sequencing into the NHS for testing but what we really need is
for it to be fast and efficient and getting those diagnoses
established quickly. And we have had that set up now and we’re
really getting there in terms of speed, but then what we need is
exactly what’s the next step and actually structure like UPNAT
that are developing these processes that we can then say to the
patient, “And from there, now that we’ve established your
diagnosis, this is what we have options to offer.” 


Ana Lisa: Brilliant. And presumably that if the diagnosis isn’t
achieved now there is a hope that it will be achieved in the
future as well. Anne... 


Anne: Well, stepping one hundred per cent into the patient’s
shoes rather than the scientific side that we don’t so much
influence....  stepping in the patient’s shoes, in 5 years’
time I would absolutely love it if we were in a situation where
all the parties that have come to the table looking at a therapy
or in the earlier research genuinely want to bring the patient
voice into the room. As Carlo talked about, there’s even going to
be more and more and more of these rare diseases, then those
voices, those few people who have experience of it, they may be
able to shed light on something. Maybe even sometimes don’t even
know it’s a fact that they know but that were brought to the
table as passionately as everything else is brought to the
table. 


[Music plays] 


Ana Lisa: We’ll wrap up there. Thank you so much to our guests,
Anne Lennox, Carlo Rinaldi and Meriel McEntagart, for joining me
today as we discuss the collaborative power of working together
and look to the future of rare therapies that could have the
potential to unlock treatments for many rare conditions. If you’d
like to hear more like this, please subscribe to Behind the Genes
on your favourite podcast app.  Thank you for
listening.  I’ve been your host, Ana-Lisa Tavares. This
podcast was edited by Bill Griffin at Ventoux Digital and
produced by Naimah Callachand.