Many genetic diseases lack a specific and effective treatment. We contributed to the development of several gene therapies. Many of these use the technique of replacing the defective gene by a functional copy (replacement therapy). The functional copy is transferred into target cells by lenti or adeno-associated viruses (AAV). The viruses are replication deficient and have been proven to be safe and efficient gene therapeutic tools.
As an alternative technique to treat genetic diseases, we developed methods to correct defective transcripts. The basic concept of these techniques is described in the following.
The vast majority of human genes are composed of coding (exons) and non-coding regions (introns). Gene transcription results in the pre-messenger RNA (pre-mRNA), which is subsequently modified by removal of the intronic regions, a complex process that is known as the splice process. Splicing produces the mature mRNAs transcripts which can be translated into proteins.
On average, about 20% of the patients show disease-causing mutations that lead to defects in the splicing of genes. This observation is largely independent from the affected disease gene. Thus, the pathogenic effect of many mutations in monogenetic diseases primarily alters the gene transcript (and only subsequently affects the protein composition).
We developed gene therapies to treat diseases that are caused by mutations affecting the splice process. We used splice factors (e.g. U-snRNAs) and designed them to correct the patient-specific splice defects. Splicing assays (using minigenes or patient-derived cell lines) were utilized to optimize the gene therapeutic approaches. We now continue to optimize these therapeutic strategies in vivo and hope that our findings will continue to contribute to better treatment options for diseases caused by splice defects.