Understanding and Ameliorating perturbed signalling and pathogenesis in FSHD
Lead Research Organisation:
King's College London
Department Name: Randall Div of Cell and Molecular Biophy
Abstract
Diseases can be treated more effectively if the causes/mechanisms underlying the symptoms are known. For muscular dystrophy, the causative defect is changes in genes or DNA that in turn, produce changes to proteins. However, it is generally poorly understood how such defects result in the progressive skeletal muscle weakness and wasting typical of muscular dystrophies.
Every cell in the body contains the same DNA, which is divided into genes, each of which carries the instructions to make a protein(s): the molecules that build, maintain and operate the body. The selection of genes that are expressed (active) in a particular cell type, such as in a muscle fibre, dictate which proteins are made. This gives the cell its special characteristics and functions. For example, muscle genes are not expressed in skin cells, and skin genes are not expressed in muscle cells.
Facioscapulohumeral muscular dystrophy (FSHD) is caused by a change in a particular region of DNA that leads to production of a protein called DUX4, that is not normally present in muscle. DUX4 is a 'transcription factor' meaning that it can control the expression of other genes by binding to their regulatory regions, and so can alter the type of proteins that are made by a cell. Thus the carefully coordinated pattern of gene expression and protein production that enables skeletal muscle to function effectively, is perturbed by the presence of DUX4. This ultimately leads to muscle weakness and wasting.
We have examined gene expression changes during human muscle formation in FSHD cells and used mathematical tools to understand which signalling process are perturbed. We found that pathways that control generation of mitochondria and processes associated with mitochondrial function such as dealing with by-products of metabolism/respiration called reactive oxygen species (oxidative stress) are suppressed. It is well known that FSHD cells are more sensitive to oxidative stress, and a recent clinical trial (clinicaltrials.gov number: NCT01596803) reported that administration of anti-oxidants, improved aspects of muscle function in FSHD patients.
We have found that inhibiting pathways that control generation of mitochondria in healthy human muscle cells makes them appear like FSHD muscle fibres. Conversely augmenting the action of these pathways controlling generation of mitochondria in FSHD muscle cells makes them more like healthy human muscle cells.
This project will investigate how regulation of this pathway controlling generation of mitochondria is perturbed in FSHD and test potential therapeutic strategies to improve its function.
Thus in summary, we will generate tools and models of FSHD that will both further reveal disease mechanisms and also provide a platform for testing potential therapies for FSHD, to underpin possible clinical trials. Better understanding the disease mechanism in FSHD may also highlight other potential therapeutic interventions.
Every cell in the body contains the same DNA, which is divided into genes, each of which carries the instructions to make a protein(s): the molecules that build, maintain and operate the body. The selection of genes that are expressed (active) in a particular cell type, such as in a muscle fibre, dictate which proteins are made. This gives the cell its special characteristics and functions. For example, muscle genes are not expressed in skin cells, and skin genes are not expressed in muscle cells.
Facioscapulohumeral muscular dystrophy (FSHD) is caused by a change in a particular region of DNA that leads to production of a protein called DUX4, that is not normally present in muscle. DUX4 is a 'transcription factor' meaning that it can control the expression of other genes by binding to their regulatory regions, and so can alter the type of proteins that are made by a cell. Thus the carefully coordinated pattern of gene expression and protein production that enables skeletal muscle to function effectively, is perturbed by the presence of DUX4. This ultimately leads to muscle weakness and wasting.
We have examined gene expression changes during human muscle formation in FSHD cells and used mathematical tools to understand which signalling process are perturbed. We found that pathways that control generation of mitochondria and processes associated with mitochondrial function such as dealing with by-products of metabolism/respiration called reactive oxygen species (oxidative stress) are suppressed. It is well known that FSHD cells are more sensitive to oxidative stress, and a recent clinical trial (clinicaltrials.gov number: NCT01596803) reported that administration of anti-oxidants, improved aspects of muscle function in FSHD patients.
We have found that inhibiting pathways that control generation of mitochondria in healthy human muscle cells makes them appear like FSHD muscle fibres. Conversely augmenting the action of these pathways controlling generation of mitochondria in FSHD muscle cells makes them more like healthy human muscle cells.
This project will investigate how regulation of this pathway controlling generation of mitochondria is perturbed in FSHD and test potential therapeutic strategies to improve its function.
Thus in summary, we will generate tools and models of FSHD that will both further reveal disease mechanisms and also provide a platform for testing potential therapies for FSHD, to underpin possible clinical trials. Better understanding the disease mechanism in FSHD may also highlight other potential therapeutic interventions.
Technical Summary
Facioscapulohumeral muscular dystrophy (FSHD) is the third commonest inherited myopathy, characterised by a descending, often asymmetric, dystrophy with initial involvement of facial and proximal upper limb musculature, and later progression to certain lower limb muscles.
We have examined gene expression changes during muscle formation in human FSHD cells and used mathematical tools to understand which signalling process are perturbed. We found that pathways that control generation of mitochondria and processes associated with mitochondrial function such as dealing with reactive oxygen species are suppressed. It is well known that FSHD cells are more sensitive to oxidative stress, and a recent clinical trial (clinicaltrials.gov number: NCT01596803) reported that administration of anti-oxidants improved aspects of muscle function in FSHD patients.
We have found that inhibiting pathways that control generation of mitochondria in healthy human muscle cells generates myofibres with an atrophic phenotype: characteristic of FSHD muscle fibres. Conversely augmenting the action of these pathways controlling generation of mitochondria in FSHD muscle cells makes them generate myofibres that are larger and indistinguishable from healthy human muscle.
This project will investigate how regulation of this pathway controlling generation of mitochondria is perturbed in FSHD and test potential therapeutic strategies to improve its function.
Main objectives
1. Determine if drugs that increase mitochondrial biogenesis improve the FSHD phenotype in vivo.
2. Validate the mechanism of perturbed mitochondrial biogenesis in FSHD myoblasts.
3. Decipher the action of drugs that improve mitochondrial biogenesis in ameliorating FSHD.
4. Understand the regulation of mitochondrial biogenesis pathways in FSHD.
5: Determine if mitochondrial biogenesis improves DUX4 induced myopathy in vivo.
We have examined gene expression changes during muscle formation in human FSHD cells and used mathematical tools to understand which signalling process are perturbed. We found that pathways that control generation of mitochondria and processes associated with mitochondrial function such as dealing with reactive oxygen species are suppressed. It is well known that FSHD cells are more sensitive to oxidative stress, and a recent clinical trial (clinicaltrials.gov number: NCT01596803) reported that administration of anti-oxidants improved aspects of muscle function in FSHD patients.
We have found that inhibiting pathways that control generation of mitochondria in healthy human muscle cells generates myofibres with an atrophic phenotype: characteristic of FSHD muscle fibres. Conversely augmenting the action of these pathways controlling generation of mitochondria in FSHD muscle cells makes them generate myofibres that are larger and indistinguishable from healthy human muscle.
This project will investigate how regulation of this pathway controlling generation of mitochondria is perturbed in FSHD and test potential therapeutic strategies to improve its function.
Main objectives
1. Determine if drugs that increase mitochondrial biogenesis improve the FSHD phenotype in vivo.
2. Validate the mechanism of perturbed mitochondrial biogenesis in FSHD myoblasts.
3. Decipher the action of drugs that improve mitochondrial biogenesis in ameliorating FSHD.
4. Understand the regulation of mitochondrial biogenesis pathways in FSHD.
5: Determine if mitochondrial biogenesis improves DUX4 induced myopathy in vivo.
Planned Impact
This research is directed at understanding pathology of the FSHD, which will inform development/optimisation of treatments. FSHD is autosomal dominant with poorly understood pathophysiology and there is no cure. FSHD presents as an asymmetric, progressive descending skeletal muscle weakness and wasting affecting many muscles that severely affects quality of life: around 30% use a wheelchair. For example, patients can undergo surgery to fix the scapular to the ribcage to stabilize the shoulder, which significantly incapacitates patients for months. FSHD is also associated with sensorineural hearing loss, which can progress to deafness, and a retinal vascular abnormality, which can compromise vision. Lifespan is not attenuated, but means that economic burden lasts many years.
