Periodic Reporting for period 1 - DREAM (Dux4-Regulated Expression and Activity by an inhibitor Molecule)
Período documentado: 2021-03-01 hasta 2023-02-28
Facioscapulohumeral muscular dystrophy (FSHD) represents one of the most prevalent neuromuscular disorder afflicting 1/8000 individuals. Weakness is slowly progressive with high variability among patients. Unfortunately, despite life expectance is not modified, affected individuals eventually requires a wheelchair. FSHD is caused by aberrant re-activation of the transcription factor DUX4, which is physiological restricted in the early stage of embryo development. In FSHD, DUX4 mis-expression initiates a cascade of processes triggering the activation of a pro-apoptotic transcriptional program leading to muscle wasting. DUX4 has been recently implicated also in the pathogenesis of solid tumors, leukemia and herpes viral infection. As today, no cure or therapeutic option are available to FSHD patients. Given its pivotal role in FSHD, blocking DUX4 activity is a plausible therapeutic option for FSHD and other diseases associated with aberrant DUX4 expression or activity.
Compelling data obtained in our laboratory identified a novel regulator of DUX4 that allows us to examine the potential of inhibiting the cytotoxic activity of DUX4 as a therapeutic strategy to treat FSHD, and represented the innovation of this proposal. The goal of the proposal was to fully elucidate the molecular mechanisms that regulate DUX4 in order to develop novel therapeutic approaches for blocking the aberrant activity of DUX4 in FSHD.
Based on our preliminary data, I hypothesized that by inhibiting DUX4 we can prevent transcriptional activation of genes toxic to muscle cells.
As a corollary, we proposed that a drug-like molecule interfering with the DUX4 pathway could be used to prevent the toxic effects of DUX4 expression in muscle cells from FSHD patients and animal model of FSHD.
With this project we demonstrated that MATR3 binds directly to DUX4 and blocks its activity. We also mapped the regions involved in the interaction and developed a gene therapy approach based on MATR3. Our results promote MATR3 as the first endogenous inhibitor of DUX4 for the treatment of FSHD that in perspective might be applied to a spectrum of related and currently incurable DUX4-associated diseases.
Compelling data obtained in our laboratory identified a novel regulator of DUX4 that allows us to examine the potential of inhibiting the cytotoxic activity of DUX4 as a therapeutic strategy to treat FSHD, and represented the innovation of this proposal. The goal of the proposal was to fully elucidate the molecular mechanisms that regulate DUX4 in order to develop novel therapeutic approaches for blocking the aberrant activity of DUX4 in FSHD.
Based on our preliminary data, I hypothesized that by inhibiting DUX4 we can prevent transcriptional activation of genes toxic to muscle cells.
As a corollary, we proposed that a drug-like molecule interfering with the DUX4 pathway could be used to prevent the toxic effects of DUX4 expression in muscle cells from FSHD patients and animal model of FSHD.
With this project we demonstrated that MATR3 binds directly to DUX4 and blocks its activity. We also mapped the regions involved in the interaction and developed a gene therapy approach based on MATR3. Our results promote MATR3 as the first endogenous inhibitor of DUX4 for the treatment of FSHD that in perspective might be applied to a spectrum of related and currently incurable DUX4-associated diseases.
By using primary muscle cells derived from FSHD patients and a mouse model of FSHD as cellular and animal model of the disease, I was able to successfully complete all the objectives proposed for the DREAM project. Specifically, based on preliminary results obtained in Dr. Gabellini’s laboratory, I elucidated the molecular mechanism through which MATR3 regulates DUX4 function and developed an innovative therapeutic approach for blocking DUX4 cytotoxic activity in FSHD. Through two main objectives, I first validated a MATR3-based approach in terms of safety and efficacy in cellular models of FSHD. This also allowed to identify a MATR3-derived peptide able to block DUX4 activity at the same extent of the whole protein. Subsequently, I validated these findings in cellular and animal models of FSHD. We found that MATR3 binds directly to DUX4 DNA-binding domain and blocks DUX4-mediated gene expression. As a result, MATR3 administration rescues cell viability and myogenic differentiation of FSHD muscle cells, while it does not affect healthy muscle cells. Notably, we also characterized a shorter MATR3 fragment that is necessary and sufficient to directly block DUX4-induced toxicity to the same extent of the full-length protein. Moreover, genome-wide experiments confirmed the proficiency of the identified fragment to decrease DUX4 bona fide target genes.
The importance and the social impact of FSHD have been divulgated during informal events especially to young and future scientists. Moreover, the results obtained in the DREAM project have been presented several times to a scientific audience during meetings organized by the host institution and international conferences receiving good feedback and thus becoming an attractive approach for the cure of FSHD.
The importance and the social impact of FSHD have been divulgated during informal events especially to young and future scientists. Moreover, the results obtained in the DREAM project have been presented several times to a scientific audience during meetings organized by the host institution and international conferences receiving good feedback and thus becoming an attractive approach for the cure of FSHD.
FSHD is a slowly progressive illness that has a significant socio-economic impact. Despite lifespan of FSHD patients is not modified, significant life style changes occurs in patients that eventually might require the use of wheelchair or respiratory devices. Financial burden represent one of the most important aspect related to the FSHD especially for the medical management of the pathology that is mainly supportive including, physical therapy, pain reduction treatment, monitoring of respiratory function and evaluation of the disease progression.
Unfortunately, no cure or treatment are approved yet for FSHD. For this reason, due to the pivotal role of DUX4 for the disease, blocking its activity is an attractive solution. With the DREAM project, I found the first endogenous inhibitor of DUX4. We are currently working to develop our findings on a drug-like molecule inhibiting DUX4 activity opening a possible therapeutic path to the treatment of FSHD. Treating FSHD not only will improve the quality of life of the patients but will have a strong socio-economic impact by dramatically reducing costs related to the management of the pathology and healthcare.
Unfortunately, no cure or treatment are approved yet for FSHD. For this reason, due to the pivotal role of DUX4 for the disease, blocking its activity is an attractive solution. With the DREAM project, I found the first endogenous inhibitor of DUX4. We are currently working to develop our findings on a drug-like molecule inhibiting DUX4 activity opening a possible therapeutic path to the treatment of FSHD. Treating FSHD not only will improve the quality of life of the patients but will have a strong socio-economic impact by dramatically reducing costs related to the management of the pathology and healthcare.