Speaker A
Welcome, everybody. Thanks for joining us today. This is Ask the Experts for LAMA2 CMDs.
Experts discuss LAMA2-related dystrophies, clinical phenotypes, natural history studies, and research updates for improved diagnosis and therapies.
Key Takeaways
- LAMA2-related dystrophies are now stratified into LAMA2 RD1 and RD2 based on motor milestones to better guide clinical trials.
- Natural history studies are ongoing internationally with collaborative efforts to harmonize data and outcome measures.
- Muscle biopsy is being replaced by clinical phenotype and genetic diagnosis for patient classification.
- Ready CMD LAMA2 natural history study is actively enrolling young children to assess clinical trial readiness.
- International collaboration is critical to advancing research and therapy development for LAMA2-related CMD.
Summary
- Introduction of expert panel including researchers and clinicians specializing in LAMA2-related congenital muscular dystrophies (CMD).
- Discussion on the updated nomenclature for LAMA2-related dystrophies, proposing LAMA2 RD1 and LAMA2 RD2 based on clinical phenotypes.
- Explanation of the importance of stratifying patients by clinical ability (sitting vs walking) for natural history studies and clinical trials.
- Review of past and ongoing natural history studies, including the Ready CMD LAMA2 study enrolling young children under 5 years old.
- Clarification on multiple international cohorts conducting natural history studies with harmonized outcome measures despite logistical challenges.
- Emphasis on collaboration among international sites, clinicians, researchers, and industry for unified research efforts.
- Highlight of the shift away from muscle biopsy-based definitions towards clinically relevant criteria for patient classification.
- Details on the geographic distribution of study sites primarily in the US, with additional cohorts in Brazil, Europe, and other countries.
- Focus on clinical trial readiness and biomarker development as key goals of ongoing research efforts.
- Commitment to improving understanding of disease mechanisms and advancing gene therapy and other treatment approaches.
Full Transcript — Download SRT & Markdown
Speaker A
Today's agenda includes meeting our experts, research questions followed by care questions, and then closing remarks.
Speaker A
And we're going to be introducing all of our awesome speakers today. Judy, you want to start?
Speaker A
Yes. So, my name is Judith Reinhard. I'm a researcher at the University of Basel in Switzerland, and I work with the animal models for LAMA2 MD for more than 10 years now. With these animal models, we try to understand the
Speaker A
disease mechanism and also develop some therapies, and I work on the development of gene therapy for LAMA2.
Speaker A
Valerie? Hello. I'm Valerie Lamond. I'm a research director in the Center of Research for Myology in Paris, France.
Speaker A
And I've been working on LAMA2 for quite some time now, starting with the genetics part and then moving on to the pathological mechanisms using animal models as well as cellular models derived from patients' biological material. And we're
Speaker A
currently focusing on understanding the mechanisms in some cellular models, skin-derived cellular models that we are forcing to become muscle cells, which are quite relevant to this disease.
Speaker A
Thank you. Anna? Hi. Good afternoon. Good morning for everybody. I'm Anna Sarkozy. I'm a clinician working at the Dubowitz Neuromuscular Centre in London in the United Kingdom. I see patients in clinic, but I'm also involved in the
Speaker A
diagnostic aspect, in particular the genetic aspect, and have completed some natural history studies for this condition.
Speaker A
Caitlin. Hello, good morning. I'm Caitlin Batley. I'm a pediatric neuromuscular neurologist, and I practice at UT Southwestern in Dallas, Texas. We are also a site for the LAMA2 natural history study that's currently ongoing.
Speaker A
Rotem. Hi everyone. I'm Rotem Orbach. I'm a pediatric neurologist. I work at the Childhood Neuromuscular Neurogenetic Group at NIH. I'm a clinical researcher. My main focus is really about biomarker imaging biomarkers for congenital muscular dystrophies.
Speaker A
Rose. Hello, my name's Rose Chinken. I'm a registered dietitian with Cincinnati Children's Hospital in Cincinnati, Ohio, and I work as part of our interdisciplinary care team for the neuromuscular outpatient center.
Speaker A
Reagan. Hello, I'm Reagan Foley. I'm a pediatric neurologist and neuromuscular specialist. I'm working with Dr. Rotem Orbach at the National Institutes of Health. Our group, the Neuromuscular Neurogenetic Disorders of Childhood group, is focused on congenital muscle diseases and particularly focused on the congenital
Speaker A
muscular dystrophies, with a special focus on LAMA2. We also are a site for the Ready CMD LAMA2 natural history study.
Speaker A
Gus. Hello, I'm Gustavo Chackalowski, scientific director at CureCMD. And I'm Rachel Alvarez, executive director for CureCMD.
Speaker A
All right, let's get into the research questions.
Speaker A
Gus. Perfect. So, let's start with clarifying the nomenclature of LAMA2.
Speaker A
People were asking about the name partial versus full deficiency in the past and now that this changed to LAMA2 RD1 or LAMA2 RD2.
Speaker A
So maybe I'll start, I think, and then Dr. Orbach can jump in anytime. We had performed this international retrospective natural history study which actually gathered data from the Congenital Muscle Disease International Registry, the CMDIR, which CureCMD
Speaker A
had gathered natural history, basically medical records of our patients that were born between the years of 2001 to 2017. Looking at the 60 patients, we decided that it would be important for us to study the different
Speaker A
clinical phenotypes. Historically, people had used muscle biopsy and the amount of expression of merosin, whether it's present or absent, to distinguish between different clinical groups. But actually, we decided for the purpose of understanding the natural history and for stratifying
Speaker A
patients for future clinical trials, it would be really important to understand the distinct clinical groups or phenotypes. So we decided for the purpose of the study, and in a way hoping that we could use this going forward to
Speaker A
try to define patients between those that sit, meaning those that can basically attain the ability to remain seated with or without support, meaning can be seated with pillows or seated by themselves, meaning the ability to remain seated, not getting to sit, but the ability to
Speaker A
remain seated. Those patients we thought could be called LAMA2 Related Dystrophy 1 or LAMA2 RD1, and those that may attain the ability to walk, meaning the ability to take any unassisted steps by three and a half years of age, as being a different
Speaker A
subgroup, LAMA2 RD2. Now, this is kind of our proposal in our paper, which we just had published on this study back in, I think, 2024. So, this is not yet fully used universally, but it's our
Speaker A
attempt with our colleagues to stratify in a way which is clinically relevant but also important for clinical trials.