FSHD is the third most common inherited myopathy (prevalence ~1/20,000 http://www.orpha.net). Recent figures indicate that 52 people/year are newly diagnosed with FSHD in the Netherlands, a prevalence of 12/100,000 (1/8333).
Financial Costs: An estimated 70,000 people in the UK in 2010 had a neuromuscular condition, (http://www.muscular-dystrophy.org/assets/0002/0463/Cost_of_Living_with_Muscle_Disease.pdf), creating a considerable financial burden. The Access Economics research published in 2007 put costs of muscular dystrophy for the 3500 Australian patients in 2005 at £258 million a year (http://www.mda.org.au/media/accesslaunch/Gullotta.asp). More recently, calculated annual per-patient costs for neuromuscular disease in the US are $63,693 for ALS, $50,952 for DMD, and $32,236 for DM. Population-wide national costs were $1,023 million (ALS), $787 million (DMD) and $448 million (DM) (Larkindale et al. Muscle Nerve (2014) 49: 431-8). For FSHD, cost per patient year in Germany is 26,240 Euros (Schepelmann et al. J. Neurol. (2010) 257: 15). In addition, > 50% of adult members of the FSHD registry reported that symptoms adversely affected their employment by forced disability, early retirement, or job loss, or that their job had been modified to accommodate physical limitations (http://www.ncbi.nlm.nih.gov/pubmed/22155025).
Quality of Life: 29.6% of FSHD registry members report use of wheelchairs for short or long distances, with 8.3% reporting as "always" using wheelchairs for both. 11.3% of FSHD registry members report use of leg braces at enrolment. The EQ-VAS quality of life score is 0.75 +/- 0.21 (0.81) for FSHD and such a low score associated with increased risk of depression (Winter et al. J. Neurol. (2010) 257(9):1473-81). FSHD registry paper: Moreover, psychological problems occurred in 28.1% of FSHD registry members, with more than one-third reporting having received psychological counselling (Hilbert et al. Contemp. Clin. Trials (2012) 33:302-11).
Direct beneficiaries with immediate impact from the work will include academics, clinicians, and the pharmaceutical industry. Researchers/clinicians will benefit as better understanding pathomechanisms will inform treatment and development of therapies, particularly relevant to progressing from the recent clinical trial involving antioxidants for FSHD that showed improvement in certain parameters (clinicaltrials.gov number: NCT01596803). Pharmaceutical companies and translational researchers will benefit as this will inform planning pre-clinical/clinical trials.
Longer term, patients and carers will benefit from relief of disease burden from better understanding disease pathology and improved therapy. Thus society and the economy benefits from improved treatments, due to reduction in NHS and care costs and both reduced loss of earnings and benefit payments for patients and carers. Biochanin A is available in food supplements and clinically tested, so could be rapidly adopted for FSHD, also encompassing MRC Priorities for Nutrition Research
https://www.mrc.ac.uk/funding/science-areas/population-systems-medicine/mrc-priorities-for-nutrition-research/
FSHD is the third most common inherited myopathy (prevalence ~1/20,000 http://www.orpha.net). Recent figures indicate that 52 people/year are newly diagnosed with FSHD in the Netherlands, a prevalence of 12/100,000 (1/8333).
Financial Costs: An estimated 70,000 people in the UK in 2010 had a neuromuscular condition, (http://www.muscular-dystrophy.org/assets/0002/0463/Cost_of_Living_with_Muscle_Disease.pdf), creating a considerable financial burden. The Access Economics research published in 2007 put costs of muscular dystrophy for the 3500 Australian patients in 2005 at £258 million a year (http://www.mda.org.au/media/accesslaunch/Gullotta.asp). More recently, calculated annual per-patient costs for neuromuscular disease in the US are $63,693 for ALS, $50,952 for DMD, and $32,236 for DM. Population-wide national costs were $1,023 million (ALS), $787 million (DMD) and $448 million (DM) (Larkindale et al. Muscle Nerve (2014) 49: 431-8). For FSHD, cost per patient year in Germany is 26,240 Euros (Schepelmann et al. J. Neurol. (2010) 257: 15). In addition, > 50% of adult members of the FSHD registry reported that symptoms adversely affected their employment by forced disability, early retirement, or job loss, or that their job had been modified to accommodate physical limitations (http://www.ncbi.nlm.nih.gov/pubmed/22155025).
Quality of Life: 29.6% of FSHD registry members report use of wheelchairs for short or long distances, with 8.3% reporting as "always" using wheelchairs for both. 11.3% of FSHD registry members report use of leg braces at enrolment. The EQ-VAS quality of life score is 0.75 +/- 0.21 (0.81) for FSHD and such a low score associated with increased risk of depression (Winter et al. J. Neurol. (2010) 257(9):1473-81). FSHD registry paper: Moreover, psychological problems occurred in 28.1% of FSHD registry members, with more than one-third reporting having received psychological counselling (Hilbert et al. Contemp. Clin. Trials (2012) 33:302-11).
Direct beneficiaries with immediate impact from the work will include academics, clinicians, and the pharmaceutical industry. Researchers/clinicians will benefit as better understanding pathomechanisms will inform treatment and development of therapies, particularly relevant to progressing from the recent clinical trial involving antioxidants for FSHD that showed improvement in certain parameters (clinicaltrials.gov number: NCT01596803). Pharmaceutical companies and translational researchers will benefit as this will inform planning pre-clinical/clinical trials.
Longer term, patients and carers will benefit from relief of disease burden from better understanding disease pathology and improved therapy. Thus society and the economy benefits from improved treatments, due to reduction in NHS and care costs and both reduced loss of earnings and benefit payments for patients and carers. Biochanin A is available in food supplements and clinically tested, so could be rapidly adopted for FSHD, also encompassing MRC Priorities for Nutrition Research
https://www.mrc.ac.uk/funding/science-areas/population-systems-medicine/mrc-priorities-for-nutrition-research/
Organisations
- King's College London (Lead Research Organisation)
- University of Mons (Collaboration)
- Newcastle University (Collaboration)
- Ludwig Boltzmann Society (Collaboration)
- KING'S COLLEGE LONDON (Collaboration)
- University of Rochester (Collaboration)
- Radboud University Nijmegen Medical Center (Collaboration)
- Toyohashi Sozo College (Collaboration)
- University of British Columbia (Collaboration)
- University of Montpellier (Collaboration)
- UNIVERSITY OF READING (Collaboration)
- University of Georgia (Collaboration)
- University of Applied Sciences Technikum Wien (Collaboration)
People |
ORCID iD |
| Peter Zammit (Principal Investigator) |
Publications
Banerji CRS
(2023)
The FSHD muscle-blood biomarker: a circulating transcriptomic biomarker for clinical severity in facioscapulohumeral muscular dystrophy.
in Brain communications
Banerji CRS
(2019)
PAX7 target gene repression is a superior FSHD biomarker than DUX4 target gene activation, associating with pathological severity and identifying FSHD at the single-cell level.
in Human molecular genetics
Banerji CRS
(2020)
Skeletal muscle regeneration in facioscapulohumeral muscular dystrophy is correlated with pathological severity.
in Human molecular genetics
Banerji CRS
(2019)
Dynamic transcriptomic analysis reveals suppression of PGC1a/ERRa drives perturbed myogenesis in facioscapulohumeral muscular dystrophy.
in Human molecular genetics
Banerji CRS
(2020)
DUX4 expressing immortalized FSHD lymphoblastoid cells express genes elevated in FSHD muscle biopsies, correlating with the early stages of inflammation.
in Human molecular genetics
Banerji CRS
(2020)
Facioscapulohumeral muscular dystrophy 1 patients participating in the UK FSHD registry can be subdivided into 4 patterns of self-reported symptoms.
in Neuromuscular disorders : NMD
Banerji CRS
(2021)
Pathomechanisms and biomarkers in facioscapulohumeral muscular dystrophy: roles of DUX4 and PAX7.
in EMBO molecular medicine
Cowley MV
(2023)
An in silico FSHD muscle fiber for modeling DUX4 dynamics and predicting the impact of therapy.
in eLife
Cowley, M. V.
