Targeting the cellular metabolism to treat tissue-specific mitochondrial diseases
Lead Research Organisation:
University of Cambridge
Department Name: Clinical Neurosciences
Abstract
The mitochondria are specialised units (organelles) within cells that are responsible for transforming nutrients into energy. Mitochondria contain their own genetic material (mtDNA) which is replicated independently from the DNA in the nucleus. mtDNA is very small and only contains the information for 13 proteins; all other proteins that the mitochondria need to function are coded in the nuclear DNA. Changes in either mtDNA or nuclear DNA can cause mitochondrial diseases. These are disabling or fatal conditions, affecting the brain, liver, skeletal muscle, heart and other organs, and currently there are no effective cures. Although all mitochondrial diseases have a similar mechanism, they can affect the body in strikingly different ways. To date, the reasons for this are poorly understood.
We study an unusual mitochondrial disease named reversible infantile respiratory chain deficiency (RIRCD). RIRCD is characterised by severe muscle weakness before 3 months of age, followed by a spontaneous recovery after 6 months of age in surviving children. RIRCD is caused by a spelling error(=mutation) in the mtDNA. Interestingly, many more people carry this mutation without getting ill, however only around 100 are affected by RIRCD worldwide. We demonstrate that a second change in the nuclear DNA in addition to the mtDNA mutation is needed to cause RIRCD.
The mutation that underlies RIRCD is situated in a part of the mtDNA molecule called transfer-RNA (tRNA). tRNAs deliver the appropriate amino acids to a machinery called ribosome, which puts the amino acids together into a protein; this process is called translation. If there are not enough amino acids available or if the tRNA is modified by a mutation, the tRNA could stay empty. Empty tRNAs are a negative sign and can be detected by a protein called GCN2. GCN2 triggers a reaction of the cell called the integrated stress response (ISR). This stress response leads to changes that either help the cell adapt to the stress or cause its death if it lasts too long.
Our hypothesis is that the total amount of tRNAs and the empty tRNAs can differ in different cell types. A higher amount of empty tRNAs could trigger a stronger stress response, which could have a negative or positive impact on the cell. We will analyse skin cells obtained from patients with various mitochondrial diseases and healthy controls. The organs affected by the disease (brain, muscles, heart) are not easily accessible for analysis. Therefore, we will turn the skin cells into stem cells through a process called reprogramming. From the stem cells we can derive brain, heart and muscle cells. By looking at different cell types from the same person we are able to compare their reactions in stress situations. We will check if levels of empty tRNAs or ISR are different in the different cell types. We will add certain amino acids to see if this can reduce the amount of empty tRNA and the stress response.
Another model that we will use are zebrafish. We can introduce different mutations into the zebrafish DNA and look at how the different organs (such as brain, heart and skeletal muscle) are affected. We will look at tRNA amounts and ISR in different organs of the fish. These experiments will help to explain why tissues are affected in a different way despite carrying the same mutations.
The spontaneous recovery of patients with RIRCD is very unusual. We will compare the cells from RIRCD patients with cells from other mitochondrial diseases caused by changes affecting tRNAs but the patients do not recover. We believe that the changes induced by ISR are helping the RIRCD cells to change their way of functioning and mobilise different energy sources, eventually leading to the recovery. We don't know, however why this does not happen in other mitochondrial diseases. If we understand the differences between RIRCD and other mitochondrial diseases we might be able to find a way to treat other forms of mitochondrial disease.
We study an unusual mitochondrial disease named reversible infantile respiratory chain deficiency (RIRCD). RIRCD is characterised by severe muscle weakness before 3 months of age, followed by a spontaneous recovery after 6 months of age in surviving children. RIRCD is caused by a spelling error(=mutation) in the mtDNA. Interestingly, many more people carry this mutation without getting ill, however only around 100 are affected by RIRCD worldwide. We demonstrate that a second change in the nuclear DNA in addition to the mtDNA mutation is needed to cause RIRCD.
The mutation that underlies RIRCD is situated in a part of the mtDNA molecule called transfer-RNA (tRNA). tRNAs deliver the appropriate amino acids to a machinery called ribosome, which puts the amino acids together into a protein; this process is called translation. If there are not enough amino acids available or if the tRNA is modified by a mutation, the tRNA could stay empty. Empty tRNAs are a negative sign and can be detected by a protein called GCN2. GCN2 triggers a reaction of the cell called the integrated stress response (ISR). This stress response leads to changes that either help the cell adapt to the stress or cause its death if it lasts too long.
