Prof. Krzysztof Sobczak is the head of Laboratory of Gene Therapy (LGT), which is a part of Institute of Molecular Biology and Biotechnology at the Faculty of Biology of Adam Mickiewicz University in Poznań. Previously, he worked at the Institute of Bioorganic Chemistry Polish Academy of Sciences in Poznań, and gained his post-doctoral experience at the University of Rochester in Charles Thornton’s lab, one of the pioneers in the field of the role of toxic RNAs in neurodegenerative disorders. Now, this subject is also investigated in Prof. Sobczak’s lab, who works on the molecular basis of fragile X-associated tremor/ataxia syndrome (FXTAS) and myotonic dystrophy (DM) and develop therapeutic strategies targeting toxic RNAs, using RNA interference tools, antisense oligonucleotides or small compounds.

Part of the team works on the gene therapy, based on the introduction to the organism different types of nucleic acids, which will either compensate insufficiency of mutated genes or correct the impaired metabolism of mutated gene products. In the case of genetic disorders which are caused by gene mutation leading to the deficiency of protein encoded by this gene, its functional version can be obtained in vitro in laboratory and administered to patients in order to alleviate disease syndromes. Another approach, widely investigated in Prof. Sobczak’s lab, is the supply of small nucleic acids or their chemical analogs in order to correct the pathological effects of mutated genes. One example is the use of antisense oligonucleotides; short chemically modified nucleic acids, which are delivered to cells and can mitigate the toxic effect of defective gene. This approach is used mainly in the monogenic, dominant genetic disorders, where one mutated copy of specific gene causes the disease, i.e. in Huntington’s disease which was investigated in LGT in the past. Now, prof. Sobczak moved his scientific interest towards other neurodegenerative diseases which are caused by the expansions of trinucleotide repeats, such as myotonic dystrophies (DM) and fragile X-associated syndromes (FXS and FXTAS). The recent promising results on FXTAS gene therapy, performed in collaboration with international partners, are currently under review and hopefully will shortly be published in Nature Communications journal.

Mutations causing DM, FXS and FXTAS are located in untranslated regions of the genes (regions which not code the protein), which used to be very challenging to investigate. One of the first reports of this phenomenon was authored by prof. Thornton, with whom prof. Sobczak worked during his post-doc in US. Even though mutated, toxic RNAs are not translated into proteins, they have very strong negative effect on the cell life. For example, in DM, toxic RNA sequestrates nuclear proteins which play crucial role in RNA biology. In result, instead of being available for various biological processes, these proteins form small aggregates with RNA in nucleoplasm. Several molecules of toxic RNA can bind up to thousands of proteins, thus impairing their biological function. Prof. Sobczak’s team try to find the cure for this pathogenic effect in both DM and FXTAS.

The results of more recent researches funded by EU grant, performed in collaboration with colleagues from University of Magdeburg, are very promising. To date, only small number of the experimental gene therapies could be applied to central nervous system. In our work, we administered short antisense oligonucleotides to the cerebrospinal fluid (CSF) of the FXTAS mouse model. FXTAS is progressive neurological disorder, characterized by neuromuscular symptoms such as ataxia and tremors, but also cognitive decline, which is result of impaired function of neurons and other brain cells. In gene therapy approach, developed by prof. Sobczak’s team, the antisense oligonucleotides were administered to mouse brain and subsequently entered neuronal cells in quantities sufficient to bind toxic RNAs, inducing therapeutic effect. After few months from the beginning of gene therapy, the classical symptoms of FXTAS were no longer observed in treated animals, giving hope to cure neurodegenerative diseases which so far are considered as incurable.