(2023)
An in silico FSHD muscle fibre for modelling DUX4 dynamics and predicting the impact of therapy
in eLife
| Title | Figure from a paper that has been adapted for Wikipedia |
| Description | Our novel illustration of muscles affected by FSHD that was published in 10.15252/emmm.202013695 has been modified and now appears on the Wikipedia page about FSHD. |
| Type Of Art | Image |
| Year Produced | 2023 |
| Impact | Our novel illustration of muscles affected by FSHD that was published in our recent review 10.15252/emmm.202013695 has been modified and now appears on the Wikipedia page about FSHD so is widely disseminated and cites the source paper and so also highlights our work in general including that performed under this funding. |
| URL | https://en.wikipedia.org/wiki/Facioscapulohumeral_muscular_dystrophy |
| Description | A member of the Core team of FSHD UK |
| Geographic Reach | National |
| Policy Influence Type | Participation in a guidance/advisory committee |
| Impact | The FSHD UK charity promotes clinical trial readiness and act as a portal for anyone with an interest in FSHD and has had a role in coordinating various stakeholders to facilitate clinical trials for FSHD in the UK. It is also working to assess the personal and socioeconomic costs of this disorder. |
| URL | https://www.facebook.com/FSHDUK/ |
| Description | Figures and illustrations about FSHD that were published in our recent review (doi: 10.15252/emmm.202013695) and doi: 10.1093/hmg/ddaa164 now appear on the FSHD Wikipedia page. |
| Geographic Reach | Multiple continents/international |
| Policy Influence Type | Implementation circular/rapid advice/letter to e.g. Ministry of Health |
| Impact | Contributing to wider understanding of muscular dystrophy via a widely and freely accessed Wikipedia page available in multiple languages will educate and inform policy, practice, patients and the public. |
| URL | https://en.wikipedia.org/wiki/Facioscapulohumeral_muscular_dystrophy |
| Description | Muscular Dystrophy Association Muscle Regeneration Summit |
| Geographic Reach | Multiple continents/international |
| Policy Influence Type | Participation in a guidance/advisory committee |
| Impact | A bespoke grant round to increase research internationally into muscle regeneration and regenerative therapies for muscular dystrophies has been conducted by the MDA, distributing grant funding internationally leading to employment of more scientists/clinicians. |
| URL | https://www.mda.org/sites/default/files/2024/12/Muscle-Regeneration-Summit-full-summary-.pdf |
| Description | Scientific Advisory Board membership of SOLVE FSHD |
| Geographic Reach | Multiple continents/international |
| Policy Influence Type | Participation in a guidance/advisory committee |
| Impact | Funding from SOLVE FSHD has facilitated further training of researchers. Recommend and actual support of biotech companies has provided economic benefits such as continued employment and buying of reagents etc. |
| URL | https://solvefshd.com/team/#scientific-advisory-board |
| Description | Scientific Advisory Board of SOLVE FSHD |
| Geographic Reach | Multiple continents/international |
| Policy Influence Type | Participation in a guidance/advisory committee |
| Impact | Being on the Scientific Advisory Board of SOLVE FSHD influences the program supported to develop therapies for this disorder, accelerating improvements in quality of life or morbidity or survival . |
| URL | https://solvefshd.com/team/#scientific-advisory-board |
| Description | Shark Tank for FSHD |
| Geographic Reach | Multiple continents/international |
| Policy Influence Type | Participation in a guidance/advisory committee |
| Impact | Certain companies have been selected for financial support from a Canadian organisation to develop and test potential therapies for FSHD. |
| Description | TREAT-NMD Advisory Committee for Therapeutics (TACT) |
| Geographic Reach | Multiple continents/international |
| Policy Influence Type | Participation in a guidance/advisory committee |
| Impact | TREAT-NMD Advisory Committee for Therapeutics (TACT) is a unique multi-disciplinary international group of internationally recognized academic and industry drug development experts as well as representatives of patient foundations and regulatory experts, who meet twice a year to review and provide guidance on the translation and development path of therapeutics programs in rare neuromuscular diseases with large unmet need including muscular dystrophies like FSHD. Was involved in an evaluation of a clinical trail for a potential new therapeutic for FSHD and provided feedback on how to improve the design. |
| URL | https://www.treat-nmd.org/what-we-do/tact/ |
| Description | TREAT-NMD Advisory Committee for Therapeutics (TACT) |
| Geographic Reach | Europe |
| Policy Influence Type | Participation in a guidance/advisory committee |
| Impact | TREAT-NMD Advisory Committee for Therapeutics (TACT) is a unique multi-disciplinary international group of internationally recognized academic and industry drug development experts as well as representatives of patient foundations and regulatory experts, who meet twice a year to review and provide guidance on the translation and development path of therapeutics programs in rare neuromuscular diseases with large unmet need including muscular dystrophies like FSHD. Was involved in an evaluation of a clinical trail for a potential new therapeutic for FSHD. |
| URL | https://treat-nmd.org/what-we-do/tact-treat-nmd-advisory-committee-for-therapeutics/ |
| Description | Characterising heterogeneity in FSHD - analysis of worldwide patient cohort |
| Amount | $13,200 (USD) |
| Funding ID | FSHDFall2019- 05482908070 |
| Organisation | FSH Society |
| Sector | Charity/Non Profit |
| Country | United States |
| Start | 03/2020 |
| End | 03/2021 |
| Description | Crick PhD programme with King's College London |
| Amount | £230,560 (GBP) |
| Organisation | Francis Crick Institute |
| Sector | Academic/University |
| Country | United Kingdom |
| Start | 08/2023 |
| End | 09/2027 |
| Description | DUX4 and PAX7 interaction in FSHD pathology- revised 2021 |
| Amount | £69,811 (GBP) |
| Funding ID | 19GRO-PG12-0493 |
| Organisation | Muscular Dystrophy UK |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 03/2021 |
| End | 03/2022 |
| Description | Engineering antibody fragments to generate cell-penetrant degrabodies targeting DUX4 for the treatment of facioscapulohumeral muscular dystrophy |
| Amount | £153,890 (GBP) |
| Organisation | UCB SA |
| Department | UCB Pharma |
| Sector | Private |
| Country | United Kingdom |
| Start | 02/2022 |
| End | 02/2025 |
| Description | Four-Year PhD studentship in Basic Science |
| Amount | £111,000 (GBP) |
| Funding ID | 222352/Z/21/Z |
| Organisation | Wellcome Trust |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 08/2020 |
| End | 09/2023 |
| Description | Induced Pluripotent Stem Cell models to decipher pathomechanisms in FSHD |
| Amount | € 46,779 (EUR) |
| Funding ID | AFM 25114 |
| Organisation | French Muscular Dystrophy Association (AFM) |
| Sector | Charity/Non Profit |
| Country | France |
| Start | 01/2024 |
| End | 01/2026 |
| Description | Investigating pathogenic mechanisms in FSHD myogenesis |
| Amount | € 47,481 (EUR) |
| Funding ID | AFM 25178 |
| Organisation | French Muscular Dystrophy Association (AFM) |
| Sector | Charity/Non Profit |
| Country | France |
| Start | 09/2023 |
| End | 05/2025 |
| Description | Investigation of metabolic adaptation in FSHD to identify novel pathomechanisms and therapeutics |
| Amount | £74,623 (GBP) |
| Funding ID | 21GRO-PG12-0530-1 |
| Organisation | Muscular Dystrophy UK |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 04/2022 |
| End | 05/2023 |
| Description | Pathomechanisms in Facioscapulohumeral muscular dystrophy |
| Amount | £930,856 (GBP) |
| Funding ID | MR/X001520/1 |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 02/2023 |
| End | 02/2026 |
| Description | Therapeutic targeting of mitochondrial dysfunction in FSHD |
| Amount | € 172,865 (EUR) |
| Funding ID | J4435-B |
| Organisation | Austrian Science Fund (FWF) |
| Sector | Academic/University |
| Country | Austria |
| Start | 03/2021 |
| End | 03/2024 |
| Description | Understanding and targeting metabolic dysfunction in FSHD |
| Amount | $55,300 (USD) |
| Funding ID | 3308289076 - FSH Society |