Our hypothesis is that the total amount of tRNAs and the empty tRNAs can differ in different cell types. A higher amount of empty tRNAs could trigger a stronger stress response, which could have a negative or positive impact on the cell. We will analyse skin cells obtained from patients with various mitochondrial diseases and healthy controls. The organs affected by the disease (brain, muscles, heart) are not easily accessible for analysis. Therefore, we will turn the skin cells into stem cells through a process called reprogramming. From the stem cells we can derive brain, heart and muscle cells. By looking at different cell types from the same person we are able to compare their reactions in stress situations. We will check if levels of empty tRNAs or ISR are different in the different cell types. We will add certain amino acids to see if this can reduce the amount of empty tRNA and the stress response.
Another model that we will use are zebrafish. We can introduce different mutations into the zebrafish DNA and look at how the different organs (such as brain, heart and skeletal muscle) are affected. We will look at tRNA amounts and ISR in different organs of the fish. These experiments will help to explain why tissues are affected in a different way despite carrying the same mutations.
The spontaneous recovery of patients with RIRCD is very unusual. We will compare the cells from RIRCD patients with cells from other mitochondrial diseases caused by changes affecting tRNAs but the patients do not recover. We believe that the changes induced by ISR are helping the RIRCD cells to change their way of functioning and mobilise different energy sources, eventually leading to the recovery. We don't know, however why this does not happen in other mitochondrial diseases. If we understand the differences between RIRCD and other mitochondrial diseases we might be able to find a way to treat other forms of mitochondrial disease.
Technical Summary
Although mitochondria are present in almost all eukaryotic cell types, mitochondrial diseases have distinct tissue-specific phenotypes that are poorly understood. Our project focuses on mitochondrial diseases characterised by impaired mitochondrial translation, which can be caused either by mtDNA mutations (often in mt-tRNAs) or in nuclear encoded proteins that play a role in mitochondrial translation. Mt-tRNA or nuclear gene mutations affect tRNA levels and structure directly or indirectly, leading to a defect of mitochondrial protein synthesis. These mutations can also lead to the presence of free tRNAs without their cognate amino acid ('uncharged tRNA'), which constitutes a stress signal for cells.
We will investigate whether different tissues have different levels of uncharged tRNAs and whether this correlates with the vulnerability for mitochondrial defects. Uncharged tRNA activates the integrated stress response (ISR), a major signalling pathway that allows eukaryotic cells to sense stress and adapt to it. We obtained fibroblasts from patients with different mitochondrial translation defects to determine tRNA and ISR levels. We will reprogram the fibroblasts to iPSCs and differentiate those to neurons, muscle cells and cardiomyocytes. Next, we will examine what metabolic changes are induced by the activated ISR in these cells.
In one disease studied by our laboratory, reversible infantile respiratory chain deficiency (RIRCD), the metabolic changes induced by the ISR in the muscle of patients allowed a recovery of the patients from severe disease. Our results indicate that the ISR is protective to some cells and damaging to others. We would like to exploit the knowledge gained in RIRCD to induce similar metabolic changes in mitochondrial conditions that are currently not reversible. Modifying the ISR or manipulating key metabolic factors (amino acids, FGF21) may enable us to devise therapeutic options for mitochondrial translation defects in the future.
We will investigate whether different tissues have different levels of uncharged tRNAs and whether this correlates with the vulnerability for mitochondrial defects. Uncharged tRNA activates the integrated stress response (ISR), a major signalling pathway that allows eukaryotic cells to sense stress and adapt to it. We obtained fibroblasts from patients with different mitochondrial translation defects to determine tRNA and ISR levels. We will reprogram the fibroblasts to iPSCs and differentiate those to neurons, muscle cells and cardiomyocytes. Next, we will examine what metabolic changes are induced by the activated ISR in these cells.
