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Periodic Report Summary 4 - NEUROMICS (Integrated European –omics research project for diagnosis and therapy in rare neuromuscular and neurodegenerative diseases)

Project Context and Objectives:
Neurodegenerative (ND) and neuromuscular (NM) diseases are amongst the most frequent classes of rare diseases, affecting life and mobility of 500,000 patients in Europe and millions of their caregivers, family members and employers. This NeurOmics project brings together the leading research groups in Europe, five highly innovative SMEs and relevant oversea experts using the most sophisticated Omics technologies to revolutionize diagnostics and to develop pathomechanism-based treatment for ten major ND and NM diseases. Specifically we aim to:
(i) use next generation WES to increase the number of known gene loci for the most heterogeneous disease groups from about 50% to 80%,
(ii) increase patient cohorts by large scale genotyping by enriched gene variant panels and NGS of so far unclassified patients and subsequent phenotyping,
(iii) develop biomarkers for clinical application with a strong emphasis on presymptomatic utility and cohort stratification,
(iv) combine -omics approaches to better understand pathophysiology and identify therapeutic targets,
(v) identify disease modifiers in disease subgroups cohorts with extreme age of onset
(vi) develop targeted therapies (to groups or personalized) using antisense oligos and histone deacetylase inhibitors, translating the consortiums expertise in clinical development from ongoing trials toward other disease groups, notably the PolyQ diseases and other NMD.
To warrant that advances affect a large fraction of patients we limited the selection to a number of major categories, some of which are in a promising stage of etiological and therapeutic research while some others are in great need of further classification. The efforts will be connected through a NeurOmics platform for impact, communication and innovation that will provide tools and procedures for ensuring trial-readiness, WP performance, sustainability, interaction with the chosen Support IRDiRC and RD-Connect project and involvement of stakeholders in the NDD/NMD field.

Project Results:
Ad aim i: 919 samples have been sent to deCODE for WES/WGS. Since the switch from WES to WGS, 330 samples have been genome sequenced. >100 new genes have been identified of which 69 have been published. Further novel candidate genes are being functionally validated in cell and animal models. Numerous novel genes have been identified in collaborations between NeurOmics partners highlighting the importance of data sharing.
The NeurOmics data sharing policy has been implemented and allows sharing of genomic data within the wider RD research community via controlled access to the RD-Connect platform to variant lists and via application to the NeurOmics DAC to the raw data stored at EGA.
Ad aim ii: Clinical information is being collected in PhenoTips in a standardised way. Clinical data sheets for each disease group studied have been mapped to the HPO. >1334 patients have been entered in PhenoTips. The CTSR was expanded and holds now 337 sites in 51 countries of which 88 sites are registered for NDD.
Targeted NGS panels have been designed for ataxia, HSP, NMD and SMA/LMND. A “supercapture” panel for neurogenetic and cardiomyopathy diseases has been developed to meet the needs of the smaller Australian population. All panels have been improved to also cover recently identified new genes. >695 patients have been sequenced with the different panels. The Australian panel has been run >1580 times. The alignment pipeline of the 3DM mutation prediction system has improved significantly. There are 1534 3DM information systems available including all genes on the HSP and SCA NGS panels. Integration with RD-Connect has been initialized.
Ad aim iii: Lipidomics data of SCA (at 2 time points), FTLD and HSP cohorts are currently being analysed. FTLD plasma samples have also been analysed using metabolomics. RNAseq data of 2 HD cohorts (incl. premanifest and early stage HD patients and CTRs) from LUMC and UCL have been combined to increase the power of the analysis. It has been found that peripheral blood transcriptome in HD parallels that in the most affected regions of the HD brain. Overlapping immune upregulation with Alzheimer’s disease suggests shared pathogenic mechanisms.
RNAseq in myeloid cells from HD patients has been completed. Transcriptional dysregulation in HD myeloid cells is characterised by increased expression of proinflammatory mediators, even in the absence of stimulation, and is driven by activation of the NFĸB signalling pathway.
Sample collection of HD and HSP patients for biomarker validation studies is ongoing. Sample collection SCA samples has been completed and sent for BCAA analysis. Given the promising data obtained by analysing metabolomics and lipidomics profiles in dystrophic mice, the same analysis has been done in fasted NMD patients. A more refined data analysis to identify the affected pathways and to bridge the findings obtained in patients and animal models is ongoing.
Two therapeutic trials with SPG5 patients have been completed.
Ad aim iv: SPG5 iPSC were successfully differentiated into hepatocyte-like cells. They secrete higher 27-OHC concentrations compared to CTR recapitulating the in vivo disease phenotype.
Generation and full characterization of iPSC-derived motor neurons of SMA patients and fully asymptomatic discordant family members has been published. Upregulated genes in unaffected discordant family members (including PLS3 and others) have been identified. The mechanism for the modifying effect of PLS3 has been unravelled and CORO1C identified as a second modifier and PLS3-interactor that rescues actin cytoskeleton dysregulation and endocytosis in SMA models.
Phenotypic characterisation of the KI/KO HSPB8_K141N has been completed and the results of the phenotypic analysis of Rosa26 HSPB1 transgenic mice have been published.
3 hiPS control cell lines with 21, 28 or 33 CAG repeats and 3 HD cell lines carrying 60, 109 or 180 CAG repeats have been differentiated into striatal neurons. HD lines show defects in striatal and cortical differentiation.
A double-mutant (Parkin-Ataxin-3 transgenic) mouse model has been generated and characterised with different behavioural and neuropathological analyses. 3 SCA3 knock-in founder lines with 92Q, 150Q and 223Q have been generated.
QPCT has been identified in a siRNA screen in cell-based systems as a target for modifying polyQ toxicity/aggregation. Druggability has been confirmed and the mechanism of action has been identified. Ariadne analysed several pathways involved in HD to identify biomarkers to monitor disease progression.
Ad aim v: Findings from HD WES samples with atypically fast or slow disease progression have been integrated with other datasets to increase power to detect rare variants influencing HD progression. The role of variants in DNA repair genes to modify age at onset in HD has been confirmed and extended to other polyQ repeat disease. To investigate the relationship between age at onset and disease progression 216 TRACK-HD subjects have been genotyped. Results have been validated in the EHDN REGISTRY cohort and confirmed a variant in a gene previously implicated in HD model systems.
20 SPG4 parent-offspring pairs with discrepant age of onset of >25 years have been exome sequenced. WES data analysis revealed two hits which are currently being functionally analysed. Additional hits have been identified in an interactome analysis by Ariadne and are currently being further investigated.
20 Bulgarian patients with the same mutation (CHRNE1267delG) but differences in phenotype (10 mild, 10 severe) have been whole genome and RNA sequenced. Analysis of the transcriptome data identified a total of 53 genes that are differentially up- or down- regulated in the severe vs mild cohort.
Sequencing data from large patient cohorts are required to find putative modifying variants for NMD/NDD. Thus, WGS, WES and targeted NGS genomic data is being collected via EGA and will be analysed once more data is available.
Ad aim vi: An efficient and selective method to block TGF-beta and myostatin signalling by targeting their type I receptors ALK5 and ALK4 with AONs has been developed. ALK4 inhibition increases myogenesis, but also regulates the tight balance of protein synthesis and degradation. Alk4 AON-mediated inhibition led to muscle atrophy rather than the expected hypertrophy.
AON-mediated exon skipping has been shown in vitro in a LGMD2B mouse model and presence of dysferlin at the protein level has been demonstrated. Testing is ongoing if exon 32 skipping can rescue the mice phenotype at a functional level.
A pilot study has been performed in the YAC128 HD mouse model showing detectable exon 12 skipping on RNA level. The following larger study gave conflicting results. For SCA3, calpain and caspase cleavage sites implicated in disease pathology are coded for in exons 8 and 9 of ataxin-3 pre-mRNA. Results of the double skip of exon 8 and 9 as a strategy to reduce proteolytic cleavage of ataxin-3 have been published.
Screening of ~30,000 chemical compounds resulted in one promising hit. Flow cytometry and immunocytochemistry results show that treatment with this compound can increase α-DG glycosylation.

