The first International Summit dedicated exclusively to collagen VI deficiency-related pathologies in Europe took place from November 27th to 29th, 2023, organized by the Noelia Foundation in the city of San Sebastián. During this event, I had the pleasure of meeting Gustavo Dziewczapolski, doctor in Neuropharmacology and scientific director of Cure CMD, a non-profit organization based in the United States dedicated to finding solutions to counteract the symptoms of congenital muscular dystrophies. As described on the Noelia Foundation’s website, Dr. Dziewczapolski oversees Cure CMD’s annual grant program, aimed at researching treatments for all forms of congenital muscular dystrophies. Additionally, he organizes and participates in scientific conferences with the same purpose. He also acts as a bridge between the community of patients and families affected by these congenital muscle diseases, who have a voice in the development of treatments, and the medical-scientific community that researches, experiments, and designs therapies to improve the quality of life and care of affected individuals.
Would you like to tell us about your academic/professional background and how you came to be involved with muscular dystrophies and Cure CMD?
My name is Gustavo Dziewczapolski, I am Argentinean with Polish ancestry, hence my surname. My academic and professional trajectory has been developed in the field of biology and neuroscience. I began my biology studies at university and later obtained a Ph.D. in neuropharmacology in Argentina. Later on, I decided to move to San Diego, United States, to improve my career by completing two postdoctoral positions in neuroscience, one at UCSD and another at the Salk Institute. At the latter, I worked for several years as a research scientist. In 2016, while exploring new professional opportunities, I became interested in the field of foundations that offer grants for scientific research. I had been researching diseases like Parkinson’s and Alzheimer’s, and I noticed the difference between the large, wealthy foundations supporting research on common diseases and the associations dedicated to rare diseases. Out of pure curiosity, I looked for available positions and quickly came across the opportunity to become the scientific director of Cure CMD, in charge of the grant program. After an interview, we liked each other, and I started working with Cure CMD in September 2016. This change marked a significant transition in my career. After over 20 years of conducting research in laboratories with animal models such as mice and rats, I now find myself more involved in public relations activities and in coordinating efforts between scientists, clinicians, representatives from the pharmaceutical industry, and public agencies, such as the FDA and European authorities. This new aspect of my work involves constant reading and learning, as the field of neuromuscular diseases and therapeutic treatments is constantly evolving.
Part of my job involves attending specific congresses on muscular diseases, such as those related to collagen VI and other subtypes of congenital pathologies that Cure CMD groups together. I also participate in broader events, such as the World Muscle Society or the congress organized by the MDA (USA) or the AFM-Téléthon (France), which address a wider range of muscular diseases, including those that already have approved treatments and are in advanced stages of clinical research, such as Duchenne muscular dystrophy and spinal muscular atrophy. Staying abreast of developments in these areas allows me to seek innovative solutions for Cure CMD and contribute to the advancement of research of these diseases.
According to the experience you’ve had so far since 2016, what are the strategies you consider most effective for driving scientific research apart from meetings like the Summit organized by the Noelia Foundation? Validation of scientific publications by other experts is fundamental in the academic realm. However, in the private industry, research dissemination may be limited due to confidentiality agreements restricting the publication of information until trials are completed. This contrasts with the transparency of the academic sphere, where the constant publication of research contributes to the advancement of knowledge and facilitates obtaining funding for future projects.
At Cure CMD, we ensure that contracts with researchers are clear regarding the need to publish results as soon as possible. One advantage of organizations like ours is that we maintain close communication with researchers, who provide us with regular reports on the progress of their research. Personally, I hold biannual virtual meetings with them, and we are in constant contact to address any questions that arise.
I consider it crucial not only to know positive results but also negative ones, as this prevents the repetition of mistakes and can open up new lines of research. At Cure CMD, we encourage interaction among researchers and promote the discussion of results and hypotheses in our meetings, allowing us to explore new opportunities and questions in the field of muscular dystrophies. This approach has allowed us to make significant progress in our mission to seek effective treatments for these diseases.