In one disease studied by our laboratory, reversible infantile respiratory chain deficiency (RIRCD), the metabolic changes induced by the ISR in the muscle of patients allowed a recovery of the patients from severe disease. Our results indicate that the ISR is protective to some cells and damaging to others. We would like to exploit the knowledge gained in RIRCD to induce similar metabolic changes in mitochondrial conditions that are currently not reversible. Modifying the ISR or manipulating key metabolic factors (amino acids, FGF21) may enable us to devise therapeutic options for mitochondrial translation defects in the future.
Organisations
- University of Cambridge (Lead Research Organisation)
- Charité - University of Medicine Berlin (Collaboration)
- Dokuz Eylül University (Collaboration)
- University of Manchester (Collaboration)
- University College London (Collaboration)
- McGill University (Collaboration)
- Pontifical Catholic University of Chile (Collaboration)
- Columbia University Medical Center (Collaboration)
- Children's Hospital of Eastern Ontario (Collaboration)
- University of Vienna (Collaboration)
- Monash University (Collaboration)
- Broad Institute (Collaboration)
Publications
100,000 Genomes Project Pilot Investigators
(2021)
100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care - Preliminary Report.
100,000 Genomes Project Pilot Investigators
(2021)
100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care - Preliminary Report.
in The New England journal of medicine
Accogli A
(2023)
Clinical, neuroradiological, and molecular characterization of mitochondrial threonyl-tRNA-synthetase (TARS2)-related disorder.
in Genetics in medicine : official journal of the American College of Medical Genetics
Atalaia A
(2024)
EURO-NMD registry: federated FAIR infrastructure, innovative technologies and concepts of a patient-centred registry for rare neuromuscular disorders.
in Orphanet journal of rare diseases
Atalaia A
(2021)
Correction to: A guide to writing systematic reviews of rare disease treatments to generate FAIRcompliant datasets: building a Treatabolome.
in Orphanet journal of rare diseases
Bardhan M
(2021)
Correction: Megaconial congenital muscular dystrophy secondary to novel CHKB mutations resemble atypical Rett syndrome.
in Journal of human genetics
Bardhan M
(2021)
Megaconial congenital muscular dystrophy secondary to novel CHKB mutations resemble atypical Rett syndrome.
in Journal of human genetics
Carmody LC
(2023)
The Medical Action Ontology: A Tool for Annotating and Analyzing Treatments and Clinical Management of Human Disease.
in medRxiv : the preprint server for health sciences
Carmody LC
(2023)
The Medical Action Ontology: A tool for annotating and analyzing treatments and clinical management of human disease.
in Med (New York, N.Y.)
Cotta A
(2021)
Muscle fat replacement and modified ragged red fibers in two patients with reversible infantile respiratory chain deficiency
in Neuromuscular Disorders
Currò R
(2024)
Role of the repeat expansion size in predicting age of onset and severity in RFC1 disease.
in Brain : a journal of neurology
De Boer E
(2021)
A MT-TL1 variant identified by whole exome sequencing in an individual with intellectual disability, epilepsy, and spastic tetraparesis.
in European journal of human genetics : EJHG
De Boer E
(2021)
Correction: A MT-TL1 variant identified by whole exome sequencing in an individual with intellectual disability, epilepsy, and spastic tetraparesis.
in European journal of human genetics : EJHG
De Boer E
(2022)
Genome-wide variant calling in reanalysis of exome sequencing data uncovered a pathogenic TUBB3 variant.
in European journal of medical genetics
Denommé-Pichon AS
(2023)
A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing.
in Genetics in medicine : official journal of the American College of Medical Genetics
Diodato D
(2023)
258th ENMC international workshop Leigh syndrome spectrum: genetic causes, natural history and preparing for clinical trials 25-27 March 2022, Hoofddorp, Amsterdam, The Netherlands.
in Neuromuscular disorders : NMD
Esapa C
(2023)
Misfolding of fukutin-related protein (FKRP) variants in congenital and limb girdle muscular dystrophies
in Frontiers in Molecular Biosciences
Ferreira T
(2023)
Career intentions of medical students in the UK: a national, cross-sectional study (AIMS study).
in BMJ open
Ferreira T
(2023)
Ascertaining the Career Intentions of Medical Students (AIMS) in the United Kingdom Post Graduation: Protocol for a Mixed Methods Study.
in JMIR research protocols
Ferreira T
(2024)
Variants in mitochondrial disease genes are common causes of inherited peripheral neuropathies.