| Organisation | FSH Society |
| Sector | Charity/Non Profit |
| Country | United States |
| Start | 04/2021 |
| End | 05/2023 |
| Title | Isolated zebrafish myofibres to study muscle stem cells in their niche |
| Description | Described a novel method to isolate zebrafish myofibres, complete with their associated muscle stem cells in situ, to study muscle fibre anatomy and the function of muscle stem cells retained in their niche. |
| Type Of Material | Technology assay or reagent |
| Year Produced | 2020 |
| Provided To Others? | Yes |
| Impact | This novel method to isolate zebrafish myofibres, complete with their associated muscle stem cells in situ, allows study of muscle fibre anatomy and the function of muscle stem cells retained in their niche. This allowed us to examine zebrafish stem cells and discover the important role that the myogenic regulatory factor myogenin plays in stem cell function. |
| Title | Multimodal method for discovering muscle pathologies that may involve muscle stem cell dysfunction |
| Description | Developed a multimodal method using publicly available data for discovering inherited muscle pathologies that may involve muscle stem cell dysfunction |
| Type Of Material | Technology assay or reagent |
| Year Produced | 2022 |
| Provided To Others? | Yes |
| Impact | Tool enabled inherited muscle pathologies to be identified that are either solely caused by muscle stem cell dysfunction, or where there is a contribution of stem cell dysfunction. Important to know to understand pathomechanisms and when developing/testing new therapies for such diseases. |
| Title | Additional file 1 of mRNP granule proteins Fmrp and Dcp1a differentially regulate mRNP complexes to contribute to control of muscle stem cell quiescence and activation |
| Description | Additional file 1: Table 1. Bio-informatic analysis of transcripts encoding mRNP components. To assess whether changes in expression of mRNP proteins resulted from changes in expression of their mRNAs, we used the recent RNA seq analysis derived from muscle satellite cells fixed by perfusion of adult mice (to prevent cell activation that results from disruption of the niche during isolation [42]. These fixed satellite cells are thought to more accurately represent the quiescent (G0 state) and have a transcriptome profile distinct from MuSC isolated without fixation, which are now understood to represent cells in an early activation state. Activated satellite cells (ASC) represent proliferating primary myoblasts 2.5 days post isolation from the animal. Transcripts encoding P body genes were selected from the RNAseq data and grouped according to their function as outlined [43, 44]. We calculated fold changes from FPKM values (Fragments Per Kilobase of transcript per Million mapped reads) RNA seq data comparing fixed (quiescent) satellite cells and activated satellite cells [44] and used a cut-off of 1.5 +/- (for up regulation and down regulation). False Discovery Rate approach: Two stage step-up method of Benjamini, Krieger and Yekutieli was used and 10% FDR was set up for generating p values for the analysis. Figure S1. Differential association of decay complex proteins in different cellular states. Immuno-staining of Dcp1a/Edc4/Pat1 (left) and Dcp1a/Ago2 (right) in muscle cells in culture: quiescent (G0), 3 hr reactivated (R3), proliferative (MB), and differentiated (MT). Blue arrows indicate co-localization of Dcp1a/Edc4/Pat1 in puncta. Red arrows indicate co-localization of Dcp1a/Ago2 in puncta. Note the absence of Dcp1a or Pat1 puncta in G0, and the rapid reassembly in R3. Also note prominent nuclear staining for Edc4 in G0. Figure S2. (A) Supplementary to Figure 4A Additional representative immunofluorescence images showing Fmrp (green) and Dcp1a (red) puncta in G0, MB and MT, as well as cells reactivated for 3 hr from G0 (R3). Arrows indicate prominent puncta. (B). Corrected Mean Fluorescence intensities (CMI) of Fmrp and Dcp1a respectively in MB, G0, R3 and MT. For quantification, more than 3 cells per group was used and CMI intensities from more than 12 puncta were analysed. Corrected mean intensity was calculated using CMI= Total intensity of signal - (Area of signal x Mean background signal). For quantification, more than 3 cells per group was used and MFI intensities from more than 10 puncta was analysed. Figure S3. Knockdown of Fmrp leads to reduced cell renewability and is not accompanied by apoptosis. (A) Colony formation assay shows that reduced EdU incorporation in Fmrp knockdown cells correlates with compromised self-renewal. Bar graph represents mean ± sd from n=3 biological replicates. Two tailed paired Student's t-test is indicated as ***p<0.001. (B) Proliferating myoblasts (MB) were treated with siRNAs (Scr, siFmr1) for 18 hr and harvested at 24 hrs for FACS analysis of 10,000 cells performed after staining for apoptosis markers. X-axis represents Annexin V and Y-axis represents propidium iodide. Upper Panel: Flow cytometric profile for MB. Lower Panel: Quantification of FACS plots shows that Fmrp knockdown cells do not undergo apoptosis. n=3, mean ± sd. Figure S4. Knockdown of Fmrp is not accompanied by senescence. (A). SA ß-galactosidase assay performed in MB cells treated with siRNAs (Scr, siFmr1) for 24 h or reactivated from quiescence for proliferation for 24 hrs (R24) does not show any significant difference in X-gal staining between control and Fmr1 Knock down cells. (B). Analysis of DNA damage-induced foci of ?H2AX in cells reactivated from quiescence for 24h (R24) does not reveal any increase in Fmr1 knock down cells. (C). qRT-PCR analysis for p21 did not reveal any significant change in Fmr1 knocked down condition in MB, G0 or R24. All bar graphs represent mean ± sd from n =2. Two tailed paired Student's t-test is indicated as ***p <0.001. Figure S5. (A): Phenotyping of 3 cellular conditions: A replicate blot is shown of the data depicted in Figure 4C. Myogenin is exclusively expressed by MT, Cyclin D1 is enriched in MB, and G0 cells lack both proteins, confirming their quiescence by the absence of both proliferation and differentiation programs. (B) Global Transcript status: The global transcript levels of Cyclin D1, p27, MyoD1, Myf5, Gapdh in MB, G0, MT were analysed using data sets from Venugopal et.al., [49] 2020. GEO database (Series GSE110742). *p < 0.05. **p < 0.01, ***p <0.001. Figure S6. Dcp1a and Fmrp Knockdowns have opposing effects on cell proliferation but compromise differentiation. This data represents quantification of western blots shown in Figure 8. (A to D): Densitometry of western blots of Dcp1a, Fmrp , Cyclin A2 , Cyclin E proteins normalized with Gapdh as internal control in MB , MT, G0 and R3 (E): Western blots of Myogenin and Myosin Heavy chain proteins in G0 and R3 with Gapdh as internal control. All bar graphs represent mean ± sd from n = 3 ,Two tailed paired Student's t-test is indicated is indicated as *p < 0.05. *p < 0.01, ***p <0.001. Figure S7. Altered expression of cell cycle and myogenic transcripts in knockdown cells held in G0-inducing conditions. Cells were transfected with siFmr1 and siDcp1a pools for 18 hours, then placed in suspension culture and 48 hours later RNA was isolated for qRT-PCR of Dcp1a, Fmr1, Ki67, Cyclin A2, Cyclin D1, Cyclin E1, Cyclin B, p27, p21, MyoD1, and Myf 5 Loss of Dcp1a leads to increased abundance of transcripts encoding positive regulators of the cell cycle (Ki67, Cyclins), along with suppression of Cdk inhibitor p21 mRNA levels, consistent with increased EdU incorporation. Transcripts encoding Pax7 and MyoD were suppressed. Knockdown of Fmr1 leads to reduced abundance of Cyclin A2, B and D1 mRNAs, consistent with decreased EdU incorporation. Gapdh was used as internal control and normalized to Scr G0 condition. All bar graphs represent mean ± sd from n =3. Two tailed paired Student's t-test is indicated is indicated as *p < 0.05. **p < 0.01, ***p <0.001. |
| Type Of Material | Database/Collection of data |
| Year Produced | 2021 |
| Provided To Others? | Yes |
| URL | https://springernature.figshare.com/articles/dataset/Additional_file_1_of_mRNP_granule_proteins_Fmrp... |
| Title | An in silico FSHD muscle fiber for modeling DUX4 dynamics and predicting the impact of therapy |
