The mission of the GRTC is to develop innovative, personalized, and broadly applicable Gene and RNA therapy approaches that are safe and affordable. By initiating and executing clinical gene and RNA therapy studies, we aspire to offer new perspectives to patients with rare diseases and target common diseases.
The unique combination of excellent basic, clinical and translational expertise at the Gene and RNA Therapy Center in Tübingen, along with the close collaborations with the MPI of Developmental Biology in Tübingen on the bioengineering of CRISPR/Cas9 and Base-/Prime-editors, the MPI of Biochemistry in Martinsried/Munich on Sendai based Virotherapy, and the biotech company CureVac on mRNA production for gene therapy, allows the development of safe, precise and affordable Gene and RNA therapy and cell therapy products for clinical use.
The existence of a Center for Rare Diseases and several International Registries for Rare Diseases at the Tübingen University working closely with the Institute of Medical Genetics and Applied Genomics, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Comprehensive Cancer Center Tübingen-Stuttgart (CCC-TS), National Center of Tumor Diseases (NCT) as well as the Tübingen Early Clinical Trials Unit (ECTU) enables the identification of novel targets for Gene and RNA therapy and, importantly, allows high-volume recruitment of patients for both academic investigator-initiated (IITs) as well as Pharma trials. This makes Tübingen a highly attractive place for Gene and RNA therapy trials.
Nucleic acids (DNA and RNA) carry the code for life, providing a major platform to regulate health and disease. In fact, the journey of discovery of nucleic acids functions in health and disease started in Tübingen in 1869, when Friedrich Miescher identified a new substance called ‘nuclein’ in the nuclei of immune cells. This discovery ignited a revolution in life sciences and more recently in medicine, offering major innovations in diagnostics and therapies. Gene (DNA) and RNA therapy provides treatment options for disorders traditionally considered ‘undruggable’ and therefore is expected to extend the scale of treatable diseases dramatically, resulting in a medical revolution similar to that of monoclonal antibodies in the past 40 years. Gene and RNA therapy also offers fast-evolving, advanced tools to treat common and rare diseases, showing rapid and groundbreaking progress and revolutionizing medicine already now and in the near future.
Prof. Dr. med., Ph.D. Julia Skokowa
Founding Director, Gene and RNA Therapy Center
Publications: Publications
Coordinator / Director: Prof. Dr. Julia Skokowa, MD, PhD
External Advisory Board - Advising the Board of Directors
The board is composed of the spokespersons of the 4 areas:
The election of the Board of Directors and the Management Committee is held every 5 years.
Matthew Porteus (Chair), Professor, Department of Pediatrics- Stem Cell Transplantation, Stanford Medical School, USA.
Annemieke Aartsma-Rus, Professor of Translational Genetics, Department of Human Genetics at Leiden University, The Netherlands.
Alberto Auricchio, Associate Professor of Medical Genetics at the University of Naples and Director of Research at the Telethon Institute of Genetics and Medicine in Naples, Italy.
Christopher Baum, Professor, Chief Translational Research Officer / Chairman of the Board of the Berlin Institute of Health, Charite, Berlin, Germany.
Hildegard Bühning, Professor of Infection Biology and Gene Transfer and Deputy Director of the Institute of Experimental Hematology, Hannover Medical School, Germany. President of the European Society for Gene and Cell Therapy and Scientific Secretary of the German Society for Gene Therapy.
Christine Engeland, Professor of Experimental Virology at Witten/Herdecke University, Germany and Head of the Research Group "Mechanisms of Oncolytic Immunotherapy" at Heidelberg University Hospital, National Center for Tumor Diseases and German Cancer Research Center in Heidelberg.
Boris Fehse, Professor, Head of the Cell and Gene Therapy Research Unit at the Clinic for Stem Cell Transplantation, UKE Hamburg. Scientific Advisory Board (past president) of the Society for Gene Therapy.
Anastasia Khvorova, Professor at the RNA Therapeutic Institute, UMass Medical School, USA.
Martin Meier, PhD, Senior Vice President, Research, Alnylam Pharmaceuticals.
Luigi Naldini, Professor of Cell and Tissue Biology and Gene and Cell Therapy at San Raffaele University School of Medicine. Director of the San Raffaele Telethon Institute for Gene Therapy, Milan, Italy.
Dirk Nettelbeck, PD Dr.,Head of the research group Oncolytic Adenoviruses in the Clinical Cooperation Unit Virotherapy at the German Cancer Research Center (DKFZ) in Heidelberg.