in Journal of neurology
Gangfuß A
(2022)
A de novo CSDE1 variant causing neurodevelopmental delay, intellectual disability, neurologic and psychiatric symptoms in a child of consanguineous parents.
in American journal of medical genetics. Part A
Gangfuß A
(2021)
NEW GENES AND DISEASES
in Neuromuscular Disorders
Gangfuß A
(2024)
A Homozygous NDUFS6 Variant Associated with Neuropathy and Optic Atrophy.
in Journal of neuromuscular diseases
Gungor S
(2021)
Autosomal recessive variants in TUBGCP2 alter the ?-tubulin ring complex leading to neurodevelopmental disease.
in iScience
Hathazi D
(2021)
INPP5K and SIL1 associated pathologies with overlapping clinical phenotypes converge through dysregulation of PHGDH.
in Brain : a journal of neurology
Hikmat O
(2024)
Status epilepticus in POLG disease: a large multinational study.
in Journal of neurology
Hiz Kurul S
(2022)
High diagnostic rate of trio exome sequencing in consanguineous families with neurogenetic diseases.
in Brain : a journal of neurology
Jennings M
(2021)
Intracellular Lipid Accumulation and Mitochondrial Dysfunction Accompanies Endoplasmic Reticulum Stress Caused by Loss of the Co-chaperone DNAJC3
in Frontiers in Cell and Developmental Biology
Jennings MJ
(2022)
NCAM1 and GDF15 are biomarkers of Charcot-Marie-Tooth disease in patients and mice.
in Brain : a journal of neurology
Jennings MJ
(2021)
Targeted Therapies for Hereditary Peripheral Neuropathies: Systematic Review and Steps Towards a 'treatabolome'.
in Journal of neuromuscular diseases
Kagiava A
(2021)
AAV9-mediated Schwann cell-targeted gene therapy rescues a model of demyelinating neuropathy.
in Gene therapy
Kleefeld F
(2024)
Multi-level profiling unravels mitochondrial dysfunction in myotonic dystrophy type 2.
in Acta neuropathologica
Kleefeld F
(2023)
Beyond vacuolar pathology: Multiomic profiling of Danon disease reveals dysfunctional mitochondrial homeostasis.
in Neuropathology and applied neurobiology
Kohlschmidt N
(2021)
Molecular pathophysiology of human MICU1 deficiency
in Neuropathology and Applied Neurobiology
Kohlschmidt N
(2021)
Molecular pathophysiology of human MICU1 deficiency.
Lochmüller H
(2021)
Results from a 3-year Non-interventional, Observational Disease Monitoring Program in Adults with GNE Myopathy.
in Journal of neuromuscular diseases
Magrinelli F
(2022)
Biallelic Loss-of-Function NDUFA12 Variants Cause a Wide Phenotypic Spectrum from Leigh/Leigh-Like Syndrome to Isolated Optic Atrophy.
in Movement disorders clinical practice
Description | Associate Editor of Brain |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Influenced training of practitioners or researchers |
Impact | Improved impact factor of the journal Brain. |
Description | Guidelines on stroke-like episodes in mitochondrial disease |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Contribution to new or improved professional practice |
Impact | Participate din a consensus workshop, which has been published at Wellcome Open Research |
URL | https://pubmed.ncbi.nlm.nih.gov/32090171/ |
Guideline Title | The workshop what I attended provides guidelines for treating mitochondrial epilepsies |
Description | Mitochondrial epilepsy workshop |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Citation in clinical guidelines |
Impact | We defined some guidelines for treating mitochondrial epilepsies |
URL | https://www.thelilyfoundation.org.uk/news/improving-the-lives-of-mito-patients-with-epilepsy/ |
Description | Nuclear mechanisms underpinning mitochondrial vulnerability in different cell-types |
Amount | £4,254,246 (GBP) |
Funding ID | 226653/Z/22/Z |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2023 |
End | 09/2028 |
Title | Identified molecular serum biomarkers in CMT |
Description | We identify proteins in sera of patients and mouse models with Charcot-Marie-Tooth disease (CMT) with characteristics that make them suitable as biomarkers in clinical practice and therapeutic trials. |
Type Of Material | Physiological assessment or outcome measure |
Year Produced | 2022 |
Provided To Others? | Yes |
Impact | Molecular markers scalable for clinical use are critical for the development of effective treatments and the design of clinical trials. We collected serum from mouse models of CMT1A (C61 het), CMT2D (GarsC201R, GarsP278KY), CMT1X (Gjb1-null), CMT2L (Hspb8K141N) and from CMT patients with genotypes including CMT1A (PMP22d), CMT2D (GARS), CMT2N (AARS) and other rare genetic forms of CMT. The severity of neuropathy in the patients was assessed by the CMT Neuropathy Examination Score (CMTES). We performed multitargeted proteomics on both sample sets to identify proteins elevated across multiple mouse models and CMT patients. We detected that GDF15 and NCAM1 are useful biomarkers in CMT and tehy should be further investigated in clinical trials. |