Speaker A
There are other nomenclatures still used. Some centers internationally will even say MDC1A, the original nomenclature, but we're trying to get a unified, harmonized clinical nomenclature going forward.
Speaker A
That's great, Betty Kia. Rodan, do you have anything to add?
Speaker A
No, just to say that it really reflects the changes we see with clinical practice, where muscle biopsies are no longer being performed. So, we need to change definitions as we go, as we
Speaker A
step into clinical trials, and we understand better what is important. The same is with SMA, so we have some other examples with other diseases that seem to be done for those.
Speaker A
Great, thank you. So, let's jump to the next question that is also related to clinical research. People were asking because they have seen reports about past and ongoing natural history studies. The question is if
Speaker A
these studies are part of the same or are different studies, and if you can clarify where we currently stand with these studies.
Speaker A
Okay, then you want to start? [clears throat] So, I'm not as familiar with the other study, but I know for Ready CMD LAMA2 natural history study that's led by Dr. Anne Connolly, we are still enrolling. I know almost all of
Speaker A
the sites, I think, are up and running. And Reagan, I think you mentioned 12 of the 14. I think that's the most updated. Perfect.
Speaker A
And so, I think thankfully we cover a wide geography throughout the United States. So, my hope is that there's a somewhat close site for most patients and their families to be involved. This is enrolling young
Speaker A
kids, as the main goal of this particular study is to assess clinical trial readiness for the very small ones, so less than 5 years old.
Speaker A
And so, we can definitely, if the link's not available, maybe we can put it in the chat for the clinicaltrials.gov information, and that has all of the sites listed on it.
Speaker A
If anyone has any more specific questions about what the trial entails or day-to-day what this looks like, what kind of time investment would be made by your family, that kind of thing, happy to talk
Speaker A
about that, too, if that's relevant. I could add that I think the question was also kind of wondering about other centers internationally.
Speaker A
So, we had attempted going as far back as 2020 to have one international prospective natural history study. The complicating factor there was logistics, different legal requirements, different countries, as well as funding. So, what's happened
Speaker A
is not a negative thing because we have now multiple validation cohorts, but we really have currently, as Dr. Batley mentioned, this Ready CMD LAMA2 across 14 sites ultimately. Now, 12 are active in the US. There's also a study
Speaker A
going on in Brazil, study in France, Netherlands, Spain, Switzerland, Italy. So, multiple cohorts. We are predominantly looking at the same exact outcome measures. Some centers have extra outcome measures. So, all this data is...
Speaker A
clinicians, and even some folks from industry that meet monthly for updating on research and also different sites internationally that are doing natural history studies have that as a forum.
Speaker A
So, we really all communicate very unified um collaborative um effort internationally in sharing all that data um for the purpose of improving clinical trial readiness.
Speaker A
Perfect. Anybody else has anything to add? I just wanted to just to add very quickly cuz there is a comment also about past studies. So, there have been some studies completed already and some that were longitudinal studies, but also
Speaker A
some centers including ours we looked at patients that have been seen over the years. So, that's what we call the retrospective clinical studies and these are also very important. Maybe not as detailed as not sometimes the data as
Speaker A
not as accurate as prospective study like the ones that the colleagues have described. So, it's very both studies are important, but the data you collect is clearly different. I just wanted also to highlight that it's very important in
Speaker A
the meantime for also for those families who are not part in the natural history study to aim to get a clear genetic diagnosis and possibly make sure that they follow standards of care. So, that perhaps in future their
Speaker A
data can also be collected. Megan, did you want to mention the original LAMA2 natural history study?
Speaker A
Uh the original Well, there's actually multiple that kind of and maybe I can mention to you again Rachel. So, Dr. uh Sarkozy had a cohort of 46 patients in the UK looked at. China had a cohort of 130 patients retrospective. Netherlands
Speaker A
had 27, Qatar is 21. So, lots of robust retrospective data. Um the original one Rachel, would that be retrospective or The COM study.
Speaker A
Oh my goodness. Yes, so we had done it at the NIH. It was over the course of 4 years CMD-COM common outcome measures study where we brought in patients with LAMA2 related dystrophy as well as patients with collagen 6A dystrophy and looked at
Speaker A
outcome measures over the course of those 4 years and that was really important for defining the number of patients we'll need for future clinical trials as well as change in motor function and pulmonary function. We did not look at children under the age of 5
Speaker A
and so the ready seem laminin 2 study that Dr. Batley mentioned is precisely looking at those first 5 years of life where we really need to know that natural history data in more detail.
Speaker A
Talking about the clinical trials that was mentioned many times already. People is wondering where are we at for clinical trials for laminin 2 and if you can comment on which research research studies are moving forward to work clinical trials.
Speaker A
And I the first the first response is that we are not having any current clinical trial going on.
Speaker A
But there are some studies in pipeline, right? Go ahead and you'll see that. Can you comment on on which research studies are moving forward?
Speaker A
Yeah, so I could try to summarize what research is is ongoing in the field and I think the potentials that have been developed are either gene therapies or also therapies which more target the downstream mechanism of the disease.
Speaker A
And there are two gene therapies in development. One is by Modalis Therapeutics, now a pharma company that tries to move this forward. Another gene therapy is developed by us. So this is actually academic research which is now under the umbrella of a startup
Speaker A
company. And on the other hand, there's a lot of research also on potential downstream mechanism of the disease and also the development of novel cellular models to study the disease and also early research also on potential cell therapies.
