Gene and RNA Therapy Center (GRTC)

Translational Genomics of Neurodegenerative Diseases

The lab of Matthis Synofzik systematically mines large-scale genomic (WES/WGS) databases it has aggregated via its leading role in several EU-funded networks (PREPARE, SOLVE-RD) over the last 5 years - with >2000 next-generation sequencing (NGS) ataxia datasets in its PREPARE-GENESIS and >2500 NGS rare neurological disease datasets in SOLVE RD  as a sheer endless source of ASO-druggable mutations. It hereby follows a systematic translational pipeline of bringing  ASO precision medicine for neurological diseases from bench to bedside, with first showcases already available on each key node of this pipeline:

1. ASO lab work: We have developed ASOs for a deep-intronic mutation in multisystemic OPA1-disease (together with the Tübingen Eye Clinic; PMID: 27874857, PMID: 24970096), now followed by developments of ASOs for deep-intronic mutations for a range of other neurological diseases, e.g. infantile WDR45 (BPAN) disease or Ataxia telegiectasia (AT), all in close collaboration with the Dutch RNA therapeutics center (Leiden). 
2. European n-of-1 ASO platform: These success stories prepare the path for a systematic platform of for n-of-1 ASO generation (PMID: 31597037) – 1 Mutation 1 Medicine (1M1M) - , which aims to provide a cross-European platform approach to generating ASOs for a large number of private or ultra-rare neurological disease mutations, together with the lab of Rebecca Schüle, scientific coordination by the Tübingen Rare Disease Center (Holm Graessner) and the Dutch RNA therapeutics centers (https://www.1mutation1medicine.eu).  
3. First-in-human ASO treatments: As a first show first-in-human showcase for this ultra-individualized n-of-1 ASO platform, we have prepared a clinical application of an individual-patient customized ASO targeting a private splice mutation in a child with Ataxia Teleangiectasia (together with Harvard Boston Children’s Hospital).
4. Larger clinical ASO trials: These n-of-1 approaches are complemented by larger first-in-human clinical ASO trials. Here Prof. Synofzik serves as a site PI for phase I ASO trials in C9orf72-associated ALS/FTD, compassionate use ASO programs for SOD1-associated ALS,  and helps word-leading ASO pharma companies like IONIS and SERVIER to bring ASO trials for spinocerebellar ataxias (SCAs) in clinical reality by providing consultancy on trial design, genetics, digital-motor and fluid-biomarkers.

List of GRT projects

• Preclinical and clinical development of individual patient-specific splice modulation ASOs in rare neurological diseases
• Establishing trial readiness for first-in-human n-of-1 and larger trial ASO approaches in neurological diseases by generating data and models for natural history, outcome and efficacy modelling (including clinical outcomes, molecular and digital-motor outcomes and statistical modelling
• Establishment of a cross-European platform for scalable individualized ASO development for a broad range of rare neurological diseases
• Site PI leadership and advice in a broad spectrum of of ASO trials,  including phase 1 trials , phase 2 trials, compassionate use and n-of-1 ASO programs for various neurological diseases (Alzheimer’s Disease, Frontotemporal Dementia, Amoytrophic Lateral Sclerosis, Spinocerebellar Ataxias, multisystemic autosomal-recessive ataxias)

 GRT expertise

• preclinical and clinical ASO development for neurological diseases
• Trial design, outcome development (clinical, patient-reported, molecular, digital-motor, patient) and outcome validation for gene therapies in neurological diseases
• Regulatory and ethical framework for individualized ASO treatments and ASO trials
• Leadership expertise in ASO phase 1 trials , phase 2 trials, compassionate use and n-of-1 programs. Advisor on ASO and gene therapy trials for a broad range of pharma companies, e.g. Ionis, Servier, Biogen, AviadoBio.

Main GRT methods applied in the lab

• Bioinformatic analyses of large-scale mutation databases of rare neurological diseases for candidate mutations and patients for development of gene therapy approaches
• In vitro validation of candidate mutations and mechanisms amenable for gene therapy approaches in a large range of rare neurological diseases
• ASO design and efficacy validation in cell models
• Transcriptomics and proteomics analyses for efficacy and toxicity evaluations of ASO strategies
• Discovery and validation of protein fluid biomarkers for capturing ASO treatment response 
• Identification and validation of sensor-based motor biomarkers for capturing ASO treatment response
  
  

Ongoing and requested funding

Prof Synofzik has received a total of >9 million EUR funding, thereof ongoing (selected):

• Else Kröner Fresenius Stiftung – Prof. Synofzik (PI/coordinator) (2022-2025):Gen, Mechanismus, Therapie: Netzwerk für eine Präzisionsmedizin genetisch-neurologischer Erkrankungen (PRECISE.net)
• European Joint Programme on Rare Diseases (EU EJP RD) - Prof. Synofzik (PI/coordinator) – (11/2021-11/2023): EVIDENCE-RND:  creating robust evidence for longitudinal progression changes and treatment effects in ultrarare neurological diseases:
• European Joint Programme on Rare Diseases (EU EJP RD) - Prof. Synofzik (PI) (06/2021-06/2024): TREAT-ARCA: Designing a toolbox of paradigmatic treatments for a targeted molecular medicine approach to autosomal-recessive ataxias
• European Joint Programme on Rare Diseases (EU EJP RD) - Prof. Synofzik (PI/coordinator) (06/2020-06/2023): PROSPAX: an integrated multimodal progression chart in spastic ataxias 
• EU Joint Programme Neurodegenerative Disease Research (EU JPND) - Prof. Synofzik (site PI) – (06/2020-06/2023): GENFI-prox: Defining measures of proximity to symptom onset in the GENetic Frontotemporal dementia Initiative 

Publications