URL | https://pubmed.ncbi.nlm.nih.gov/35148379/ |
Title | We generated human brain organoids of patients with mitochondrial disease. |
Description | We used iPSCs which were generated from fibroblasts of patients with the common m.3243A>G mutations. We have differentiated them into human brain organoids. We generated such organoids from 3 different patients with different heteroplasmy rates. These organoid models enable studying cell type specific signatures of the mitochondrial translation defects kin the brain. |
Type Of Material | Technology assay or reagent |
Year Produced | 2022 |
Provided To Others? | No |
Impact | We will investigate single cell RNA sequencing in our organoids with m.3243A>G to better understand the mechanism of the neuronal dysfunction in Mitochondrial Encephalomyopathy with Stroke-like Episodes and high Lactate (MELAS). Stroke-like episodes are the most severe complications in this condition and they determine the prognosis of the disease. |
Title | iPSC neuronal conversion |
Description | We established the conversion of neurons from iPSCs of patients with mitochondrial disease. |
Type Of Material | Cell line |
Year Produced | 2020 |
Provided To Others? | No |
Impact | We are currently working on these cells and we will publish our results. |
Title | induced neuronal progenitor cells |
Description | We can successfully convert human finroblasts into induced neuronal progenitor cells. |
Type Of Material | Model of mechanisms or symptoms - human |
Provided To Others? | No |
Impact | We have already converted 4 patient and 2 contol cell lines into induced neuronal progenitor cells. Currently the analysis of mitochondrial function is in progress in these cells. |
Title | zebrafish |
Description | I used zebrafish to model human disease. |
Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
Provided To Others? | No |
Impact | Published a paper (Boczonadi et al. 2014) |
Title | Treatabolome |
Description | My group has participated in the "Treatabolome" project, which is part of the EU Solve-RD. We have performed a systematic review and established the database for treatable genes and variants in Charcot-Marie-Tooth Disease (CMT). |
Type Of Material | Computer model/algorithm |
Year Produced | 2020 |
Provided To Others? | Yes |
Impact | We collated evidence for the effectiveness of pharmacological and gene-based treatments for hereditary peripheral neuropathies. We searched several databases for randomised controlled trials (RCT), observational studies and case reports of therapies in hereditary peripheral neuropathies. Two investigators extracted and analysed the data independently, assessing study quality using the Oxford Centre for Evidence Based Medicine 2011 Levels of Evidence in conjunction with the Jadad scale. The 'treatable' variants highlighted in this project will be flagged in the treatabolome database to alert clinicians at the time of the diagnosis and enable timely treatment of patients with hereditary peripheral neuropathies. |
URL | https://pubmed.ncbi.nlm.nih.gov/32773395/ |
Title | Treatabolome database |
Description | My group has participated in the "Treatabolome" project, which is part of the EU Solve-RD. We have performed a systematic review and established the database for treatable genes and variants in Leigh Syndrome. |
Type Of Material | Computer model/algorithm |
Year Produced | 2020 |
Provided To Others? | Yes |
Impact | Leigh syndrome (LS) is the most frequent paediatric clinical presentation of mitochondrial disease. The clinical phenotype of LS is highly heterogeneous. Though historically the treatment for LS is largely supportive, new treatments are on the horizon. Due to the rarity of LS, large-scale interventional studies are scarce, limiting dissemination of information of therapeutic options to the wider scientific and clinical community. We conducted a systematic review of pharmacological therapies of LS following the guidelines for FAIR-compliant datasets. We searched for interventional studies within Clincialtrials.gov and European Clinical trials databases. Randomised controlled trials, observational studies, case reports and case series formed part of a wider MEDLINE search. Though interventional randomised controlled trials have begun for LS, the majority of evidence remains in case reports and case series for a number of treatable genes, encoding cofactors or transporter proteins of the mitochondria. Our findings form part of the international expert-led Solve-RD efforts to assist clinicians initiating treatments in patients with treatable variants of LS. |