Do you have any numbers on how many patients with collagen 6 deficiency are registered in the Congenital Muscle Disease International Registry (CMDIR)?
Currently, we have about 600 [COL6-affected] individuals from 44 countries worldwide.
How often does Cure CMD organize international meetings and where are they held? Are they open to everyone or do you need to be a registered member?
Every few years, Cure CMD organizes a scientific and family conference open to the public, known as the “Scientific and Family Conference.” This conference takes place somewhere in the United States, and we prefer it to be on the East Coast to facilitate the attendance of people from Europe. The number of families participating in these conferences has been increasing, and we are currently seeking funding to organize the conference next year in 2025.
In 2024, we faced difficulties in obtaining funds and organizing the conference.
In addition to these biennial conferences, we hold webinars open to everyone. It is not necessary to be an associate member or be registered in the CMDIR to participate in these meetings, although we encourage registration in the CMDIR, which is a fundamental database to be prepared when clinical trials occur. Last year, we organized an event called the “Research Round Table,” which consisted of six Zoom meetings for each subtype of CMD, using a university educational platform. Before each meeting, experts in each area provided explanations through short videos of less than 10 minutes about their work, and participants received information through scientific publications covering basic, translational, clinical research, and condition management. During the Zoom meetings, concepts were discussed and questions about the “pre-digested” material were answered. The program was very well received, so we hope to host another series when new research results have accumulated.
Most of our events can be found on the Cure CMD YouTube channel, where videos of conferences, annual meetings, and presentations are posted to be available for everyone. According to the information we read on the CMDIR website, in 2019 and then in 2021, there have been two clinical trials with Col6 patients: “MRI in Patients With Collagen VI Related Myopathies” in Denmark and “Congenital Muscular Dystrophy Ascending Multiple Dose Cohort Study Analyzing Pharmacokinetics at Three Dose Levels In Children and Adolescents With Assessment of Safety and Tolerability of Omigapil (CALLISTO)” in the United States.
If you could briefly tell us something about the results of these two clinical trials?
The CALLISTO trial was sponsored by Santhera Pharmaceuticals, with support from the NIH, Cure CMD, an FDA grant, the European Union’s EndoStem consortium, and the Swiss Foundation for Research on Muscle Diseases (FSRMM).
Cure CMD, with the CMDIR, also provided support in patient recruitment for this study, which was sponsored by Santhera Pharmaceuticals and involved the drug Omigapil, previously tested for amyotrophic lateral sclerosis and Parkinson’s disease but did not yield the expected results.
The mechanism of action of the drug was interesting as it reduced cell death in various types of cells, including muscle fibers. The idea was that this drug could help maintain muscle for a little longer while waiting for another therapy like gene therapy. It was believed from the beginning that it would not be the cure but at least could slow down the progression of the pathology. It was the first time a clinical trial was conducted in a congenital muscular dystrophy of COL6 and LAMA2 deficiency at a single NIH center with 20 patients, 10 of each genotype. Phase 1 of the clinical trial, which basically evaluates whether the drug is safe for affected people, excluding any potential toxicity or side effects, was thus performed. Various doses of the drug were tested and the highest dose causing any harm was found. At the same time, several physical and biochemical measurements were taken from drug treated patients.
The problem was essentially that the pharmaceutical company, following an internal pipeline review, decided to discontinue development of Omigapil. Cure CMD tried to intervene with the help of the NIH and move forward, but millions of dollars were needed with limited indication that the intervention would be beneficial to those living with CMD.
Nevertheless, the NIH group led by Drs. Carsten G. Bönnemann and A. Reghan Foley, the principal investigators of the clinical study, are working on a manuscript that will present the results of the CALLISTO trial. This publication will highlight the successful efforts of recruiting patients and completing Phase 1 of a clinical trial in CMD. Plus, it will share the lesson learned, that is the need for COL6 and LAMA2 patients to receive the proper level of care, and which clinical, morphological and functional evaluations and assessments will have to be explored when measuring the efficacy of a therapeutic intervention.This paper is under review in a scientific journal, and we hope it will lay the groundwork for future clinical trials in CMD.
