The World Rare Diseases Day. The key role of IIMCB research in progressing patients’ care

Gaucher's disease, tuberous sclerosis, neurodegenerative diseases, hearing disorders, epilepsy, heart disease - February 28th is World Rare Disease Day. On this occasion, we would like to bring this subject and indicate the importance of research conducted in this area by scientists from the International Institute of Molecular and Cell Biology in Warsaw (MIBMiK), expressing our solidarity with patients and their families.

In the case of rare and ultra-rare diseases, treatment and correct diagnosis is a great challenge. With a relatively small number of patients, it is sometimes difficult to determine whether the symptoms are related to a specific disease entity or are due to other causes. Even in the case of diseases of known origin, many questions remain unanswered because it is difficult to pinpoint the points that allow an effective drug to be developed.

Animal models - crucial for understanding the development of the disease process

The use of animal models has contributed to overcoming such barriers. One of them is zebrafish (Danio rerio). In addition, this fish has set new trends in genetics and development, pharmacodynamics, toxicology, environmental control, behaviour, etc., offering new ways to find treatment for patients.

Examples of such activities include research conducted by the Laboratory of Neurodegeneration led by prof. dr hab. Jacek Kuźnicki. Using the CRISPR-Cas9 technology, scientists created zebrafish lines with mutations similar to those of the patients. These lines were used to create models for the study of childhood neurodegenerative diseases such as Niemann-Pick type C disease (NPC) (Wiweger et al. Front Cell Neurosci.2021) and mucopolysaccharidosis type III (MPS-III), also known as Sanfilippo syndrome. These models were developed by dr Małgorzata Korzeniowska and are characterized at the Neurodegeneration Laboratory. Fish with a mutation in the npc2 gene and fish with a damaged sgsh gene have similar symptoms patients have. Changes at the cellular and molecular levels also bear many similarities. As a result, they can be used to understand the complicated and complex processes that accompany the development of the disease. They also provide a chance to identify new markers whose diagnostic value can be checked in clinical trials. This activity aims to support patients and doctors in the field of new tools facilitating earlier diagnosis and more accurate monitoring of changes during the development of NPC and MPS-III. It is also essential to understand the multidimensionality of changes brought about by the diseases in question to indicate areas that have not been explored so far, which are worth paying attention to when planning therapy. Since NPC and MPS-III have a lot to do with Alzheimer's disease, the identified drug targets may find application in treating a wide range of common neurodegenerative disorders.

Another laboratory the IIMCB that is engaged in research on rare diseases is thethe Laboratory of Zebrafish Developmental Genomics, led by dr hab. Cecilia Winata, is concerned.  One of their main research focus is the elucidation of the gene regulatory network that underlies heart development and disease. We employ the zebrafish (Danio rerio) as a model organism in our research. The zebrafish heart exhibits remarkable similarities with the human heart in terms of basal heart rate, electrophysiological properties, as well as action potential shape and duration. Thus it is an ideal organism to model human clinical conditions affecting this organ. Our investigation focus on two distinct cell types of the heart: cardiomyocytes (CMs) and cardiac pacemaker cells, which are two of the most important cell types responsible for the heart’s contractile function. In our earlier study, we characterized the dynamics of the gene regulatory landscape during heart development by combining transcriptome profiling (RNA-seq) and an assay for chromatin accessibility (ATAC-seq) at several key stages of heart development. Our analyses revealed genetic regulatory hubs that drive crucial events of heart development (Pawlak et al., Genome Res, 2019). Additionally, we recently reported the transcriptome profile of pacemaker cells which revealed numerous genes enriched in this particular cell type, some of which possess human paralogs that are implicated in various forms of congenital heart diseases (Minhas et al., BMC Genomics, 2021; Abu Nahia et al., Cell. Mol. Life Sci., 2021). The discovery of genes and genetic regulatory hubs regulating multiple aspects of heart development represents a rich resource for identifying novel factors contributing to rare human diseases.

As an effort to pursue the study of rare diseases, we have recently initiated in-depth functional studies of candidate genes identified from various genetic screens. One of these initiatives focuses on med13b, a zebrafish paralog of the human gene encoding the mediator complex protein MED13L. Mutations in this gene are known to cause the MED13L haploinsufficiency syndrome. This is a rare condition, until now only about 70 cases world-wide have been reported, and is characterized by intellectual disability associated with characteristic facial features and severe language impairment, as well as congenital heart defects in some cases. Combining the power of zebrafish as a model organism with the available genomics toolbox including RNA-seq, ATAC-seq, and single-cell transcriptomics, we plan to determine the global effect of disturbing the expression and function of med13b on the development of the embryo. We hope to contribute to a better understanding of the pathological mechanisms underlying this rare disease.

The most important research directions – hope for patients and medical staff

One of the rare diseases intensively studied in the Laboratory Molecular and Cellular Neurobiology is Tuberous Sclerosis also known as Tuberous Sclerosis Complex (TSC) or Bourneville-Pringle disease. SG is caused by a mutation in the TSC1 or TSC2 genes. It is estimated that one in six thousand people are born with this mutation. The clinical picture of TSC varies greatly and it can present in different ways, even in people with the same mutation. The most common manifestations of SG include benign tumors of the brain (called cortical tubers and giant cell astrocytoma), skin, or kidneys. Approximately 90% of patients suffer from epilepsy, often drug-resistant, occurring very early in life. In addition, an important aspect of TSC are the so-called TANDs (TSC Associated Neuropsychiatric Disorders) including intellectual disability and autism spectrum disorders, which occur in varying severity and combination in a large proportion of patients. Treatment of TSC is largely symptomatic and often symptom oriented. Some of the most important directions for TSC research include basic research into the cellular mechanisms of TSC, the search for new drug targets as well as the identification of new biomarkers that would help physicians better predict at the earliest possible stages how TSC will develop in individual patients. All these directions are being pursued in the MIBMiK laboratory led by Prof. Jaworski. For example, in 2021, together with teams from across Europe, Prof. Jaworski's team demonstrated a new mechanism for positioning TSC proteins in the cell, crucial for understanding the disease process (Prentzell et al., 2021, Cell). In turn, a year earlier, Prof. Jaworski together with Dr. Justyna Zmorzyńska and Ms. Magdalena Kędra, identified, using a model of TSC in zebrafish, the TrkB protein as a potential new therapeutic target for neuropsychiatric symptoms of SG (Kedra et al., 2020, PNAS). In turn, projects funded by sources such as the EU Framework Programs (Epistop) or the National Center for Research and Development (Epimarker) performed in the Laboratory of Molecular and Cellular Neurobiology are focused on developing novel molecular biomarkers for epilepsy in SG patients. 

To sum up: there is a lot of research concerning rare diseases, conducted within various laboratories of IIMCB. Consequently we can indicate constant progress in the area of better understanding the reasons of the disease process, as well as the possibilities of using new medications, implementing experimental therapies and finally – the improvement of the patients’ quality of life.