Speaker A
Great. Very nice summary. Anybody else has something to mention? Valerie? Yes, if I may.
Speaker A
Yeah, I just wanted to add also for what we're doing as early research in cell models.
Speaker A
That is a therapy targeting specific mutations, nonsense mutations that lead to premature termination codons using some tools called uh tRNAs. And so it's one type of gene therapy, but not bringing the defective gene, but bringing a tool to correct a
Speaker A
mutation. Perfect. Great. And and last part of that question was people was wondering if resources are communicated across international groups or if they are siloed by country.
Speaker A
Yeah, so I think this already Reagan mentioned that scientists, also clinician and researchers are very regularly meeting and actually exchanging their knowledge, also their scientific approaches and their results.
Speaker A
And which means we are very much communicating with each other. And so if there is progress, this is actively shared within the community.
Speaker A
Yes, and I'd like to add that this is the communication is also greatly facilitated by patients association.
Speaker A
Um in the US, Cure CMD of course, but also in Europe and and other countries.
Speaker A
So that's a very very important contribution from the patients association. Yes, thank you for mentioning that.
Speaker A
Can we Can we pause for 1 second and introduce our other two guests? Yes.
Speaker A
Clara, do you want to introduce yourself? Thank you, Rachel. Hi, I'm Clara. I'm a child neurologist from Brazil. I work in University of São Paulo and I'm interested in their muscular disorder, especially in Lama2.
Speaker A
Hank. I'm Hank Meyer. I'm a pulmonologist from Children's Hospital of Philadelphia and have had a long-standing interest in their muscular disease um and defining the pulmonary uh standards of care and some pulmonary outcomes.
Speaker A
Thank you. Okay guys. Okay, so um what are we uh Uh there was a question about uh if there is use of the of CRISPR if it's research on on the use of CRISPR in Lama2.
Speaker A
Maybe Judith can comment on the technology that Modalisa is using. It's a bit complicated, yeah.
Speaker A
Yeah, so um Modalisa is using uh therapy or an approach which was originally developed um in in Toronto. And this is an approach which does not use the classical CRISPR um to fix or correct a certain mutation, but it's approach that
Speaker A
uses a modified version of CRISPR to upregulate another gene. In this case, this is Lama1 and then the expression or upregulation of this gene should correct for Lama2 deficiency.
Speaker A
Great. And um I I can add that CRISPR has been looked for Lama2 especially because Lama2 is a very large gene, so the classical um gene therapy will not work because you cannot pack that big of a gene in a
Speaker A
AAV vector, so uh people was is looking at the use of CRISPR uh to to do a gene editing um in inside. Um so yeah, CRISPR but CRISPR behind in the pipeline to the clinical trials. Um [snorts] Um
Speaker A
there are many safety issues that are still not resolved. Um but yeah, it's it's used uh in in LAMA2.
Speaker A
Um I was going to ask you mentioned uh you did about the LAMA1 upregulation. And so uh any of mention about the uh protein replacement that uh in the past a couple of companies have tried to Yeah, I can also add to this. So, in in
Speaker A
in the research community, it's very clear and there's a lot of data that we could replace LAMA2 with LAMA1. And so, one approach is to try to actually upregulate or to express this gene in the patients. And the other approach um
Speaker A
was to try if LAMA1 as a protein replacement therapies. And this is um also academically developed originally and was then um tried to move forward in several companies.
Speaker A
Okay, thank you. Um one question is about uh stem cell therapies if they have a real potential in LAMA2.
Speaker A
So, I think So, the the the general challenge for cell therapies is actually to bring in sufficient cells that can um improve the muscle in a sufficient amount to actually lead to meaningful improvements of muscle function. And this was so far not achieved, but also
Speaker A
there there is a lot of research ongoing also for other diseases. and eventually there is a breakthrough in the future and then cell therapies also become more applicable eventually also for Lama2.
Speaker A
But at the moment this is not something that has shown very efficient very much efficiency in these diseases.
Speaker A
If I may add, I think also one of the challenges for cell therapy is identifying the right cells to bring into the muscle to express whether it's Lama2 or any other protein.
Speaker A
So I think that's also why and then their survival once they're in the tissue. So that's why it's behind I think and hasn't been developed so much for Lama2.
Speaker A
Yeah, okay. Yeah, and and I I can also add that this is something that has been going on for for many years now since researchers were able to manipulate cells and grow within the labs and and modify them. So it's a brilliant idea.
Speaker A
It's a very nice idea but but the the technicalities and safety issues in injecting those cells into patients is still a big barrier. But there are many many labs in the world working with with stem cells to because they have really
Speaker A
potential to be but we to be effective but but we are very far away of the real solution or real treatment with them yet.
Speaker A
And so just to clarify when we talk about potential or upcoming clinical trials we mentioned children. So are the a trials planned only for children or all in or there are some for more young or adult patients.
Speaker A
Maybe I can start and anyone can take it further, but I think what happens is we any any therapy in development that has to go in application to regulatory agency like the FDA and the EMA. And sometimes that
Speaker A
feedback is that they prefer to start in a older age group. For certain therapies uh uh that we've talked about the gene therapies, we're probably going to aim initially towards the younger patients, but that does not mean it could not be
Speaker A
expanded to the older patients. Uh we had done that in the past we had done um trial phase one safety and pharmacokinetics of omaveloxolone that was for laminin 2 patients ages 5 through 16 and collagen 6 patients 5
Speaker A
through 16. That data showed that that oral compound, which is an anti-cell death or anti-apoptotic medication, is safe and has a nice profile in the blood. It's not taken forward yet because of some need for further um animal data uh animal model
Speaker A
data for the collagen 6 patients, but also some need for further defined uh biomarker signatures. But that may be used in the future as an adjunctive therapy and definitely applicable for adults. So the that's yet to be determined the ultimate age range for
Speaker A
patients in clinical trials and ultimately the approval of these therapies. Thank you. And I think also if I can add that independent of age, um we still need to understand what would be our goals, what would be the end points that prove that
Speaker A
the drugs are actually working. So I think that we're still not quite clear uh even in in children and especially in adults what would be expected from the patients if they're improving with the drug and how we could
Speaker A
prove to the agencies that the drug is actually working. I think this well well connects with the next question about the biomarkers, which would be also outcome measures.