As for the other experimentation in Denmark in 2019? I must clarify that in the CMDIR, we promote all clinical trials related to CMDs published by the U.S. Government’s clinical trials data repository regardless if we are involved or not. In the case of this study, there has been no information whether it actually took place or its possible outcomes . However, this study was non-interventional, and purely observational, using MRI (magnetic resonance imaging) to analyze the pattern of involvement of different muscle groups. Despite finding any information on the results of this study, I can affirm that several research groups are dealing neuromuscular diseases, including COL6-CMDs with MRIs with the great potential of using the observed dystrophic pattern as a biomarker, both for diagnosis and for monitoring the progression of dystrophy, as well as to measure the efficacy of a given therapeutic treatment.
Among the various advanced and precision therapies, gene therapy stands out as one of the first to have been conceived. How would you explain to partners what gene therapy is?
Gene therapy is a revolutionary strategy in medicine that aims to treat diseases by directly addressing their genetic cause. In the context of collagen 6 deficiency, for example, where mutations in the COL6A1, COL6A2, and COL6A3 genes have been identified as the underlying cause of the disease, gene therapy aims to reverse this process. The fundamental principle is to address the root of the problem, namely the genetic mutations responsible for the disease, using biological tools to correct the mutation, inhibit, or replace the defective genes with functional ones.
The basic idea behind gene therapy is to provide the body with a correct version of the defective gene or an accessory gene that can compensate for malfunction in the affected cells. This would be achieved by directly administering mutation-correcting tools or the therapeutic gene into the patient’s body, either through local injections into the affected organ or systemically through the bloodstream, or ex vivo, by genetically modifying cells extracted from the patient in the laboratory before reintroducing them into the body.
In summary, gene therapy represents a promising approach to treating genetic diseases by targeting the underlying cause of the disease and offering the possibility of correcting genetic defects to restore cellular health and function.
What are the fronts of scientific research on COL6 deficiency pathologies that Cure CMD is funding until 2024?
Here is the list of the 5 active ones at the moment:
Francesco Saverio Tedesco, Advanced models of human myofibrogenesis in 3D for modeling COL6 diseases and therapy development. Funding: 2022-2024. Co-funded with Muscular Dystrophy Canada;
Jeanette Erdmann and Franziska Haarich, Further steps toward an RNA-based therapy for COL6-RD. Funding: 2022-2024. Co-funded with Muscular Dystrophy Canada.
Vittoria Cenni, Targeting molecular pathways related to primary cilia to correct defects in tendon cells in congenital collagen VI muscular dystrophies. Funding: 2023-2025. Co-funded with AFM-Téléthon;
A. Reghan Foley, Biomarker Discovery Project Using Patient Samples with COL6 and LAMA2 Related Congenital Muscular Dystrophies. Funding: 2023-2024. Co-funded with COL6 Fund, Noelia Foundation, LAMA2 France, ImpulsaT, Voor Sara, and CMD Turkey.
Carsten Bönnemann and Veronique Bolduc, Directed evolution of adeno-associated virus (AAV) capsids for effective beneficial delivery to the muscle fibro-adipogenic progenitors (FAPs). Funding: 2021-2024. Co-funded with Noelia Foundation.
What types of gene therapy are being investigated in relation to collagen VI deficiency pathologies?
If you allow me, I would broaden it a bit and mention the quintessential gene therapies, known as gene transfer or addition, and variants of gene therapies, such as the use of other biological tools that can modify the gene or its expression to decrease the negative effects of the mutation in question.
Pseudo-Exon Skipping: This variant of gene therapy involves skipping the addition of an unwanted section of the gene to restore its function.
Antisense or RNA interference: In many cases of dominant mutations, where only one of the two copies of the gene is affected, this approach seeks to inhibit the expression of the defective gene, allowing the unaffected gene to restore functionality, at least partially.