| Description | Facioscapulohumeral muscular dystrophy (FSHD) is an incurable myopathy linked to the over-expression of the myotoxic transcription factor DUX4. Targeting DUX4 is the leading therapeutic approach, however, it is only detectable in 0.1-3.8% of FSHD myonuclei. How rare DUX4 drives FSHD and the optimal anti-DUX4 strategy are unclear. We combine stochastic gene expression with compartment models of cell states, building a simulation of DUX4 expression and consequences in FSHD muscle fibers. Investigating iDUX4 myoblasts, scRNAseq, and snRNAseq of FSHD muscle we estimate parameters including DUX4 mRNA degradation, transcription and translation rates, and DUX4 target gene activation rates. Our model accurately recreates the distribution of DUX4 and targets gene-positive cells seen in scRNAseq of FSHD myocytes. Importantly, we show DUX4 drives significant cell death despite expression in only 0.8% of live cells. Comparing scRNAseq of unfused FSHD myocytes to snRNAseq of fused FSHD myonuclei, we find evidence of DUX4 protein syncytial diffusion and estimate its rate via genetic algorithms. We package our model into freely available tools, to rapidly investigate the consequences of anti-DUX4 therapy. |
| Type Of Material | Computer model/algorithm |
| Year Produced | 2023 |
| Provided To Others? | Yes |
| Impact | This is a mathematical model of DUX4 expression in differentiated FSHD myoblasts, based on ordinary differential equations and stochastic gene expression. By analyzing human myoblasts expressing inducible DUX4 as well as scRNAseq and snRNAseq of FSHD patient myocytes and myotubes, we compute experimental estimates for the parameters underlying our model. These include the first estimates of DUX4 transcription, translation, and mRNA degradation rates. Simulating our model with experimentally derived parameters we find that it accurately predicts the proportion of DUX4 +ve/-ve and DUX4 target gene +ve/-ve cells observed in actual scRNAseq of FSHD patient myocytes. We package our model into graphical user interface tools to allow investigators to rapidly observe the impact of any given anti-DUX4 therapy on cell viability.This model of DUX4 expression is a theoretical setting to understand the complex dynamics of this important disease gene and as an open source, in silico platform to rapidly and cheaply pre-screen anti-DUX4 therapy for FSHD. Compartment Models: https://crsbanerji.shinyapps.io/compartment_models/ Cellular Automaton: https://crsbanerji.shinyapps.io/ca_shiny/ Survival Analysis: https://crsbanerji.shinyapps.io/survival_sim/ |
| URL | https://crsbanerji.shinyapps.io/compartment_models/ |
| Title | RNA-Sequencing data |
| Description | RNA-Sequencing data of muscle cells from muscular dystrophy patients and family controls. |
| Type Of Material | Database/Collection of data |
| Year Produced | 2018 |
| Provided To Others? | Yes |
| Impact | Freely available through GSE for other researchers to re-analyse and use. |
| URL | https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE123468 |
| Title | Transcriptomic Dataset from skeletal muscle of 24 FSHD patients and 11 control individuals. |
| Description | Transcriptomic Dataset: RNA-Sequencing data from 24 FSHD patients from two muscle biopsies each, one from a non-inflamed muscle (TIRM- on MRI) and one from an inflamed muscle (TIRM+ on MRI). Fifteen FSHD patients were also sampled for PBMCs for RNA-Sequencing. Eleven control individuals underwent muscle biopsy for RNA-Sequencing. |
| Type Of Material | Database/Collection of data |
| Year Produced | 2023 |
| Provided To Others? | Yes |
| Impact | This dataset has been used to identify a circulating biomarker for FSHD and two publications to date have been based on its analysis (10.1093/braincomms/fcad221 and 10.1093/hmg/ddad175). The RNA-sequencing data generated in this study is available upon reasonable request from the European Genome-phenome Archive (https://ega-archive.org) under accession number EGAS00001007350 for re-use by academics and industry. |
| URL | https://ega-archive.org |
| Title | Transcriptomic data of Muscle and Lymphoblastoid cells from FSHD patients |
| Description | RNA-Sequencing was performed on primary Muscle and Lymphoblastoid cells from FSHD patients, together with suitable controls lines to provide a dataset of their transcriptomes. |
| Type Of Material | Database/Collection of data |
| Year Produced | 2020 |
| Provided To Others? | Yes |
| Impact | Transcriptomic analysis provided insights into pathomechanisms in the muscular dystrophy FSHD, and is freely available via the GEO database. Results are described in Banerji, C.R.S., Panamarova Macura, M. and Zammit, P.S. (2020). DUX4-expressing immortalised FSHD lymphoblastoid cells express genes elevated in FSHD muscle biopsies, correlating with the early stages of inflammation. Human Molecular Genetics 29, 2285-2299 (doi: 10.1093/hmg/ddaa053). |
| URL | https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE153523 |
| Description | Biomimetic humanized FSHD muscle disease model |
| Organisation | University of Applied Sciences Technikum Wien |
| Country | Austria |
| Sector | Academic/University |
| PI Contribution | Expertise and cell lines to establish a biomimetic humanized FSHD muscle disease model using a bioreactor-based dynamic 3D culture system. |
| Collaborator Contribution | Access and expertise in using a prototype bioreactor for dynamic 3D culture systems. |
| Impact | We expect the first version of a biomimetic humanized FSHD muscle disease model to be ready by autumn 2021. Expertise of cell biology and muscle disease models from London, combined with biophysics and engineering expertise of University of Applied Sciences Technikum Wien. |
| Start Year | 2020 |
| Description | Control of myogenic differentiation |
| Organisation | University of Georgia |
| Country | United States |
| Sector | Academic/University |
| PI Contribution | Examining myogenic differentiation and how it is affected by altering signalling pathways known to be perturbed in the muscular dystrophy FSHD. |
| Collaborator Contribution | Supplied a range of human myoblasts engineered to lack key genes involved in myogenic differentiation and fusion. |
| Impact | Project at a preliminary stage at present. |
| Start Year | 2021 |
| Description | Erasmus exchange |
| Organisation | University of Mons |
| Country | Belgium |
| Sector | Academic/University |
| PI Contribution | Trained an Erasmus student as part of their MSc project. |
| Collaborator Contribution | Organised a student to undertake their project in the lab at King's. |
| Impact | Student obtained a PhD position. |
| Start Year | 2020 |
| Description | Erasmus sponsored visiting 6 month MSC project Students (x2) |
| Organisation | University of Applied Sciences Technikum Wien |
| Country | Austria |
| Sector | Academic/University |
| PI Contribution | Provided experience and training in muscle cell biology in healthy and muscular dystrophy and redox assessment as part of two Erasmus sponsored 6 month MSC projects for the Tissue Engineering and Regenerative Medicine Masters of the University of Applied Sciences Technikum Wien, Austria. |
| Collaborator Contribution | Provided two highly trained and competent MSc students to undertake projects in the lab to support ongoing work funded by MRC and MDUK. |
| Impact | Projects will very likely contribute data to publications from the Zammit lab. |
| Start Year | 2022 |
| Description | Impact of smoking/vaping on skeletal muscle redox homeostasis |
| Organisation | University of Reading |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We have developed methods to test mitochondrial function and free radical generation/handling in human myoblasts and immature muscle fibres (as detailed in - Interplay between mitochondrial reactive oxygen species, oxidative stress and hypoxic adaptation in facioscapulohumeral muscular dystrophy: Metabolic stress as potential therapeutic target. Heher P, Ganassi M, Weidinger A, Engquist EN, Pruller J, Nguyen TH, Tassin A, Declèves AE, Mamchaoui K, Banerji CRS, Grillari J, Kozlov AV, Zammit PS. Redox Biol. 2022 Jan 29;51:102251. doi: 10.1016/j.redox.2022.102251.). Using these techniques we are now testing the Impact of smoking/vaping on skeletal muscle redox homeostasis in healthy and diseased muscle cells. The impact of smoking/vaping on skeletal muscle redox homeostasis" |
| Collaborator Contribution | Supplied solute extracts from tobacco smoke and vaping vapour and other reagents to test in our system. |