Speaker A
So, perhaps this might be very different in adult populations. So, we might need to have natural history studies in older patient groups to then develop, you know, assess the efficacy of these, right?
Speaker A
And to speak on behalf of Dr. Nicole Wermuth, I think she would say she is looking at the So, her focus is adult patients with congenital onset diseases, and so her team has in Netherlands has a natural history
Speaker A
study that includes adults with limb-girdle muscular dystrophy and data to have. Yeah, so that what we talked at the beginning about natural history studies and you mentioned all these studies going on.
Speaker A
We are covering with these natural history studies the whole range from from newborns to very adult population to have those tools to be clinical trial ready for when any potential therapy can be moved forward to patients.
Speaker A
So, Anna mentioned already about the next question and about biomarkers. So, can you give an update about the search for suitable biomarkers for limb-girdle muscular Sure, I'll start with someone and I'll pass the baton also to others including
Speaker A
Rotem who's looking at imaging biomarkers. So, I've been looking at basically biomarkers in the blood. So, easy way to test if we can would be to get a blood sample during So, during the course of a clinical trial instead of
Speaker A
having to do repeated muscle biopsies. And so, I've done a pilot study and that data is being finalized now. Some exciting data. So, looked at a cohort of patients with limb-girdle muscular dystrophy looking at the serum for certain markers including microRNA which
Speaker A
are these small [snorts] non-coding RNAs that are stable in the blood at room temperature and easily can be tested. And what we are looking at is a disease specific signature meaning findings in the blood both microRNA also proteins proteomics related to
Speaker A
limb-girdle muscular dystrophy and also disease specific, meaning you basically a different profile at a different age um because it it changes over time. And that data is uh very promising data, which we also like to be able to use in
Speaker A
the course of future clinical trials. And that work has been supported by CureCMD, LAMA2 France, LAMA2 Europe, For Sarcoma, ImpulsaT. So, a lot of LAMA2 patient and family organizations have helped to support that work. And I was able to get um control uh samples uh for
Speaker A
that control cohort um from uh colleagues at the Infant Centre, University College Cork, Ireland. So, that's coming out that data is shortly, but there's also very promising um other outcome measures and biomarkers, including imaging biomarkers that Dr. Orbe can mention.
Speaker A
Yes, so just to give a little also additional context from a regulatory perspective, all the performance-based outcome measures are great and but if we can supplement them with a surrogate biomarker that is strong enough to reflect on treatment response or disease
Speaker A
progression, um that would really make the claim to the regulatory authorities uh much stronger when we come to ask for approval. And as Dr. Foley mentioned, she looked at some blood biomarkers, but we can also look at other stuff like
Speaker A
electrophysiology and imaging. Specifically, I've been focused on a new It's still investigational research technology, multispectral optoacoustic tomography, where you can use light and to know how much collagen and how much fat you have in the tissue. So, even
Speaker A
before maybe the patient shows you by performance that he's being affected by the disease, you can look um at other more kind of deep tissue changes that you don't need to have a biopsy for them. Um so, all of that, if proved
Speaker A
effective, could help us when we come to the next stage, to clinical trials and um make a claim about what the treatment is doing for our patients.
Speaker A
Great, thank you. And um uh there were some uh people asking if uh international patients could be accepted to participate in clinical trials.
Speaker A
Uh so, maybe we can try to educate uh our your recruit for clinical trial and the international barriers.
Speaker A
Should I start? And maybe maybe Dr. Sarcosi wants to mention too. So, what happens ultimately is when we start these um studies, whether it be natural history or interventional studies, a few sites are the initial sites for those
Speaker A
studies and then ultimately we intend always to to to have a network of other sites internationally. Um we often say, at least for our site the National Institutes of Health, that if you're international patient and you want to come be part of a study, wait
Speaker A
until there's a therapeutic study, a medication. The natural history studies, we wouldn't recommend traveling. The burden of travel is so much and the risk of, you know, of a long haul flight. But when there are therapies that are
Speaker A
available, they will be available at multiple sites internationally. And if you do want to participate and you're not in the country where the clinical trial is being run, then you can have a conversation with the different sites about what's feasible.
Speaker A
Yeah, I mean, I don't know how many of the attendees are from from countries outside the US, but in Europe we often hear families who, for example, think about traveling quite far away for trials. And it's always something that
Speaker A
has to be put in the context of family situation, possibility, and um and different aspects of of how this is feasible for a family and for the patient themselves. So, I I I think what's also important is as Reagan
Speaker A
mentioned before the if it's a therapeutic trial, also please remember that many of these compounds are being investigated. So, there is no proof that this trial this therapy is will be of you know, of of clear benefit. So
Speaker A
this is these are clinical research studies. So it's important to think carefully about these difficult decisions and very often some also to other countries in Europe and around the world and hopefully once the therapies are shown to work will be you know
Speaker A
more widely available. So it's a complex discussion I think but we often are and also I think it's important you speak with your clinician if you are interested in a trial and ask advice to the person who knows you best
Speaker A
and and can maybe contact the specific center and and advise. Yeah, the the ideal of course is to bring the clinical trial to all the countries all the cities but uh is impossible but let's the try and yeah. So
Speaker A
and usually what if if if a site or a country can cannot reach to the uh number of patients they need for the clinical trial so then they can be probably search outside the country of that city, right?