Gene Replacement Therapy: Classic gene therapy approaches are used for recessive or loss-of-function mutations, i.e., replacing the defective gene with the healthy or functional gene.
Nonsense Mutation Masking (“Stop Codon Read-Through”): This molecular intervention uses compounds, drugs, or transfer RNA, which can mask the stop signal for protein synthesis after a truncation mutation, thus enabling the synthesis of functional Collagen 6 to be completed.
It is worth mentioning that efforts are also being made to improve tools for Col6 gene therapy. The best example is:
Optimization of Vectors that can deliver elements for gene therapy (functional gene, antisense, etc.) to the main Collagen 6-producing cells, which are fibroblastic cells (FAPs) in the interstitial tissue of the muscle.
What is the difference between Gene Editing and CRISPR-Cas9?
Actually, there isn’t one. The use of CRISPR-Cas9 has revolutionized the possibilities of gene editing. However, efforts are still being made to optimize its properties to make it more precise and safer.
Which gene therapy do you think could yield results more quickly?
It would be irresponsible to make predictions in this regard. It’s not possible to determine with certainty which treatment will be most effective, as it depends on the specific gene that is mutated and the methodology required to address that mutation. This is known as precision medicine. For example, patients with mutations in intron 11 will require a particular therapeutic approach (pseudo-exon skipping), while those with glycine mutations, which are the most common and dominant (affecting only one gene of the pair), may benefit from inhibition of the mutated gene, which is toxic and affects the effective production of collagen 6 by the normal gene.
In summary, there is no universally effective gene therapy, so it is crucial to conduct precise genetic diagnosis to identify the specific mutation of the affected individual and then see which of the different tools being investigated simultaneously could be most suitable for each case.
What is the treatment that is in the most advanced stage as of today?
To my understanding, the treatment that is in the most advanced stage is the modification of intron 11 of the COL6A1 gene. In laboratory studies, this modification has shown very promising results with significant correction. Likely, the correction of this mutation could be among the first to advance to the clinical trial phase. However, we know that collagen 6 is not produced by muscle cells but by fibroblasts (FAPs), which are interstitial cells located between muscle cells. Therefore, there is ongoing work to find a vector that can deliver the therapy to these specific cells, rather than targeting the muscles directly. Once this is achieved, there will be more chances to conduct the first clinical trials.
The Noelia Foundation and Cure CMD are funding part of this research at the NIH. Additionally, Saverio Tedesco’s group in London is studying a more selective vector for collagen 6-producing cells as part of the MAGIC project, which has received significant European funding. One of the objectives of this project is to develop a therapy targeted at muscle fibroblasts. Cure CMD is part of this project, participating in all discussions and learning from the progress made to then communicate these findings to the patient community.
Apart from gene therapy, what other studies are being investigated in relation to collagen VI deficiency pathologies?
Despite the limited number of researchers and available funds, we have excellent research groups, with admirable dedication, trying to investigate the various aspects of Col6 pathology to have more and greater possibilities of developing therapies for affected individuals. We can make a long list of research beyond gene therapies, for example:
Improving diagnostic methods, especially by trying to further understand the effects and consequences of each specific mutation.
Obtaining better biological models to study the different mechanisms altered by mutations (animal models in mice and fish, creation of muscles from patient cells, etc.).
Studies on the muscle regeneration capacity and properties of muscle stem cells (satellite cells).
Identification of molecules that interact with collagen VI in the extracellular matrix and on the surface of muscle cells.
Large-scale testing of drugs approved for other diseases or recognized as safe drugs to be administered in humans that may have a use in ColVI patients that was not previously suspected (drug repurposing).
Research on contractures: It has been identified that contractures are one of the progressive and debilitating symptoms that most affect the quality of life in the ColVI deficiency patient community. There is now fundamental research trying to understand not only the alterations of muscle fibers but also of tendons to have a better understanding of this unwanted symptom.
