We are honored to support groundbreaking discoveries related to LAMA2-Related Dystrophy (LAMA2-RD), thanks to our generous supporters and advocacy partners.
Dean Burkin, Biomarker Development Using Digital Spatial Profiling for LAMA2-RD. Funding: 2022-2024.
Studies originated in Dr. Burkin’s lab, have shown Laminin-111 can serve as an effective protein therapy for LAMA2-RD. This current study will provide new mechanistic insights into the role human recombinant Laminin-111 (rhLAM-111) plays in restoring muscle cell signaling and remodeling the extracellular matrix (ECM) in a mouse model. The ECM provides a 3D network of stability for cells while regulating cell development and regeneration.
As experimental therapeutics progress toward clinical trials, there is a clear need to develop robust and informative biomarkers that can be used to assess the efficacy of these potential treatments. Dr. Burkin’s team is using a cutting-edge technology tool, called Digital Spatial Profiling, to scan multiple regions of muscle tissue, such as the ECM, sarcolemma, and sarcoplasm, to identify new potential biomarkers. They are testing whether these biomarkers indicate changes in the mouse model and cultured cell models after applying rhLAM-111.
So far, the results indicate that treatment with rhLAM-111 after 7 days reinstates signaling pathways associated with muscle growth and suppress immune markers associated with muscle disease. They have also shown that LAMA2-deficient muscle exhibits defective glycosylation (sugar coating) of key membrane proteins that bind LAMA2 from the ECM. That sugar coating is fundamental for adhesion between these two muscle regions, The treatment with rhLAM-111 restores the glycosylation modifications to wild-type levels. The researchers hypothesize that the broader alterations in glycosylation modifications they found could serve as novel biomarkers in clinical trials for LAMA2-CMD and they will follow this direction in the experimental next steps.
Avnika Ruparelia, Integrin Signaling as a Novel Therapeutic Strategy to ameliorate LAMA2-CMD. Funding: 2023-2024.
Laminin-α2 (LAMA2) deficiency causes muscle fiber detachment and fiber loss, which drives the pathology of LAMA2-RD. Dr. Ruparelia’s team has recently reported findings of another important driver in LAMA2-RD pathology: impaired muscle stem cell dynamics. The team is exploring a muscle component that seems important for each of these drivers, to focus on designing a therapy that targets both to achieve better restoration of muscle function.
One possible approach is to manipulate integrin signaling. Integrins are cell membrane receptors that bind laminin in the ECM to provide a “Velcro-like” adhesion, transmitting signals between the ECM and the interior of the cell. The integrin signaling pathway is not only dysregulated following the loss of LAMA2, but is also a critical regulator of muscle cell adhesion and muscle stem cell activation.
In this context, this pilot project aims to characterize the expression of integrin receptors in the zebrafish model and perform a drug toxicity assay to identify suitable doses of various integrin targeting compounds that could be tested as a potential therapeutic strategy.
Francesco Muntoni, Modulation of a Transcription Factor Expression as a Novel Therapeutic Approach for LAMA2-RD. Funding: 2023-2024. Co funded with Olivia Bloomfield Foundation and LAMA2 France.
Research previously funded by Cure CMD studied two affected siblings, in which the older sibling has much more mild symptoms than the younger sibling. The team speculated that the presence of a different gene that modifies disease, being only expressed in the older sibling, is the cause of the milder phenotype. They compared DNA sequences for both siblings and found that, in the older sibling, a small portion of a gene involved in muscle regeneration, inflammation and fibrosis is deleted. Some genes controlled by this DNA region are also dysregulated in the muscle.
In the next stage of this research, the team obtained skin cells from the older sibling, as well as other affected individuals, in order to investigate differences attributable to the lacking DNA region of the older sibling. They aim to design molecules that are able to mask this DNA region to emulate the pattern of gene expression observed in the older sibling’s cells that could improve pathology. Data from this study could support the generation of new therapies for LAMA2-RD.
A. Reghan Foley, Biomarker Discovery Project Using Samples from Patients with COL6 and LAMA2 Related CMDs. Funding: 2023-2024. Co funded with LAMA2 France, ImpulsaT, Voor Sara, COL6 Fund, Noelia Foundation, and CMD Turkey.
This project is focused on identifying biomarkers for LAMA2 and COL6-RD using samples collected at the NIH from affected individuals. Biomarkers are biological “markers” that indicate a particular process of disease, important in measuring changes from a potential treatment in future clinical trials.
The INFANT Centre of the University College Cork, Ireland, has expertise in microRNA and proteomics biomarker research, and hosts a large cohort of biosamples from unaffected infants and children. Dr. Foley will use this biorepository as age and weight-matched controls and will work with these experts to discover biomarkers for LAMA2-RD. The first update is expected before the end of this year, so stay tuned!
Nicol Voermans, Natural history, outcome measures and trial readiness in LAMA2-related muscular dystrophy and Selenon-related myopathy in children and adults: The LAST STRONG study. Funding: 2023-2025. Co funded with Prinses Beatrix Spier Fonds and Stichting Voor Sara.
As we expand our understanding of LAMA2-RD and SELENON-RM and make progress in the discovery of potential treatments, natural history data and outcome measures important for clinical trials are lacking. In 2020, Dr. Voerman’s team launched the LAST STRONG Study, a 1.5-year project to collect natural history data from affected individuals (27 with LAMA2-RD and 11 with SELENON-RM), ages 3 to 50 years.
With support from our three organizations, the study has now been extended, aiming to analyze and publish all follow-up data, and select outcome measures that are sensitive, patient friendly, and sustainable. Baseline results have been published, including decreased bone quality leading to fragility fractures and impaired pulmonary function. The team will now assess the pathophysiology of decreased bone mineral density, correlation of neurocognitive functioning with brain MRI, quality of life, affected individuals’ expectations about clinical trials, biomarkers, and the collection of skin and muscle biopsies. Altogether, this work will contribute to implementation of improved clinical care and future clinical trials.
Learn more about LAMA2-RD on Cure CMD’s LAMA2 information page. You can also check out Cure CMD’s Research Funding Portfolio to learn about other projects we’ve funded, and our research strategy for the CMD’s.