Speaker A
Yes and and and and for sure for sure but I think in particular internationally the other aspect to consider is if there would be so if you travel far away for your clinical trial would your standard of care be provided
Speaker A
in that country where you're traveling so so I think that's also maybe another aspect to to maybe consider but we hope that uh more and more trials will be more you know available in multiple sites in multiple countries.
Speaker A
Yeah and and and one uh clarification is that the a clinical trial is an experimental use of a drug is not the treatment so um of course the idea is that if the treatment then is approved it will be available in
Speaker A
around the world. Exactly. So and and related to that uh there was a question of how do you get involved and how do you learn about clinical trials and I can respond from QCNB that one important tool is if you register in
Speaker A
the in our registry called the CMBIR and I think if we put the link already in the chat and from there you will get notifications about any clinical trial or clinical study that is going on worldwide and specifically in your case for for LAMA2.
Speaker A
Um, and I don't know if anybody else has any how do you get involved? I think we we already covered. Yeah.
Speaker A
Yeah, I think I think the a registry like you mentioned or and also in Europe there are maybe I in other countries there might be other, you know, registries of patients with muscle conditions and so on that that could possibly link the
Speaker A
families up with ongoing clinical trials and for example larger clinical centers there might be internal data sets of patients who you you know, just to log interest of families about clinical research so that if there is a research
Speaker A
ongoing in that country or in that center the families could then be put in touch with the specific clinical studies.
Speaker A
Great. Uh, one last question about research there was a couple of families asking about research into the use of creatine for keeping and growing muscle.
Speaker A
So, I can say from the research side that also in the animal models and so on there was no research done on the specific use of creatine and LAMA2.
Speaker A
Um, um, but I think I pass over to the clinicians if they recommend to use any supplements for for patients.
Speaker A
Yes, I think we have a question in the in the clinical side Uh, about supplement in general.
Speaker A
But I think in particular I also I didn't know about the use of creatine in in Lama2, so I I I did some maybe some search in bibliography and I I found a couple studies in in in Duchenne or other
Speaker A
um muscular dystrophies. But as far as I understood there is was not benefit using it. I don't know anybody else has a comment.
Speaker A
I find response very individual to creatine and it's generally speaking a benign supplement, so I'm not objecting when my patient wants to try that. But at the same time I don't think there are like Judith said like a specific
Speaker A
rational here for Lama2 and creatine supplementation. Um as you know, many people take it even like healthy people that wants to build and improve the endurance of the of the muscles.
Speaker A
Can I just maybe jump in on this? I think it's important generally with others in supplement just in in thinking forward thinking about future clinical trial that is very important however that if you take supplements to always disclose the supplements that you take
Speaker A
to your clinician because some of this compound may be perhaps uh you know, compounds that may not be allowed if you are in a clinical trial.
Speaker A
So just to be sure that you if you decide to take any supplements that you discuss them with your clinician, make them aware and just to log the information in your records.
Speaker A
Okay, and maybe we can finish the research part with a question of how can the community contribute to research?
Speaker A
I think the community already has. I mean I think I mean I would I know that Dr. Sacosi he just at the Lama2 international Meeting in Istanbul. I had I spoken yesterday with um a company in Modalis who are developing
Speaker A
a therapy and they their comment was like they were so impressed by the patient community, blown away. Having been in multiple different patient different community days and whatnot, but the communities really showed up in many ways, not just at conferences, but
Speaker A
in sharing their data, their medical records, giving blood samples, doing outcome measure studies. So, I think the community should feel proud about that.
Speaker A
And where is she studying in the in the research industry, especially in the CNDIA?
Speaker A
Yeah, I can't advocate more for that and just for the community to know whenever someone like an investigator comes to the authorities to submit a grant funding to run something, they need to show the patient input in that grant
Speaker A
application. It's super important for the community to participate, to support. That's the way to get the money going the right way, to the right direction.
Speaker A
Yeah, that can also add kind of as a researcher who usually does not see patient, it's actually also a great motivation for us to actually see patients, to be in contact with them also at Cure CND meetings, for example.
Speaker A
This is a great motivation to keep research ongoing also. Very good, yeah. Thank you.
Speaker A
And uh I just think it also helps us and academic researchers also to know what's important for the patients in terms of clinical output or clinical difficulties and that can in a way orientate a little bit also the
Speaker A
academic research and that's very important because there might there might be things that we don't think about because we are using cellular models.
Speaker A
But then if something can be replicated in a dish um cell culture dish or in an animal and that's very important also to somehow orientate a bit um the focus of the research because what's important to the patients is what
Speaker A
we need to improve with clinical trials. Yeah, and I I I can add that has been it's going to to be an ongoing basis meetings research meetings workshops where usually from the CMDA we reach out to to families that are registered to ask
Speaker A
specific questions and then we bring those that data to the to the meeting to inform the clinicians and researchers about what patient voice is at.
Speaker A
Anything else or we move to the care questions Rachel? Time-wise, I think we Yeah, we we need to move on.
Speaker A
[snorts] All right. so Thank you everybody for those research responses. Moving into care now. My first question is about kind of the things that we need to be informing primary care providers like [clears throat] pediatricians or for adult primary care providers
Speaker A
during routine examinations or routine care and then also for acute care. So if you're in the emergency department or the urgent care, what are the key things about LAMA2 that you really need to make sure that your current provider [clears throat] is
Speaker A
aware of. I can jump in here and start because I feel like I have this conversation a lot with my [laughter] family.
Speaker A
And so, you know, I think one of the most important things is to help providers who might not be as familiar with neuromuscular disorders to know where to access or how to access the information that they need.