Discovery of biomarkers, both biochemical and imaging (MRI), to facilitate the monitoring of the pathology and to be able to detect changes when testing a therapy.
Palliative care on breathing, nutrition, etc., that improve the quality of life of affected individuals.
With which entities has Cure CMD established collaborations to finance research projects?
Cure CMD has established partnerships with several entities to finance various projects.
Among them are:
The National Institutes of Health (NIH) in the United States
The “Million Dollar Bike Ride,” an annual initiative conducted in collaboration with the Orphan Disease Center at the University of Pennsylvania. There, a group from the Collagen VI community formed the “Team Cure CMD” and raised funds for pilot projects in Col6. In the last edition, 2023, approximately $140,000 was raised. These funds were allocated to two projects: Dr. Haiyan Zhou’s, which focuses on improving the use of antisense to correct mutation effects, and Dr. Russell Butterfield’s, which focuses on the use of a gene editing tool for the treatment of specific Col6 gene mutations.
What are the pros and cons of personalized therapies?
The basic concept is highly positive. The specificity of a therapy should reduce the adverse effects of a more generalized therapy. However, the development of personalized treatments involves considerable cost, and there is currently no established business and regulatory model for this. That said, it is important to note that there are efforts by experts to generate sustainable models for precision medicine that will be more accessible to a greater number of cases, especially the rarest ones. This is a very active debate today.
Can you explain what adverse events have occurred in cases of gene therapy in Duchenne and Myotubular Myopathy (MTM)?
To date, some issues related to immunity against the virus used as a vector to deliver gene therapy have been identified, as well as some cases of immunity against the newly introduced gene. Additionally, it has been observed that the vector used may target organs other than the muscle, primarily the liver, where it can produce toxicity that must be urgently counteracted.
In particular, the four deaths in gene therapy for MTM studies show a liver pathology characteristic of many of these patients that was not previously known, and the vector exacerbated this liver involvement. To address these issues, vectors with greater affinity for muscle tissue and lower affinity for the liver are being developed, and protocols are also being developed to reduce immunological effects with pre- and post-treatment interventions. So, if there is an adverse event, can gene therapy be interrupted?
Gene therapy is administered through a single injection, and there is no way to interrupt it once administered. Therefore, it is fundamental to monitor each case to accumulate knowledge and increasingly anticipate any adverse effects.
It is important to note that the gene therapies being tested in Duchenne and MTM mostly involve pediatric patients, and overall, there is satisfaction with the results. Some patients have maintained functionality for longer periods after treatment, with a slower decline in their condition. Currently, methods are being investigated to perform gene therapies that allow for more than a single administration with the aim of prolonging the benefits for a longer period. It is a complicated task but worth pursuing.
As of today, is it not possible to perform more than one injection?
Currently, it is not possible to perform more than one injection because once the vector, which is a virus, is administered, the body develops immunity against it.
Would another injection with a different vector be needed?
Exactly. As of today, a second vector is not available. However, there is an active search for new viral and non-viral vectors (for example, nano particles), and research is also being conducted on how to “trick” the immune system with a second vector so that it does not recognize it as similar to the first one.
Is there a difference noted between adult and pediatric Duchenne patients (with a life expectancy of 30-40 years) who have received gene therapy?
At the moment, most Duchenne patients who have received gene therapy have been pediatric patients (under 18 years old). However, it is important to note that the more advanced the disease and the older the patient, the more likely there is to be more muscle damage, making it more difficult to reverse its progression. It is crucial to understand that gene therapy acts by halting the progression of the disease but cannot recover what has already been lost. For this reason, complementary therapies are being considered, as was the idea in the CALLISTO study.
The idea behind the CALLISTO trial was to administer a drug to prevent damaged muscle cells from dying. This means that once gene therapy is administered, there will be more muscle tissue available for correction and improvement. By preventing muscle cells from dying, even though they remain damaged, the effect of gene therapy is enhanced. It is essential to research therapies for concomitant side effects that can be supportive and not just target the primary cause of the disease.