URL | https://pubmed.ncbi.nlm.nih.gov/34308912/ |
Title | bioinformatic analysis of RNAseq |
Description | performed RNAseq in several human cell and muscle samples and analysed different parameters to gain understanding of the metabolic signature of neurogenetic diseases |
Type Of Material | Data analysis technique |
Year Produced | 2017 |
Provided To Others? | No |
Impact | papers are currently in progress |
Title | proteomic analysis of cells/tissues |
Description | performed proteomic analysis of paatient cells and skeletal muscle samples |
Type Of Material | Data analysis technique |
Year Produced | 2017 |
Provided To Others? | Yes |
Impact | papers in progress |
Description | Collaboration on mitochondrial changes in inclusion body myositis |
Organisation | Charité - University of Medicine Berlin |
Country | Germany |
Sector | Academic/University |
PI Contribution | A neurology fellow Dr. Felix Kleefeld visited my lab for 3 months and studied muscle biopsies of IBM patients in my lab. |
Collaborator Contribution | Muscle biopsy samples of patients with IBM and controls |
Impact | conference abstract so far, but manuscript will be in preparation in the coming months |
Start Year | 2023 |
Description | Consequitur - cohort of patients from Turkey for WES |
Organisation | Dokuz Eylül University |
Country | Turkey |
Sector | Academic/University |
PI Contribution | We collaborate with Dr. Yavuz Oktay and Dr. Semra Hiz on identiying new disease genes in consanguineous Turkish families with various neurogenetic diseases. |
Collaborator Contribution | Collected 400 families and DNA samples, perfomred phenotyping |
Impact | We are currently writing abstracts for conferences from the first results and drafting papers. |
Start Year | 2016 |
Description | Next Generation Sequencing |
Organisation | Broad Institute |
Country | United States |
Sector | Charity/Non Profit |
PI Contribution | Prof. Daniel McArthur`s group in the Broad Institute agreed to perform WES in >300 Turkish families with neurogenetic disease. |
Collaborator Contribution | Performed WES for free. |
Impact | currently writing up conference abstracts and papers. |
Start Year | 2016 |
Description | Search for modifyers in reversible COX deficiency |
Organisation | Columbia University Medical Center |
Department | Neurological Institute of New York |
Country | United States |
Sector | Academic/University |
PI Contribution | I contribute a large family and performed exome sequencing |
Collaborator Contribution | contributing further families |
Impact | currently being worked up |
Start Year | 2011 |
Description | Studying 2-thiolation of mt-tRNA Glu, Lys, Gln |
Organisation | McGill University |
Department | Department of Molecular Neurogenetics |
Country | Canada |
Sector | Academic/University |
PI Contribution | I have started to collaborate on the function of TRMU |
Collaborator Contribution | common publication |
Impact | There is a Hom Mol Genet paper (Sasarman et al. 2011) already out of this collaboration. |
Start Year | 2011 |
Description | TEFM |
Organisation | Monash University |
Country | Australia |
Sector | Academic/University |
PI Contribution | We are working together on proving the pathogenicity of novel genes causing mitochondrial protein synthesis defect. |
Collaborator Contribution | Exchanging cell lines, collecting data. |
Impact | not yet, paper in progress |
Start Year | 2019 |
Description | confirming the role of PTPMT1 in human disease |
Organisation | University College London |
Department | Institute of Neurology |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We made a zebrafish model of this novel gene and supported that it causes decreased cardiolipin and movement problems. |
Collaborator Contribution | The UCL team (Rob Pitceathly) identified another patient and did cardiolipin studies. |
Impact | paper is currently being drafted |
Start Year | 2020 |
Description | joint work on a new gene TEFM |
Organisation | Children's Hospital of Eastern Ontario |
Country | Canada |
Sector | Hospitals |