| Impact | Found that smoking adversely affects skeletal muscle redox homeostasis, but disproportionately so in facioscapulohumeral muscular dystrophy, which is being prepared for publication. |
| Start Year | 2021 |
| Description | Ludwig Boltzmann Institute |
| Organisation | Ludwig Boltzmann Society |
| Department | Ludwig Boltzmann Institute for Experimental and Clinical Traumatology |
| Country | Austria |
| Sector | Academic/University |
| PI Contribution | Provide expertise on muscle cell culture and insight into/provide muscle disease models such as for facioscapulohumeral muscular dystrophy. |
| Collaborator Contribution | A PhD student visit to test potential therapeutics for muscle diseases including FSHD. |
| Impact | Laid the groundwork for further exploring therapeutics for muscle disease and spurned an unsuccessful grant application. |
| Start Year | 2022 |
| Description | Measuring oxidative stress |
| Organisation | Ludwig Boltzmann Society |
| Department | Ludwig Boltzmann Institute for Experimental and Clinical Traumatology |
| Country | Austria |
| Sector | Academic/University |
| PI Contribution | We have generated human cell samples to send to Ludwig Boltzmann Institute for Experimental and Clinical Traumatology for analysis of free radicals |
| Collaborator Contribution | Ludwig Boltzmann Institute for Experimental and Clinical Traumatology analyse our samples of human cells for free radical content. |
| Impact | A better understanding of free radical generation in muscular dystrophy will be the outcome, with this joint publication. Publication 10.1016/j.redox.2022.102251 (2022) Interplay between mitochondrial reactive oxygen species, oxidative stress and hypoxic adaptation in facioscapulohumeral muscular dystrophy: Metabolic stress as potential therapeutic target. Redox Biology Jan 29;51:102251 |
| Start Year | 2018 |
| Description | Mechanisms of oxidative/metabolic stress in FSHD |
| Organisation | Ludwig Boltzmann Society |
| Department | Ludwig Boltzmann Institute for Experimental and Clinical Traumatology |
| Country | Austria |
| Sector | Academic/University |
| PI Contribution | Performed a series of Reactive Oxygen Species measurements, respirometric analyses and hypoxia experiments to pinpoint the interplay between hypoxia signalling, ROS and mitochondria in the muscular dystrophy FSHD. |
| Collaborator Contribution | Supply expertise and facilities for examining redox biology to investigate mechanisms of oxidative/metabolic stress in the muscular dystrophy FSHD. |
| Impact | This work has led to the discovery of novel pathomechanisms and potential new class of FSHD therapeutics for FSHD. Combined our expertise in cell biology and FSHD with specialised biochemistry platforms. |
| Start Year | 2020 |
| Description | Mechanosensitive Ion Channel Piezo1 Regulates Myocyte Fusion during Skeletal Myogenesis |
| Organisation | Toyohashi Sozo College |
| Department | School of Health Sciences |
| Country | Japan |
| Sector | Academic/University |
| PI Contribution | Performing experiments to support the investigation of the role of the mechanosensitive Ion Channel Piezo1 in Myocyte Fusion during Skeletal Myogenesis |
| Collaborator Contribution | Performing main body of work for the investigation of the role of the mechanosensitive Ion Channel Piezo1 in Myocyte Fusion during Skeletal Myogenesis |
| Impact | Fine-Tuning of Piezo1 Expression and Activity Ensures Efficient Myoblast Fusion during Skeletal Myogenesis. Ortuste Quiroga HP, Ganassi M, Yokoyama S, Nakamura K, Yamashita T, Raimbach D, Hagiwara A, Harrington O, Breach-Teji J, Asakura A, Suzuki Y, Tominaga M, Zammit PS, Goto K. Cells. 2022 Jan 24;11(3):393. doi: 10.3390/cells11030393 |
| Start Year | 2020 |
| Description | Metabolic disorder in muscular dystrophy - John Walton Muscular Dystrophy Research Centre |
| Organisation | Newcastle University |
| Department | Translational and Clinical Research Institute |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Supplying specialist knowledge/techniques/data/models of mitochondria/dysfunction/metabolic disturbance in muscular dystrophy. |
| Collaborator Contribution | Access to clinical data, biobank/clinical samples and sequencing platforms - spatial and single cell transcriptomics. |
| Impact | Spatial transcriptomic analysis of FSHD muscle planned. |
| Start Year | 2025 |
| Description | Muscle biopsy transcriptomic analysis |
| Organisation | Radboud University Nijmegen Medical Center |
| Country | Netherlands |
| Sector | Academic/University |
| PI Contribution | Will map and analyse gene expression from STIR-positive and STIR-negative muscle biopsies from the same 24 FSHD patients together with 11 control individuals. |
| Collaborator Contribution | Have obtained muscle biopsies from FSHD patients that were then subject to commercial RNA-Sequencing and we have analysed the data |
| Impact | Data made available and results published in two peer reviewed publications • Banerji, C.R.S., Greco, A., Joosten, L.A.B., van Engelen, B. and Zammit, P.S. (2023). A circulating biomarker of facioscapulohumeral muscular dystrophy clinical severity, valid in skeletal muscle and blood. Brain Communications 5, fcad221 (doi: 10.1093/braincomms/fcad221). • Engquist, E.N., Greco, A., Joosten, L.A.B., van Engelen, B., Zammit, P.S. and Banerji, C.R.S. (2024). FSHD muscle shows perturbation in fibroadipogenic progenitor cells, mitochondrial function and alternative splicing independently of inflammation. Human Molecular Genetics 33: 182-197 (https://doi.org/10.1093/hmg/ddad175). Multi-disciplinary: Clinical assessment and biopsy collection, Bioinformatics, Cell biology |
| Start Year | 2020 |
| Description | Muscle regeneration in FSHD |
| Organisation | University of Rochester |
| Department | University of Rochester Medical Centre |
| Country | United States |
| Sector | Academic/University |
| PI Contribution | Performed transcriptomic analysis to measure muscle regeneration in muscular dystrophies including FSHD, DM2 and DMD. |
| Collaborator Contribution | Provide muscle samples labelled with antibodies to assess the amount of regenerating muscle fibres in biopsies from patients with FSHD and DM2. |
| Impact | Banerji, C.R.S., Henderson, D., Tawil, R.N. and Zammit, P.S. (2020). Skeletal muscle regeneration in Facioscapulohumeral muscular dystrophy is correlated with pathological severity. Human Molecular Genetics 29, 2746-2760 (doi.org/10.1093/hmg/ddaa164). Multi-disciplinary - transcriptomics with histopathology. |
| Start Year | 2019 |
| Description | RNASeq of primary FSHD cells |
| Organisation | University of Montpellier |
| Country | France |
| Sector | Academic/University |
| PI Contribution | Performed RNASeq in primary muscle cells from FSHD patients supplied by University of Montpellier, and shared the data. |
| Collaborator Contribution | Performed and analysed RNASeq in primary muscle cells from FSHD patients and healthy controls supplied by University of Montpellier, and shared the data. |
| Impact | Data has contributed to a paper under review for Human Molecular Genetics. |
| Start Year | 2019 |
| Description | Understanding how metabolism is perturbed in muscular dystrophy |
| Organisation | King's College London |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Preparing samples from healthy and diseased human myogenic cells for analysis by the collbaorators. |
| Collaborator Contribution | Advising on experimental design and data interpretation after performing Quantifiable high-resolution NMR spectroscopy at the King's College London (KCL) NMR facility on a Bruker Avance NEO 600 MHz equipped with a TCI Cryoprobe Prodigy and autosampler (https://www.kcl.ac.uk/innovation/research/corefacilities/smallrf/biospectroscopy), under guidance from expert collaborators of the metabolomics facility expert. Data will be analysed using Topsip (Bruker), Matlab and Metaboanalyst providing a quantitative measurement of changes in metabolome, alongside an analysis of potential metabolic pathways affected. |
| Impact | Resulted in successful grant applications to fund this work. Multi-disciplinary: Cell and molecular biology combined with quantifiable high-resolution NMR spectroscopy |
| Start Year | 2021 |
| Description | University of British Columbia |
| Organisation | University of British Columbia |
| Country | Canada |
