Rare diseases often present significant medical challenges for patients and their families: diagnosis is complex, and therapeutic options are limited or sometimes nonexistent. Modern precision medicine now offers the possibility to understand diseases at the genetic level and treat them in a targeted way. As part of the joint funding program zukunft.niedersachsen by the Lower Saxony Ministry of Science and Culture and the Volkswagen Foundation, nine particularly innovative research projects were selected. A total of around €13.5 million is available for these projects.
One of these projects is based at the Clinic for Cardiology and Pulmonology at the University Medical Center Göttingen (UMG). The project “CRISP-RAS: Testing of CRISPR-based gene therapies for RASopathies” is led by Dr. Lukas Cyganek, head of the Stem Cell Unit, and Dr. George Kensah. It is funded with €1,050,230 and focuses on children with a rare, genetically caused heart muscle disease.
From Symptom Management to Tackling the Root Cause
The Göttingen research focuses on Noonan syndrome, a congenital genetic developmental disorder that affects multiple organ systems. Typical features include characteristic facial traits, short stature, and congenital heart defects. The cause lies in genetic alterations in the RAS/MAPK signaling pathway, which plays a central role in cell growth and development. Particularly severe in some patients is hypertrophic cardiomyopathy, where the heart muscle—usually the left ventricle—is abnormally thickened. This impairs the filling and ejection of the heart and can lead to life-threatening complications in infancy and early childhood. So far, treatment options have been largely symptomatic—this is exactly where the Göttingen research takes a different approach with its gene therapy strategy.
“Children with Noonan syndrome and severe heart muscle disease currently have very limited treatment options. Our goal is to correct the genetic cause of the disease, not only to alleviate the symptoms but to halt—or even reverse—the disease process at its root,” says Dr. Cyganek.
The project focuses on correcting the disease-causing changes in the genome using CRISPR-based gene therapies. This technology acts like a molecular “gene scissors,” allowing defective sections of DNA in cells to be precisely altered or repaired.
To achieve this, cells are first collected from the blood or skin of affected children and reprogrammed in the laboratory into induced pluripotent stem cells (iPS cells). These cells have the unique ability to develop into nearly any cell type in the body. From these patient-derived cells, researchers first generate heart muscle cells and then grow small heart tissues in the lab that closely mimic the diseased heart.
These customized 3D heart models allow scientists to study the genetic defects and their effects on the heart muscle in detail and to test new gene therapies before they are eventually applied in patients.
Individually Tailored Therapies
The interdisciplinary team is testing different variants of this gene-editing technology to find the most effective therapy for each genetic cause of Noonan syndrome. Some approaches act directly on the genome, correcting faulty DNA building blocks, while others intervene one step further and selectively silence disease-causing gene signals.
In the long term, the goal is to develop a unique gene therapy that not only slows the heart muscle disease but ideally stops it permanently—or even reverses it.
A Perspective Beyond the Heart
“The strategies developed in this project are intended, in the long term, to be applied to other organ systems affected by Noonan syndrome. Furthermore, this approach could serve as a model for treating other rare genetic diseases,” says Dr. Cyganek.
The project is supported by a clinical-scientific translational committee at UMG, which guides the transition of successful laboratory results into individualized therapeutic trials for affected children.
Source: Press release Göttingen University Medical Centre