PI Contribution | Joint molecular work on characterizing TEFM as a new mitochondrial disease gene |
Collaborator Contribution | One out of 5 families were from CHEO. CHEO scientist Emily O`Connor made a zebrafish model of TEFM deficiency. |
Impact | Paper under review in Nature Communications This is a multi-disciplinary partnership including clinicians and scientists |
Start Year | 2020 |
Description | metabolomics in myoblasts of patients with mitochondrial myopathies |
Organisation | University of Vienna |
Country | Austria |
Sector | Academic/University |
PI Contribution | We grew and peletted 8 mitochondrial myopathy patient and 4 control cell lines. My post doc Dr. Denisa Hathazi dsigned the standards together with the lab in Vienna. |
Collaborator Contribution | The team in Vienna measured the metabolomics in our patient cells. |
Impact | The group of Dr. Robert Ahrend measured metabolomics with selected standards in 8 patient cell lines and 4 controls. This collaboration is multidisciplinary, as the team in Vienna is a lipidomics/metabolomics group and I am a clinical academic neurologist. |
Start Year | 2020 |
Description | mitochondrial fusion/fission |
Organisation | Pontifical Catholic University of Chile |
Country | Chile |
Sector | Academic/University |
PI Contribution | I have sent cell lines to Dr. Veronica Eisner for studiying mitochondrial fusion/fission. |
Collaborator Contribution | studying mitochondrial fission in cells with a special technique |
Impact | A novel mechanism causing imbalance of mitochondrial fusion and fission in human myopathies. Bartsakoulia M, Pyle A, Troncosco D, Vial J, Paz-Fiblas MV, Duff J, Griffin H, Boczonadi V, Lochmüller H, Kleinle S, Chinnery PF, Grünert S, Kirschner J, Eisner V, Horvath R. Hum Mol Genet. 2018 Jan 19. doi: 10.1093/hmg/ddy033. [Epub ahead of print] PMID: 29361167 |
Start Year | 2015 |
Description | mitochondrial tRNA synthetase related diseases |
Organisation | University of Manchester |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | I started a collaboration with Prof. William Newman on mt tRNA synthetase diseases. I sent him DNA samples of patients with potential Perrault syndrome. |
Collaborator Contribution | Dr. Newmn is sequencing with a NGS panel novel genes which could cause Perrault syndrorme. |
Impact | no output yet |
Start Year | 2015 |
Title | KL1333 - An interventional, randomised, double-blind, parallel-group, placebo-controlled, flexible-dose, adaptive study of the efficacy of KL1333 in adult patients with primary mitochondrial disease (PMD). |
Description | I am the PI in Cambridge of the new phase of the KL1333 clinical trial. We have activated the site at CUH in February 2023 and will screen the first patients in March 2023. |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Late clinical evaluation |
Year Development Stage Completed | 2022 |
Development Status | Actively seeking support |
Clinical Trial? | Yes |
Impact | Patents are getting in touch with us about this trial and we communicate with the Lily Foundation. |
URL | https://clinicaltrials.gov/ct2/show/NCT05650229 |
Description | AT Society |
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 | I have been selected as a member of the advisory board of the AT Society. We have participated in an international project to write a review on AT Biomarkers. |
Year(s) Of Engagement Activity | 2022 |
Description | Cure_ARS |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | Cure-ARS symposium was organised by the Cure-ARS charity. I gave a presentation and I have discussions with the Charity for joint research |
Year(s) Of Engagement Activity | 2022 |
URL | https://www.curears.org/event-details/mt-aars-scientific-symposium-2022 |
Description | HNF |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | We discussed and initiated a natural history study on C12orf65 mutations |
Year(s) Of Engagement Activity | 2021 |
URL | https://www.hnf-cure.org/ |
Description | Hereditary Neuropathy Foundation |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | We discussed and initiated a natural history study on C12orf65 mutations. The study opened in November 2022 and we have recrruited 6 patients to date. |
Year(s) Of Engagement Activity | 2021 |
URL | https://www.hnf-cure.org/ |
Description | Webinar for MDUK |
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 | I gave a presentation at a MDUK webinar about the research in my group. |
Year(s) Of Engagement Activity | 2023 |