Pediatrics
Autosomal recessive and early onset ataxias
Friedreich's ataxia
Glioblastoma
Hearing impairment
Hereditary spastic paraplegia
Inherited Leukemias
Ba-Wü HemPred Board für Leukämie-Prädisposition
Inherited Neutropenia
Neuroendokrine Tumore (NET)
Spinocerebellar Ataxia
Sporadic cerebellar ataxia and Multiple system atrophy
Angeborene Neutropenie
Hämophilie
Hereditäre Spastische Spinalparalyse
Neuroendokrine Tumore (NET)
Schwerhörigkeit und Taubheit
Shwachman Diamond Syndrom (SDS)
Prof. Dr. Ludger Schöls
Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen
AG Schöls - Clinical Neurogenetics
Hereditary spastic paraplegia type 5 (SPG) is a rare neurodegenerative disease that leads to progressive spastic gait disturbance and wheelchair dependency. SPG5 is caused by mutations in the enzyme CYP7B1 that is involved bile acid synthesis in the liver. Lack of CYP7B1 leads to increased concentrations of its substrates 25-hydroxycholesterol and 27-hydroxycholesterol in blood but also in brain of SPG5 patients. As 25- and 27-hydroxycholesterol are neurotoxic, these oxysterols are considered the primary factor causing neurodegeneration in SPG5.
In our previous work we aimed to restore CYP7B1 in the liver by injections of mRNA. As RNA supplementation shows only to short term effects, we developed a gene replacement approach via an adeno associated virus type 8 (AAV8) which has been used earlier for gene supplementation in other human diseases. AAV8-CYP7b1 resulted in the normalization of hydroxycholesterols in blood and liver but unfortunately had only limited effect in brain. This suggests that CYP7B1 needs also to be replaced in the central nervous system (CNS) to prevent its neurotoxic effects in SPG5.
Therefore, this flagship project aims to develop novel AAV vectors like AAV-PHP.eB and AAV.CAP-B22 which are able to cross the blood-brain barrier in mice as well as in non-human primates. Intravenous injection of these vectors is supposed to result in expression of its “cargo gene” not only in the liver but also in the CNS. We will investigate therapeutic efficacy and potential toxicity of the new vectors in cyp7b1 knockout mice. Oxysterol levels in blood, liver, and brain will be determined as the primary readout parameter by mass spectrometry. Vectors will be evaluated for liver and CNS toxicity. In addition, neural tropism and potential neural toxicity of the new vectors will be tested in vitro human neuronal cell cultures and brain organoids derived from induced pluripotent stem cells (iPSC).
Prof. Dr. Matthis Synofzik
Division Translational Genomics of Neurodegenerative Diseases, Center of Neurology and Hertie-Institute of Clinical Brain Research, University of Tübingen
AG Synofzik - Translational Genomics of Neurodegenerative Diseases
Gene-targeted therapies hold promise for treating many currently untreatable diseases. In particular for manifold rare neurological diseases (RND) - for which treatments had seemed out of reach for long. However, existing drug development and regulatory processes are inadequate for very rare RNDs affecting only a few or even just one patient globally. To overcome this gap, we here propose a completely new drug-development paradigm in neurology: development of individual patient-customised molecular therapies tailored to each single patient’s very individual mutation. For this we will leverage a highly-programmable RNA therapy - antisense oligonucleotide (ASO)-mediated splice modulation (Figure 1) - that allows to target various nano-rare or private mutations across different RNDs, enabling personalized therapies tailored to individual patients' mutations; but which is at the same time - by targeting the same mutation types shared across many RNDs- scalable to multiple RNDs alike (Figure 2)
To test this novel RNA therapy paradigm, this project will establish a systematic platform for developing patient-customized ASOs. As a demonstration showcase, we have selected particularly severe childhood-onset brain disease: ataxia telangiectasia (A-T). As an end-to-end platform, the platform starts off with the individual patient, develops an individualised ASO through all pertinent preclinical and clinical steps, and then brings the individual ASO back into clinics to treat that very individual patient. The preclinical ASO platform module hereby follows a comprehensive approach from patient identification to ASO design, RNA and protein analysis, functional assessments, and various toxicity assays (Figure 3). Our platform will simultaneously explore four different ASO target strategies, each addressing specific clusters of shared mutation types in the A-T gene. If successful, this comprehensive approach could revolutionize genomic medicine for RND patients. The concept of individualized genomic therapeutics could become a groundbreaking paradigm, impacting a significant number of patients with rare neurological diseases.