Speaker A
You know, obviously as a general practitioner they have to know a little bit about everything. And so, you know, really need to be able to depend on us as specialists and then the resources that we're able to provide to then give
Speaker A
more specialized care to to an individual with neuromuscular disorders. So, I typically print out the CureCMD guidelines for especially for respiratory care management and I highlight the sections that I think are important for emergency physicians if they're seeing one of my
Speaker A
patients in the ER for for instance for a respiratory issue. Um and then I tell families, I'm like, "This is something important that you can bring to your doctors that can tell them what they need to know." And so, I think you know,
Speaker A
that document as well as how to contact us. We have an on-call physician, you know, 24/7 at our university and so, they can always reach out to us if they need additional guidance. And so, I think that's one of the most important
Speaker A
things is being able to connect to um you know, to the people who can help them answer the questions they need because it's a lot of information and and often times it can be a lot for families to convey all of the details
Speaker A
because especially if you're in an emergency situation, there's a lot of, you know, emotions and high stress. So, um so, just to be able to reach out to us, I think is is important.
Speaker A
Clara, what do you think? I I I completely agree actually. I think that what people need to know is the basics and I think that understanding that not all doctors from the ER is going to be aware of every specific
Speaker A
thing that a patient with LAMA2 has to be [clears throat] attended. But um I think that here we have to combine both the fact that we as the primary physicians give this letter to the patient so, they understand especially about the
Speaker A
pulmonary care, what is the most important things that they should know. But I think that it's really important to have this kind of conversations with the families and the patients themselves so, they too can be their own experts. I
Speaker A
think that this allows them to be more safe and um in a way they also can help their physicians in the ER and go through some specific aspects that we should be aware.
Speaker A
It's impossible for all the physicians to know everything about rare diseases. So, it's important for us to spread the word, but also for the patients and families to be a little bit um owner of their own history, especially
Speaker A
on those specific moments of need. Great. Hank pulmonary-wise what do you Yeah, I echo a lot of what was just said and I think you need to assume that if you're not going to a large university-based emergency room, that
Speaker A
you're going to an emergency room with people that don't understand the general concepts of respiratory care and neuromuscular disease. And certainly providing resources like the uh the the care document that CureCMD has and other other similar uh documents is helpful, but I I think
Speaker A
going with the care plan that the respiratory team that supports your child or you has put together and going ready to advocate for what needs to be done, I think is absolutely critical.
Speaker A
Mary, did you want Oh, Reagan, go ahead. Sorry, go ahead. Sorry, I'll be I'll be brief [clears throat] and then Rose definitely needs to jump in. I just want to mention one thing for parents to be aware of
Speaker A
that may occur, not to not to be surprised by and to also inform the local ER about is in young children with LAMA2-related dystrophy, probably mostly related to a young liver and small muscle size, there's a tendency for low
Speaker A
blood glucose. We call that hypoglycemia. It's part of the condition. Does not require a long hospitalization and endocrine consult to look for some sort of pancreatic tumor.
Speaker A
No, it's part of the condition and they actually we've seen the children grow out of it. But the first few years are tough. And so if the child's vomiting and not eating, there's a fever going on an illness or you had a long haul
Speaker A
flight, you missed a meal, the child with LAMA2 dystrophy is going to be very very much inclined to have low glucose.
Speaker A
You tell your local team that they can provide you with glucometer. So if your child's vomiting at 4:00 a.m. and looks gray, you can check the glucose, get a sugary drink and address it in real time. So again, that awareness is key
Speaker A
for decreasing stress but also able to address situation in real time. Rose, did you want to add anything?
Speaker A
Um yeah, I think um you know what Dr. Foley said and then to kind of echo that, you know, with our patients having smaller uh muscle tone and uh less ability um to have reserves stores during these periods of illness,
Speaker A
um you know, just stay in communication with their neuromuscular care team along with their primary care um and letting them know, you know, if there's a dietitian on staff, you know, this is what they've been eating the past couple of days. I've really
Speaker A
noticed, you know, a decrease um and just keeping an eye on that and and in communication with the team.
Speaker A
Um anybody else have anything for a primary or emergency doctors before we move on?
Speaker A
Okay. Um in terms of diet, medication and supplement recommendations, um Rose, I'll start with you but I think um let's talk a little bit about what we recommend in general for those with living with LAMA2.
Speaker A
Yeah, so um you know, with LAMA2, feel like specifically with diet, um you know, we often see more patients with underweight or poor growth. Um so, you know, taking into account the whole picture of the patient, knowing that growth charts may not necessarily
Speaker A
be, you know, the best um only indicator of of you know, how the patient's growing and and and what their nutrition status looks like, but you know, if possible, having a dietitian um available to see the patient every 6
Speaker A
months to monitor weight gain, um daily weight gain and linear growth between visits, um you know, looking at diet recalls with the dietitian who can, you know, check to make sure that protein, carbohydrate, fat goals are being met along with micronutrient
Speaker A
goals. Um and then another part of our assessment is really looking at calcium and vitamin D goals.
Speaker A
Um so in our clinic, dietitians will go through go through a daily recall for calcium just because blood levels of calcium aren't a great indicator of how much calcium we're getting in the in our diet. Um and calcium's a really important mineral
Speaker A
along with vitamin D for supporting supporting overall bone health and preventing um you know, bone loss and fracture risk.
Speaker A
Um and then again, vitamin D really um monitoring that uh serum level, so getting labs.
Speaker A
Um in our clinic, we do every 6 months. Um as that's another important vitamin that works with calcium to ensure that calcium's getting to our bones and keeping our bones healthy and strong.
Speaker A
Does anybody else have anything to add? Great. That was easy. Is there a point at which physical or occupational therapy is no longer beneficial? This is kind of [clears throat] an interesting question.
Speaker A
Um I don't think so. I think that goals will change um depending on, you know, where where a patient is at and their current muscle function, but I think that there is always um a benefit from physical and occupational therapy and
Speaker A
you know, whether that looks like um stretching to improve joint range of motion and um you know, the kind of optimization of splinting with orthotics, hand splints, AFOs or whether that looks like you know increasing physical activity through
Speaker A
using the standing frame. I think there's always something that they can add and you know use to optimize quality of life as well.