| Sector | Academic/University |
| PI Contribution | Expertise on muscular dystrophies (particularly facioscapulohumeral muscular dystrophy) and providing access to myoblast lines derived from FSHD patients. |
| Collaborator Contribution | Provide expertise on fibroadipogenic progenitors and assessing epigenetic regulation. |
| Impact | Only recently started. Combining cell biology, bioinformatics and epigenetic analysis. |
| Start Year | 2022 |
| Title | A circulating biomarker of facioscapulohumeral muscular dystrophy clinical severity, valid in skeletal muscle and blood |
| Description | Facioscapulohumeral muscular dystrophy (FSHD) is incurable. DUX4 mis-expression is believed to underlie FSHD pathogenesis, alongside PAX7 target gene repression, yet clinical trials lack robust biomarkers of severity. FSHD entails fatty replacement of muscle, accelerated by inflammation, we thus performed RNA-sequencing on both an MRI guided inflamed (TIRM+) and non-inflamed (TIRM-) muscle biopsies from clinically-characterised FSHD patients, alongside peripheral blood mononucleated cells (PBMCs). PAX7 target gene repression in muscle correlates with levels in matched PBMCs. A refined biomarker computed in PBMCs associates with severity in FSHD patients, and also validates as a classifier of severity in an independent set of 54 FSHD patient blood samples. In summary, we present a minimally-invasive, circulating, transcriptomic biomarker of FSHD clinical severity valid in muscle and blood. |
| Type | Support Tool - For Medical Intervention |
| Current Stage Of Development | Refinement. Clinical |
| Year Development Stage Completed | 2022 |
| Development Status | Under active development/distribution |
| Impact | A minimally-invasive, circulating, transcriptomic biomarker of FSHD clinical severity valid in muscle and blood that can be used to monitor patient disease progression and evaluate the outcomes of clinical trials. |
| URL | https://doi.org/10.1101/2022.08.31.506017 |
| Title | Consutled on an ongoing clinical trial for FSHD |
| Description | Losmapimod is a selective p38a/ß mitogen activated protein kinase (MAPK) inhibitor. Fulcrum exclusively in-licensed losmapimod from GSK following Fulcrum's discovery of the role of p38a/ß inhibitors in the reduction of DUX4 expression for a treatment of FSHD and an extensive review of known compounds. "We are deeply disappointed that the REACH trial did not replicate the clinical results observed in the Phase 2 ReDUX4 trial," said Alex C. Sapir, Fulcrum's president and chief executive officer. "In light of these results, we plan to suspend the losmapimod program in FSHD. We would like to thank the FSHD patients who participated in losmapimod clinical trials, their families, the investigators, the FSHD Society, and the broader FSHD community for their unwavering support for this program." |
| Type | Therapeutic Intervention - Drug |
| Current Stage Of Development | Refinement. Non-clinical |
| Year Development Stage Completed | 2024 |
| Development Status | Closed |
| Clinical Trial? | Yes |
| UKCRN/ISCTN Identifier | CTIS2024-512737-33-00 |
| Impact | Clinical trail failed but much data generated on the natural history of FSHD and methods to assess clinical trial progress. |
| URL | https://ir.fulcrumtx.com/news-releases/news-release-details/fulcrum-therapeutics-announces-topline-r... |
| Title | An in silico FSHD muscle fibre for modelling DUX4 dynamics and predicting the impact of therapy |
| Description | Three GUI tools were written using the shiny package in R. The first tool outputs the compartment models for user parameter inputs and is implemented using the deSolve package. The second tool outputs a dynamic realisation of the stochastic cellular automaton model for user parameter inputs, the automaton is displayed using the lattice package in R55. The third tool displays the proportion of dead cells under the compartment model comparing our experimentally derived parameter regime to a user selected parameter regime. In addition the third tool simulates 2 realisations of the cellular automaton model, one using our experimentally derived parameter regime and another using the user selected regime (A and B are kept the same for both simulations to allow comparable starting populations). Survival analysis using Cox-proportional hazard models are implemented via the survival package in R, to compare cell death rates in the two realisations, with p-values displayed on a corresponding Kaplan-Meier plot. The 3 tools can be accessed at: 4. Compartment Models: https://crsbanerji.shinyapps.io/compartment_models/ 5. Cellular Automaton: https://crsbanerji.shinyapps.io/ca_shiny/ 6. Survival Analysis: https://crsbanerji.shinyapps.io/survival_sim/ |
| Type Of Technology | Webtool/Application |
| Year Produced | 2022 |
| Impact | The in silico FSHD muscle fibre for modelling DUX4 dynamics can be used for predicting the impact of a potential therapy, to aid in therapeutic development and clinical trail design. |
| URL | https://doi.org/10.1101/2022.12.12.520053 |
| Title | Biomarker analysis software |
| Description | Software that gives a biomarker score for a muscular dystrophy using inputted RNA-Sequencing data. To facilitate consideration of PAX7 target gene repression in the analysis of FSHD transcriptomic data, we provide a simple pipeline for extraction of PAX7 target gene repression, as well as three validated DUX4 target gene expression biomarkers, from normalized gene level expression data. Available as supplementary data from a publication - doi: 10.1093/hmg/ddz043 |
| Type Of Technology | Software |
| Year Produced | 2019 |
| Impact | A simple pipeline for extraction of PAX7 target gene repression, as well as three validated DUX4 target gene expression biomarkers, from normalized gene level expression data |
| URL | https://academic.oup.com/hmg/article/28/13/2224/5376488#supplementary-data |
| Title | Image analysis |
| Description | Image analysis software to determine the degree of myogenic differentiation in a culture of cells. |
| Type Of Technology | Software |
| Year Produced | 2019 |
| Impact | Allows myogenic differentiation to be quantified in a high throughput way. |
| Description | 9th TERMIS Winterschool 2022 "A Workshop Series on Current Hot Topics in Regenerative Medicine" |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Postgraduate students |
| Results and Impact | Co-chaired and spoke at a session on skeletal muscle at the 9th TERMIS Winterschool 2022 "A Workshop Series on Current Hot Topics in Regenerative Medicine" to an audience of mainly post-graduate students and professionals to educate on skeletal muscle, explain our work funded by MRC and MDUK, and foster collaborations. Other members of the group (2 postdocs) also presented. |
| Year(s) Of Engagement Activity | 2022 |
| URL | https://trauma.lbg.ac.at/news/neuer-termin-die-termis-winterschool-2022/?lang=en |
| Description | Amis FSH Site Visit |
| Form Of Engagement Activity | Participation in an open day or visit at my research institution |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Patients, carers and/or patient groups |
| Results and Impact | Board and members of charity AMIS FSH performed a site visit to King's College London on 20/2/2020. This involved visits to the lab and then talks/discussions with Zammit group members explaining facioscapulohumeral muscular dystrophy and our research activity in lay terms. This better informed the participants about the disorder and research approaches, that will also be fed back to other charity members. Outcomes are dissemination of information and potential for research funding. |
| Year(s) Of Engagement Activity | 2020 |
| URL | http://www.amisfsh.fr |
| Description | CIRM WORKSHOP Numeric Approaches to FSHD research |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | Centre international de rencontres mathématiques (CIRM) has been, for more than 40 years, a tool of excellence at the service of the French school of mathematics and researchers from all over the world. Facioscapulohumeral muscular dystrophy (FSHD) represents a compelling case study in computational biology, characterized by high patient heterogeneity and complex genetic mechanisms operating across multiple molecular scales. The emergence of high-dimensional, multimodal datasets - spanning multi-omics, and including spatial and single-cell resolution data - creates opportunities for sophisticated mathematical modeling and analysis. This workshop will focus on the novel mathematical frameworks and numerical methods for analyzing these complex biological systems, with particular emphasis on machine learning approaches for multi-omics integration, topological data analysis, and dynamical systems modeling of disease progression. Zammit and Heher and other group members presented their research and plans initiated to further examine and integrate FSHD datasets. |