PD Dr. med. Dr. rer. nat. Dipl. Biol. Markus Mezger
Dr. rer. nat. Tahereh Mohammadian Gol
Dr. rer. nat. Justin Antony Selvaraj
Department of General Paediatrics, Cell & Gene Therapy group University Children's Hospital Tübingen, University of Tübingen
β-hemoglobinopathies are inherited hematological disorders caused by mutations in the human hemoglobin beta (HBB) gene that reduce or abrogate β-globin expression. Allogeneic hematopoietic stem cell transplantation (HSCT) using stem cells from a foreign donor is the standard therapy but has certain limitations such as finding an HLA matched donor and HSCT associated complications. In addition, previous gene therapy approaches have utilized lentiviral vectors (LVs) to introduce a functional copy of the β-globin gene into the patient's hematopoietic stem and progenitor cells (HSPCs). Alternatively, reactivating fetal hemoglobin (HbF) using CRISPR-Cas9 method can reduce or even prevent the symptoms of disease. These approaches have significant disadvantages including risk of insertional mutagenesis and continued expression of defective β-globin.
To overcome these limitations, we have combined CRISPR-Cas9 technology with adeno-associated virus (AAV) based gene delivery method to apply a precise gene correction of mutated HBB gene (Lamsfus-Calle et al. The CRISPR Journal 2021). Using this approach, we attained high rates of gene correction in HSPCs of β-thalassemia patients, achieving a significant increase in adult hemoglobin (HbA) level.
Following promising result in preclinical studies, in this project we aim to develop an optimized transfection protocol for correction of CD34+ HSPCs at a clinical and GMP production scale following a recently established protocol for CRISPR/Cas9 transfection on the CliniMACS Prodigy platform (Ureña-Bailén et al. The CRISPR Journal 2023). Moreover, we will implement our findings to conduct a Phase 1/2 clinical trial to assess safety and efficacy of this approach in patients with transfusion dependent β-Thalassemia.
Prof. Dr. Julia Skokowa1, Dr. Masoud Nasri1, Malte Ritter1, Prof. Claudia Lengerke1, Prof. Wolfgang Bethge1,2, PD Dr. Dr. Markus Mezger3, Prof. Dr. Peter Lang3, Prof. Dr. Johannes Schulte3, Prof. Dr. Karl Welte3, Dr. Cornelia Zeidler1.
1Department of Oncology, Hematology, Clinical Immunology, and Rheumatology, University Hospital Tübingen, Germany
2Center for Clinical Trials, University Hospital Tübingen
3Department of Pediatric Hematology and Oncology, Children`s Hospital, University Hospital Tübingen, Germany
Congenital neutropenia, a condition caused by specific genetic mutations (ELANE-CN), leads to a significant decrease in the number of infection-fighting white blood cells, making individuals highly prone to severe bacterial infections. This condition also elevates the risk of developing myelodysplastic syndromes or acute myeloid leukemia. The conventional treatment involves daily injections of a substance called recombinant human granulocyte colony-stimulating factor (rhG-CSF) to boost white blood cell counts. However, this approach does not address the underlying genetic issue and may have side effects. Some patients don't respond to this treatment.
To address these challenges, we have developed a gene therapy called MILESTONE for ELANE-CN patients. This innovative approach utilizes CRISPR/Cas9 technology, employing a double Cas9 nickase strategy to target the genetic mutations and inhibit the expression of the faulty ELANE gene. This not only restores the production of infection-fighting white blood cells but also enhances precision and minimizes unintended effects. MILESTONE has the potential to revolutionize the treatment of ELANE-CN.
Our next step is to initiate an Investigator-Initiated Trial (IIT) for this gene therapy. The trial will focus on editing CD34+ cells derived from patients, incorporating MILESTONE technology, and utilizing autologous transplantation. This single-site trial will involve ELANE-CN patients from the European Registry, attracting participants not only from Germany but also from across Europe and potentially from other regions. It is worth noting that our innovative approach, protected by patents, has broader applications beyond ELANE-CN and can be adapted for other genetic disorders and even for inhibiting cancer-related genes in the future.
Furthermore, the establishment of a Good Manufacturing Practice (GMP)-grade gene editing facility for CD34+ cells at the University Hospital Tübingen (UKT) will be a significant development. This facility will not only benefit ELANE-CN patients but also attract interest from biotech companies and patients, given the current scarcity of such facilities in Germany and Europe at large.