Why do you think that in some countries gene therapy studies for neuromuscular diseases are still not funded? What is the added complexity regarding gene therapy for neuromuscular disorders?
Gene therapies require development and infrastructure that currently have high costs, and it is logical that less wealthy countries may not yet be able to develop their own studies. Eventually, and this is the work of patient groups like yours in each region, they will be able to access treatments designed in more advanced countries.
Regarding the added complexities, it is generally easier to intervene in diseases such as blood disorders (sickle cell anemia, beta-thalassemia), as gene therapy can be performed ex-vivo on blood cells extracted from the patient and then reintroduced with the genetic correction. It is also simpler to perform localized gene therapy, for example, in a localized tumor or in an ocular disease where gene therapy can be applied directly to the eye.
However, in the case of muscular diseases, the difficulty lies on the struggle to reach all muscles in the body. 40% of the body weight is constituted by skeletal muscle, and therefore, there is currently a limitation in how the therapeutic vector is distributed and in what quantity to the most affected muscles. Some people believe that localized injections could be made to improve even the most affected and most important muscles. Various options are being investigated.
Do you know how the latest gene therapy trial for patients with Duchenne Muscular Dystrophy is going to be?
In 2023, the United States Food and Drug Administration (FDA) authorized delandistrogene moxeparvovec, the first gene therapy for Duchenne Muscular Dystrophy (DMD) to reach the market. Elevidys (brand name) is a gene therapy administered as a single dose by intravenous infusion that uses an adeno-associated viral vector to deliver a “mini-dystrophin” gene to the muscle tissues of patients with DMD. The treatment is intended for pediatric patients aged 4 to 5 years old, ambulatory, with confirmed mutations in the dystrophin gene.
After the injection, the patient will be monitored for many years, if not for life. We don’t know for sure if the correction injected will be expressed throughout life or if it will decay over time. Laboratory results for the various gene therapy options are inconclusive in this regard. The sustenance of the expression of the therapeutic gene varies depending on the tool used. Generally, a decay is observed, which is why there is much research on how to perform a second and a third injection, avoiding immune reactions induced by the first administration.
What causes the decay?
Muscles naturally attempt to regenerate themselves. This regeneration mechanism is slower than the speed at which the muscle dies due to neuromuscular pathology. It means that at the time of the injection of the therapy, only the existing muscle will benefit, while those that are regenerating will not be reached by the therapy. It is crucial to study tools to prevent this gene therapy from diluting. Additionally, our own genes have a very precise regulatory system that controls their expression at different physiological times and stages of life. When an external gene is introduced, these regulations are not fully understood. In the laboratory, we know that there are situations when the administered gene is present, but inactive. How can we activate it? This process involves many cellular mechanisms that are still being investigated. It’s an interesting, albeit somewhat extravagant, idea to think of the day when a millionaire might spend a large amount of money to change the color of their eyes or improve their physical appearance through gene therapy. However, I believe it would be an exciting step, as we could harness the advances made in the field of neuromuscular diseases. In which area do you think it will be achieved first?
It’s not so extravagant when we consider, as we discussed before, that there are already ongoing gene therapies, including one for Duchenne (Elevidys) and one for spinal muscular atrophy (Zolgensma). Moreover, there are gene therapies approved for some types of cancers, blood disorders, and eye diseases. There are also other types of gene therapies already approved, such as antisense oligonucleotides. There is much to learn and improve upon. Undoubtedly, there will be many cycles of trial and errors that will improve the therapeutic potential and broaden the scope of this treatment modality. The path forward is not trivial but it is very hopeful. For me as a scientist, setting aside the anxiety of finding effective treatments tomorrow, it is fascinating and exciting to see the passion and intelligence of colleagues contributing to the increasingly accelerated progress in this field of gene therapies.
It’s been a pleasure to hear your explanations! Thank you very much Gustavo!
You are welcome to the Party of the Collagen VI Association Italy APS!