| Year(s) Of Engagement Activity | 2025 |
| URL | https://conferences.cirm-math.fr/3557.html |
| Description | FSHD UK |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Patients, carers and/or patient groups |
| Results and Impact | FSHD UK is a patient-lead advocacy group of which I am a member, with the overarching aim of organising patients to take part in clinical trials, disseminating information and, ultimately, contributing to finding a cure for FSHD. We have liaised with Pharma about bringing a US-based clinical trial to the UK. |
| Year(s) Of Engagement Activity | 2021 |
| Description | Friends of FSH Research website update on research |
| Form Of Engagement Activity | Engagement focused website, blog or social media channel |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Supporters |
| Results and Impact | An update to funders, patients, stakeholders and their supporters hosted on the charity Friends of FSH Research website. Lay update on research conducted as part of an MRC grant that was subsequently funded by a fellowship and Friends of FSH Research. |
| Year(s) Of Engagement Activity | 2022 |
| URL | https://www.fshfriends.org/blog/progress-update-novel-therapeutics-fshd-mitochondria-targeted-antiox... |
| Description | K+ Academic Day Taster Lecture |
| Form Of Engagement Activity | Participation in an open day or visit at my research institution |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Schools |
| Results and Impact | Taster day for sixth form pupils potentially interested in studying biomedical sciences or medicine at King's College London. Gave a lecture about muscular dystrophy incorporating some of our work. Hopefully influenced some pupils to consider higher education. |
| Year(s) Of Engagement Activity | 2024 |
| Description | King's College website outreach |
| Form Of Engagement Activity | Engagement focused website, blog or social media channel |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Patients, carers and/or patient groups |
| Results and Impact | King's College Website presentation directed to the general public and interested audiences, titled "New studies highlight a common mechanism for declining muscle function" describing in lay language our recent work on the direct contribution of muscle stem cell to muscle disease. |
| Year(s) Of Engagement Activity | 2022 |
| URL | https://www.kcl.ac.uk/news/new-studies-highlight-a-common-mechanism-for-declining-muscle-function |
| Description | MDUK Muscles Matter online seminar series 2021 Facioscapulohumeral muscular dystrophy |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Patients, carers and/or patient groups |
| Results and Impact | Gave a lay talk on the background to Facioscapulohumeral muscular dystrophy for the MDUK Muscles Matter online seminar series 2021 attended by patients, care-givers, supporters and stakeholders which helped people understand the disorder better and then participated in a panel discussion to answer questions from the audience. |
| Year(s) Of Engagement Activity | 2021 |
| URL | https://www.youtube.com/watch?v=nsV2YK7II38&list=PLryAKPouaA__KVZa4pSVxYieRWYi57p97&index=6 |
| Description | Muscular Dystrophy UK: Virtual Information Seminar Series - Facioscapulohumeral Muscular Dystrophy (Adults and Paediatric) |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Patients, carers and/or patient groups |
| Results and Impact | The charity Muscular Dystrophy UK hosted a Virtual Information Seminar Series on Facioscapulohumeral Muscular Dystrophy (Adults and Paediatric) at which I presented a talk on the basics of FSHD cause and pathology to a largely lay audience to help them better understand this form or muscular dystrophy and the approaches being taken to better understand and cure it. |
| Year(s) Of Engagement Activity | 2024 |
| URL | https://www.youtube.com/watch?v=8CHrqc-nA8I |
| Description | Neuromuscular Diseases: the next 10 years |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Patients, carers and/or patient groups |
| Results and Impact | Over the last decade our centre has been performing translational research to bring diagnosis, care and therapy to people with neuromuscular disease. At the conference, we aim to reflect on our last ten years of success. We will also explore exciting developments in the field, as we look forward to what the next ten years of work will bring to the neuromuscular field. The conference will be arranged around our four strands of work, featuring exciting lectures from staff at the JWMDRC and panel discussions including leading neuromuscular experts. The programme will feature talks on the following topics: Advancing neuromuscular diseases through research (PZ participated in this panel discussion on the future of lab-based research) Clinical Research for patients with neuromuscular diseases Diagnostic & Clinical Services for patients with neuromuscular diseases National & international networking initiatives |
| Year(s) Of Engagement Activity | 2024 |
| URL | https://jwmdrc.org/jwmdrc-anniversary |
| Description | Patient Group Workshop |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Patients, carers and/or patient groups |
| Results and Impact | FSHD Information Day - Muscular Dystrophy UK Talk: - title - What causes FSHD and how can we treat it? York Racecourse, Knavesmire Road, York YO23 1EX 23/11/19 Talk explaining FSHD and current research to a lay and specialist audience. Many comments about this being the first time that they had actually understood the causes of their disease. Pdf of the talk was requested for dissemination to patents/carers/supporters. |
| Year(s) Of Engagement Activity | 2019 |
| URL | https://www.musculardystrophyuk.org/wp-content/uploads/2019/11/Information-Day-November-2019-full-pr... |
| Description | School Visit to King's College London |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Schools |
| Results and Impact | Approximately 80 male and female year 7 pupils, with 6/7 school staff undertake histological staining and examining tissue sections under light microscopes. They were highly engaged with the topic, generating an active discussion and expressions of interest in STEM subjects. Useful experience for Zammit lab members who reported it an enlightening and rewarding activity. |
| Year(s) Of Engagement Activity | 2018,2019,2020 |
| Description | Site visit by executives of Charity FSHD Soc |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Patients, carers and/or patient groups |
| Results and Impact | FSHD Soc charity site visit by Chief Science Officer and Chief Executive Officer of one of the major funders in FSHD research, to discuss our research activity, funding opportunities and further engagement by the Zammit group in charity events. |
| Year(s) Of Engagement Activity | 2020 |
| URL | https://www.fshdsociety.org |
| Description | Tissue Engineerung and Regenerative Medicine International Society (TERMIS) 10 Winterschool |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Postgraduate students |
| Results and Impact | The event was held in the name of the Tissue Engineerung and Regenerative Medicine International Society (TERMIS), organized by LBI Trauma and the Austrian Cluster for Tissue Regeneration, with support from the Society of the Advancement of Research in Shock and Tissue Regeneration. Zammit presented at a session on skeletal muscle at the 10th TERMIS Winterschool 2022 "A Workshop Series on Current Hot Topics in Regenerative Medicine" to an audience of mainly post-graduate students and professionals to educate on skeletal muscle, explain our work funded by MRC and MDUK, and foster collaborations. Other members of the group (a postdocs and PhD student) also presented. |
| Year(s) Of Engagement Activity | 2023 |
| URL | https://trauma.lbg.ac.at/news/the-termis-winterschool-2023/?lang=en |