Prof. Dr. Christopher Cederroth,
Prof. Dr. Ellen Reisinger,
Prof. Dr. Steffen Hage
Department for Otolaryngology, University Hospital Tübingen
Hearing impairment affects 1 to 2 newborns, and the same number becomes hearing impaired in childhood. At least half of the cases are due to mutations in certain genes. In affected people, more than 300 genes are screened for mutations to find the individual cause. For many forms of inherited hearing impairment, researchers aim to find out which cells of the inner ear require the respective protein encoded by this gene, and how a mutation leads to hearing loss. The long-term aim of many groups of researchers is to provide targeted gene therapies for as many forms of hearing impairment as possible. To transfer genetic information, we employ modified viruses, so-called recombinant adeno-associated viruses (AAVs), of which a number of naturally occurring and engineered variants are known. However, to date, only a limited number of these viral vector variants have been tested for the inner ear. As consequence, only few inner ear cell types can currently be targeted with gene therapy.
In this project, we aim to inject a series of AAV variants into the inner ear of mice and marmoset monkeys. Each of the vector variant will contain a genetic “barcode” for later identification. We will compare two different injection routes: the direct injection into the bony cavity of the inner ear, and an indirect injection via the cisterna magna, a fluid-filled compartment of the hindbrain which is connected to the inner ear. By sequencing the genetic information of individual cells from the inner ear, the brain, the liver, and more tissues, we will find out which viral vectors transduced which cell types. This information is crucial to design targeted gene therapies for the inner ear, but potentially also for brain disorders.
Thomas Gasser, Hertie Institute for Clinical Brain Research ...
Learn moreGene therapy is the use of genetic material in the treatment or prevention of disease. Gene therapy can be used to reduce the causes of a disease or increase the ability of the body to fight such diseases.
Gene therapy is the treatment of disorders by fixing faulty gene functions that would otherwise cause disease and disorders, instead of using drugs or surgery to treat those disorders. In short, the traditional focus on treating disease and disorders turns toward the more optimistic vision of stopping diseases and disorders.
Gene therapies are still new and so there is still some uncertainty around their efficacy and long-term effects. Therefore, safety is paramount. This is the reason why there is extensive basic research, pre-clinical and clinical trails to make sure, like traditional therapies, it is as safe as possible.
Some people say that any interventions on DNA is dangerous and unnatural. Some uses – such as enhancements – might be considered problematic in this way. However, focusing on therapy suggests that it is not more intrinsically unnatural then modern medicine itself.
DNA-based gene therapies should create permanent changes, thus valuable if beneficial changes; while RNA therapies should not be permanent, thus treatment can be modified or halted if necessary.
Your health data, especially your genetic data is very sensitive material, which can be very impactful in terms of insurance, employment, and future health and family decisions. Therefore, it is a priority to ensure its security and to ensure your privacy. Adherence to the General Data Protection Regulation (GDPR), your genetic data is treated as a special category of importance.
Incidental findings are results which were not related to the intention of the genetic (or other) test and research undertaken. Sometimes they may have important clinical implications. Other times, they may be risk factors which may be of uncertain significance (e.g. a possible increased chance of a later-life onset disorder). This would require careful assessment of risk and discussion with you would be undertaken should this arise.
Something called informed consent is a central value in all modern medicine, especially genome/RNA medicine. An informed consent is not just asking – but asking in a context where you have all the relevant information about what is involved (risks and benefits), and that you are supported in your decision-making, so that you can make the right decision for you.
In the context with your GP, treatment is generally with established methods, with well-known risk/benefit balances and a relative confidence that there will be a positive, intended therapeutic outcome. In the context of therapeutic research, it is still to be determined what the therapeutic outcome will be, how good it will be, what the balance of risks and benefits will be. Therefore, the therapeutic research context requires a more stringent form of informed consent, with greater protections for you.
The interventions that take place at the GRTC are not passed to your children. Some genetic interventions are called somatic which involves interventions on genes in the body’s cells where needed – e.g. eye, blood. This does not affect germ cells that produce the eggs and sperm and so does not affect the patient’s children or descendants. If they did, they would be called germline interventions.
As your genetics is shared with your family members, so too is information that may arise regarding genetic abnormalities. However, confidentiality is a central principle in western medicine, and you have control over who will learn about such information. Genetic councilling is important in such situations so that you are helped to discuss and reflect, in a non-judgemental context, on what you should do.
