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Development of advanced molecular diagnostic methods for the accurate diagnosis of congenital muscular dystrophies and novel gene therapies for the treatment of collagen VI deficiency.


Project description

Part 1: Improved diagnosis of muscular dystrophies caused by mutations in collagen genes

 Over the last 10 years, Dr. Jiménez-Mallebrera’s team has achieved numerous improvements in the diagnosis of collagen VI congenital muscular dystrophy using a series of quantitative and increasingly precise techniques to study the expression of this protein in fibroblasts and biological samples. In addition, they have developed and published artificial intelligence learning algorithms, specifically aimed at the study of this pathology, which are key in the process of diagnosis and research of the disease. Also, over the last year, by using X-ray tomography, they have studied the changes that occur inside the cell as a consequence of the alteration of collagen VI.

All these methods provide an unparalleled level of detail in the interpretation of the effects of collagen VI mutations on cells and tissues. Thanks to the experience gained over the years, they are now in an optimal position to offer the most accurate diagnosis, to date, for this group of pathologies.

These advances are key in the diagnostic process, both in children and adults, as they allow for the interpretation of the effect of genetic variants of uncertain significance (there is no information on whether they are pathological or not) or of mutations with variable expression in different members of the same family, which, until now, were very difficult to characterize.

Throughout the last 8 years, they have conducted more than 250 studies on cells obtained from over one hundred patients with suspected collagen VI deficiency, from both Spain and other countries.

In addition to mutations in the collagen VI genes, there are also alterations related to mutations in one of the collagen XII genes (COL12A1), another extracellular matrix protein associated with collagen VI. In recent years, the laboratory has received regular requests from healthcare institutions to perform these diagnostic studies, evidencing an unmet need in this area. As a matter of fact, it may well be that the frequency of these Col12 alterations is grossly underestimated due to the lack of biochemical and cellular diagnostic tools for these types of mutations.

Capitalizing the experience acquired in the analysis of collagen VI, and the work conducted by the team to fine-tune the techniques to study collagen 12 in fibroblast cultures, the project aims at expanding the diagnostic capacity of these techniques to offer an accurate diagnosis also to collagen XII patients.


Part 2: Development of novel molecular therapies for DMC-Col6

 In previous projects, Dr. Jimenez-Mallebrera’s research team showed that CRISPR/Cas9-based gene therapy tools are highly specific and effective in correcting point mutations, reducing the expression levels of mutated alleles, and restoring in vitro collagen matrix structure in fibroblasts from DMC-Col6 patients. However, despite their ability to block the expression of the mutated allele, these techniques are very ineffective in replacing mutations with the correct sequence through the process of homologous recombination (HDR), in cases where it is necessary to restore the original sequence.

The project addresses this and other limitations that must be overcome before CRISPR/Cas9 technology can be effectively applied in vivo. The overall goal is to learn more about CRISPR/Cas9 and antisense oligonucleotide-based therapies in order to pave the way towards safe and effective therapies for the treatment of CMD-Col6 and other similar pathologies.

Thus, the key objectives of the project are:

  • Carry on providing biochemical and cellular diagnosis to patients with suspected collagen VI deficiency, improve the technique through the use of advanced microscopy and artificial intelligence systems, and extend the scope of the diagnosis to include mutations of collagen 12 genes.
  • Develop therapies to correct pathogenic mutations in collagen VI genes, in particular:
    1. Investigate various gene editing approaches based on CRISPR/Cas9, including the most recent techniques (base editors and prime editing) as well as synthetic ancestral variants of the Cas protein, to correct different types of mutations in collagen VI genes.
    2. Investigate delivery systems for these gene therapies, both in vitro and in vivo. This includes, on the one hand, using the SMARTY platform, developed and patented by the Institute of Material Sciences of Barcelona (ICMAB), that consists in the use of fibroblast-targeted nanoparticles to deliver the genetic therapeutic tools to the cells. On the other hand, in collaboration with Dr. Ana Buj-Bello (Gènèthon, France), different types of adeno-associated viruses (AAV) will be studied as vectors to specifically deliver the therapies to the muscle tissue.
    3. In collaboration with Hospital Clínic de Barcelona, investigate the pre-existing immunity against Cas9 proteins in the Spanish children population, in order to assess the potential immune response that patients may display in response to the administration of these therapies.


Place of development:
HSJD Hospital San Juan de Dios de Barcelona

Research Group:
Dra. Jimenez Mallebrera, Cecilia: Coordinadora Grupo de Investigación.
Dr.  López Márquez, Arístides
Dra. Badosa, Carmen

Duration of the project and period of support by Fundación Noelia:
2 years (March 2023 – June 2025)

136,180 EUROS

Contributions made by Fundación Noelia:
March 2023: 29.995€ (Proof of payment)
June 2023: 38.095€ (Proof of payment)

Contributions pending to be made by Fundación Noelia:
March 2024: 29.995€
June 2024: 38.095€

Collaboration agreement [ESP]: Read 

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