Speaker A
Would you say the same for adults? I would. Okay. Anybody else? Hank has a question.
Speaker A
Yeah, I would strongly advocate for continuing as long as possible even if functional preservation isn't there because of improving or maintaining flexibility of and function of muscles and joints preventing contractures.
Speaker A
It's exceptionally [snorts] important and I wanted to throw in speech therapy also to maintain swallowing function even if you get to the point where you are unable or your child's not able to maintain a safe nutritive swallow and
Speaker A
feedings have to be administered through a gastrostomy tube but still critically important to maintain swallowing function to be able to handle upper airway secretions during acute illnesses and that can really be the the a major determining factor between
Speaker A
a cold versus a cold that leads into a lower respiratory tract illness or pneumonia.
Speaker A
Okay. Hassan, thank you to lead into the cough assist maybe? Yeah, that's a way.
Speaker A
[snorts] Yeah, so um there's a device called the cough assist or generically mechanical in exsufflator and it's a device that has a little turbine inside that either blows air into a patient when they're trying to breathe in or helps to pull it out when
Speaker A
they're trying to breathe out. And it can loosely replicate the uh, the uh, cough maneuver that um, that one does. And when you lose the ability to take a deep breath and cough effectively, you're at risk of having
Speaker A
prolonged and more severe lower respiratory tract illnesses. Um, and it's really the only way to clear the lungs of secretions, period. There's nothing else other than, uh, a cough assist device. Um, there are devices that people will add on such as
Speaker A
vest therapy to vibrate the chest and other devices to, um, help inflate the lungs. But, it's really the only way to facilitate getting secretions out. Um, and the optimal time of doing that is ideally before you have that first big,
Speaker A
um, illness, um, should you be so unfortunate. Uh, the challenge is figuring out what time that is. And there are some outcome measures such as peak cough flow that can be used to loosely, um, uh, determine when when
Speaker A
that time, uh, would uh, what at what time you should start using a, uh, an in-exsufflator or cough assist. But, it can be very, very, um, important in maintaining respiratory health when you are unable to, um, adequately clear
Speaker A
secretions on your own. Can you talk briefly a little bit about that those first those early years when kids are not quite tuned in to how to use the cough assist. Like, what are the techniques you're using to get them
Speaker A
Um, persistence and, uh, art. Um, I What I mean by that is, um, when you do a treatment, you put the mask over the mouth and nose. Or, if it's somebody that's able to hold a mouthpiece in their mouth, they can do
Speaker A
it that way. And you then will say, "Okay, breathe in." And then you apply positive pressure and then push the air out and you apply negative pressure. That's the ideal situation.
Speaker A
When you have a child that's uncooperative because of, uh, their developmental status, meaning a young uh, infant or toddler, or somebody that is unable to cooperate because of a you know, a sort of a central nervous system challenge then
Speaker A
it becomes a challenge in trying to predict when the patient's breathing in, applying the air, and then trying to predict when the patient's breathing out. And it is doable. It just takes a lot more practice and teaching from
Speaker A
an experienced respiratory provider. Great, thank you. And [clears throat] on the topic of pulmonary care, when are we starting pulmonary function testing, sleep studies, how often?
Speaker A
What are the indicators to begin breathing support, and what are the benefits of breathing support?
Speaker A
Typically, patients who are cooperative are able to produce reliable pulmonary function between 4 and 5 years of age.
Speaker A
And so, at least in our practice, we routinely start doing testing in patients when they become 5 years of age.
Speaker A
And we have accurate normative data to go from 3 all the way up and until the late '80s, early '90s. And so, if you do have a cooperative patient, you can certainly attempt doing pulmonary function testing and then get useful data normalized um
Speaker A
normalized data starting at 3 years of age. Um um In terms of a sleep study, you know, there's no strict guideline as to when to start using it.
Speaker A
The simple answer is when you have a concern about sleep quality and need to from that standpoint assess for hypoventilation or respiratory failure.
Speaker A
There have been some general recommendations to get an annual sleep study just as a screening tool. I typically don't like to do screening tests. I like to do tests that for which I I have concerns about what you're testing for.
Speaker A
The challenge, however, is you know, having a provider that's um in a position to be able to you know, ask proper screening questions and make a judgement as to when to do a sleep study. Borrowing from other conditions where we have much
Speaker A
better natural history data such as Duchenne muscular dystrophy, the general guideline is once the vital capacity, which is the volume of air you can move through your lungs when you take a full deep breath and breathe out completely, when that number drops below
Speaker A
50% of predicted, at least in Duchenne muscular dystrophy, the recommendation is to strongly consider the possibility of nighttime respiratory insufficiency and getting and going ahead and getting a sleep study. So, that's the best not validated in LAMA2 recommendation I
Speaker A
can make. I'm going to add just one little thing which is our retrospective study Dr.
Speaker A
Orbeck was involved in the 60 patients internationally LAMA2 dystrophy. What we have seen is those kids that are less than 5 years of age, who cannot yet do pulmonary function testing, 40% of them internationally were already on non-invasive ventilation before age 5
Speaker A
years. Meaning, if we look, we find issues. And so, in those children whose maximum motor milestone is getting to a sitting position, most of those will be need to be on non-invasive ventilation and most by 2 years of age and 96% by 5
Speaker A
years of age. So, I think we should to looking uh we have the ability now to look and we hadn't done so historically before like you know the year 2000 or so.
Speaker A
Okay. And what are the benefits for breathing using breathing support? Let me just make one final comment about sleep study. The one thing that makes me uncomfortable about having a blanket recommendation to get a sleep study at a
Speaker A
certain frequency without symptoms is access. Um yeah, we have uh a sleep lab that has roughly 20 I think 20 beds um which sounds like a lot but the typical wait time getting to the end of the line is about 9 months.