Potential Impact:
NeurOmics will have significant impact for a large group of patients with rare diseases - 120-150 patients/100,000, (500,000 patients in Europe). The project will integrate and extend existing networks and tools within the NDD/NMD field to ensure maximum impact and benefit from these and avoid duplication of efforts.
This will be done in close interaction with the RD-Connect project to address the major challenges identified through the IRDiRC initiative in the field of rare neurological diseases. Specifically, WP13 will extend the care and trial site registry (CTSR) developed for the neuromuscular field in order to incorporate neurodegenerative centres and ensure that the information gathered includes that needed for –omics research, supporting future clinical trials in these areas. The extended CTSR will also enable members to search for undiagnosed patients in other centres across the world fitting a particular phenotype profile. With RD-Connect, we will ensure that high quality, well annotated biospecimens are collected through harmonized biobanks and registries. Through its bioinformatics work, NeurOmics will provide a comprehensive knowledgebase for pathway informed target and biomarker search, to increase our understanding of unique and shared pathogenic mechanisms for rare and common NDDs/NMDs. Stakeholders including patient organizations, regulatory authorities and industry will be integrated into the study to support joint studies and widen the project’s reach. All major outcomes of NeurOmics will have an impact directly linked to clinical utility:
- Diagnostic kits for up to 80 % of NMD/NDD will result in the availability of targeted genetic testing for familial NMD/NDD mutations This will help physicians provide the most appropriate treatment, allow affected families to make informed family planning decisions, form better-stratified patient cohorts for interventional trials, shorten the time to diagnosis and avoid unnecessary or invasive test procedures.
- Discovery and validation of biomarkers will increase implementation and appropriateness of new treatments by better stratifying patient cohorts. Monitoring of treatments will be improved. Better insight into pathogenic commonalities for NMD/NDD/RD will be achieved.
- Proof of concept of new therapeutic approaches for NDDs/NMDs will lead the way towards clinical trials of therapeutic interventions for up to 10 diseases eventually improving the quality of life of thousands of patients with NDDs/NMDs. Not only may patients already benefit from participating in clinical trials, but the resulting new therapies will enable physicians worldwide to treat currently incurable diseases.
- NeurOmics will improve health and quality of life of NMD/NDD patients and decrease disease related costs through improved and early diagnoses, characterization of stratified patient cohorts, improved understanding of disease complications through deep phenotyping and development of new treatments.
- NeurOmics’ communication tools and procedures across all stakeholder groups will help to ensure trial-readiness, efficient and effective testing of new hypotheses and the rapid implementation of new recommendations by disseminating the latest findings, promoting data-sharing, extending existing tools and networks and developing appropriate SOPs (see Neuromics website at This will reduce time-to-trials significantly, reach most appropriate patients to form specific cohorts and ensure standards of care throughout the entire care and trial sites network through tailored training programs.

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