Speaker A
So um we can often uh arrange for an um you know a a more facilitated uh sleep study if truly needed but I just want to caution about making sort of a very broad recommendation of getting sleep studies at a certain frequency. Very
Speaker A
much in favor of them but I think we need to be a little cautious because it's you know it's difficult to get. There is an alternative and that is doing capnography studies um which are now able to be done at home with something
Speaker A
called a transcutaneous carbon dioxide monitor or T-con. I mean, at least in our practice uh doing that at home and our adult colleagues um at the University of Pennsylvania are doing this routinely to both um uh monitor their patients and then uh
Speaker A
evaluate. Um in term uh to answer the question um a respiratory support device or ventilator um uh is helpful to um take it over uh take uh improve breathing at night when you go into deep sleep and your
Speaker A
muscles don't move quite as broadly. Um what it does effectively is through uh a nasal interface over the nose or into the nose uh it applies um positive pressure synchronized with breathing in and then drops to a lower pressure during
Speaker A
breathing out. Um and that can help improve minute ventilation or the volume of air that goes through the lungs in a in a minute.
Speaker A
Um and um decrease retained carbon dioxide, um which is how we diagnose um uh respiratory insufficiency. Then also help to prevent low oxygen, which if uh which which if is if it's persistent and significant can cause right heart
Speaker A
strain. So, um when I've started uh when I start non-invasive ventilation on patients irrespective of condition because of um high CO2 and low oxygen the night afterwards, I'm sorry, the morning afterwards they feel absolutely tremendous. And so, it's not just a
Speaker A
matter of supporting ventilation but it also improves sleep, it can improve daytime function uh um and just can make you feel a lot better.
Speaker A
Excellent. Okay. So, we're running low on time, but I want to get through two pretty critical questions. Um I'd like to discuss the frequency of cardiac symptoms that we expect to see in LAMA2. Um what are the recommendations for routine monitoring?
Speaker A
We don't unfortunately don't have a cardiologist today, but um Clara, do you want to mention briefly?
Speaker A
Yeah. So, well from what we've seen here in Brazil in our patients, it's really rare for the patient to have any cardiac symptom.
Speaker A
But um from the second decade on in life, they might have some rhythm problems. So, it's good to have um a halter at least see if the patient has some kind of blockage or something like that that needs specific treatment. But it's
Speaker A
usually not common. So, in that scenario, I think that um from the age 10 and older, it's good to have at least one exam and over every 2 years. And prior to that, we can do at least once.
Speaker A
And if the patient has a really severe pulmonary function, then I think because the heart can be affected, then we should also check the heart.
Speaker A
We're talking about echocardiogram, right? Yeah. Okay. Maybe can I just just quickly add on this? I I fully agree with this and but also just to add the off and children have to have surgeries earlier than uh than, you know, before their teenage
Speaker A
years. So, perhaps it's a very very very more important to look into cardiac aspect before surgery. And also, we perhaps don't know yet because these aspects were less investigated so far.
Speaker A
Perhaps uh um we just don't know yet the real incidence. And sometimes, as you said, symptoms may not be there. So, uh you know, perhaps we need to have a bit more un- research to a fully understand the prevalence of cardiac
Speaker A
involvement. So, if possible, routine cardiac investigation would be helpful. Perhaps in you know, all ages, but definitely more if you're a little bit older.
Speaker A
Okay. Um can we talk briefly about uh brain abnormalities that are we expect to see in limb two and the likelihood for seizures?
Speaker A
And I wanted to take that one to to start. Yeah, so I mean, brain abnormalities, we know that there has been described in quite a number of patients. The prevalence have been different in different studies, but it's definitely
Speaker A
something that is seen in many patients and then can be small change that only present on the brain MRI, but there might be also more obvious abnormalities. And in some patients, they might evolve in seizures. Again, numbers of frequencies of of, you know,
Speaker A
the involvement is relatively you know, it's variable between studies, but it's definitely something that is seen in quite a number of patients with LAMA2.
Speaker A
And and and treatment are possible, so it's important that these you know seizures are investigated and treated.
Speaker A
And this is something where you know there are medications available for children. So that is important aspect to monitor.
Speaker A
But brain MRI changes are seen almost in all the patients, but they might not equal to presence of seizures. So it's important to be aware of that that you know brain changes do not equal to onset of seizures.
Speaker A
Are we still expecting that there was a statistic that's been long-standing in the community that about 30% experience seizures? Do we feel like that's still probably right?
Speaker A
Yes, but again you know our cohort for example was a bit lower than that, so I guess it said probably it's it's somewhere around that number, but some studies had slightly lower or slightly higher, but yeah.
Speaker A
And we're seeing that sometimes they grow out of them, correct? I think yes, but also probably treatment intervention and so on. Yeah.
Speaker A
Okay. Does anybody else have anything on seizures? I think it's really important also to mention to the parents what seizures look like in in the LAMA2 patients because it's usually not the common seizures that people expected tonic-clonic seizures. So they might be
Speaker A
just an experience of nausea or the perception of different lights and and visions because of the area of the brain that's affected can be a little bit different. So it's important to make the parents and the patients be
Speaker A
aware what would they look like so they can mention to the physio they're experiencing something that's different.
Speaker A
Okay. Anybody else? All right. Well, I'm going to end it there. We're going to have some questions we didn't get to, but we were going to The plan is to create a document for the community for the questions that we
Speaker A
didn't get to and then we'll probably be reaching out to some of you for help with this. So thank you so much everybody for joining today. Really appreciate your time. We're grateful for your expertise and your collaboration and [clears throat] uh we look forward
Speaker A
to seeing you again soon. Take care, everybody. Thank you all. Thank you.
Topics:LAMA2congenital muscular dystrophyLAMA2 RD1LAMA2 RD2natural history studygene therapyneuromuscular disordersclinical trialsReady CMDbiomarkers
