Advances in neurological research highlight breakthrough therapies

Q. How will advanced methodologies like screening and sophisticated models benefit patients in India and around the world who suffer from neurological disorders?

Response: Advanced methodologies like high-throughput screening and sophisticated models, such as human iPSC-derived organoids, fast-track the process of identification and validation of potential therapeutic compounds which is otherwise is slow and cumbersome. In addition, they also allow precise targeting of disease mechanisms, reducing the overall cost associated with drug development which means faster access to effective treatments for neurological disorders to patients not only in India but worldwide. This approach also shakes hand with the personalised medicine approaches, tailoring treatments to individual genetic and epigenetic profiles, that promotes better patient outcomes and improved quality of life. Besides that, advanced in silico models coupled with AI and machine learning (ML) will be of great start in predicting how neurological disorders develop and respond to treatment and also help in identifying the most promising therapeutic approaches before even moving to expensive and time-consuming clinical trials.

Q. How does this research by BITS Pilani identify new therapeutic targets in epigenetics and set the stage for further studies exploring ESI1’s potential in other neurodegenerative diseases?

Response: This work brings HDAC3 as the forerunner by being a crucial epigenetic regulator of myelination, and a novel therapeutic target for treating demyelinating diseases. By demonstrating that inhibition of HDAC3 with ESI1 promotes CNS myelin regeneration, we are moving toward new avenues for investigating epigenetic therapies. This sets the stage for further studies exploring ESI1’s potential in other neurodegenerative diseases, such as Alzheimer’s and ALS, where similar epigenetic mechanisms may be involved. Further research can build on these findings to develop targeted epigenetic treatments, potentially transforming the therapeutic landscape for these conditions.

Q. How did the research discover ESI1 (PT3), a small molecule inhibitor that promotes CNS myelin regeneration, crucial for treating MS and Alzheimer’s?

Response: The discovery of ESI1 (PT3) involved a high-throughput screening process to identify small molecules that inhibit HDAC3 that plays role in epigenetic regulation of myelin formation. It was not only a small molecule with selective HDAC3 inhibition but also the druggable characteristic of the small molecule was very crucial. We tested a number of compounds for their ability to modulate epigenetic markers and enhance the process of myelination. ESI1 emerged as the most promising lead to inhibit HDAC3 strongly and has shown convincing effects in preclinical models. Through rigorous in vitro and in vivo testing, including the use of transgenic reporter mice and human iPSC-derived organoids, we validated ESI1’s efficacy in promoting CNS myelin regeneration. This process highlighted ESI1’s potential as a therapeutic agent for treating demyelinating diseases.

Q. How does ESI1 show promise in enhancing myelin production and reversing cognitive decline in animal models and human organoids?

Response: ESI1 inhibits HDAC3 which leads to a reduction in repressive chromatin markers and promotes active chromatin state conducive to myelination. In animal models, this leads to an increased myelin sheath formation thereby improving neurological function. In aged mice, ESI1 treatment also reversed cognitive decline, indicating its potential to restore cognitive abilities affected by demyelination. Additionally, in human iPSC-derived organoids, ESI1 significantly boosted myelin production, further validating its therapeutic potential. These findings suggest that ESI1 can effectively promote myelin regeneration and improve cognitive outcomes, making it a promising candidate for treating demyelinating and neurodegenerative diseases.

Q. How did the students from different universities contribute to this research?

Response: Students from different universities of all the collaborator were the crucial helping hands in this project and were involved in multiple aspects, including:

• Collection of data from different designed experiments followed by analysis: Students are very crucial in collecting experimental data, performing statistical analyses, and interpreting the results, ensuring rigorous and accurate outcomes in discussion with their faculty mentors.
• Experimental design: They participated in designing experiments, optimising protocols, and troubleshooting technical issues, which was crucial for refining the research methodologies.
• Laboratory work: Students conducted various laboratory procedures, such as cell culture, molecular biology techniques, and histological analyses, contributing to the overall progress of the project.
• Manuscript draft: They performed extensive literature reviews to support the research framework, and provide context for our findings. They were also involved in drafting and editing the manuscript, preparing figures and tables, and ensuring the final publication met high scientific standards. Overall, they are the main workforce for this outcome. These contributions were invaluable in fostering a collaborative and innovative research environment that enabled the successful completion of the project.

Q. What role did global institutions like Cincinnati Children’s Hospital and Harvard Medical School play in validating the research’s international significance and credibility?

Response: We were fortunate to have a team of experts playing crucial role at every step in this research. Dr. Ghosh’s Epigenetic Research Lab at BITS-Pilani, Hyderabad campus have discovered the lead therapeutic molecule ESI1 (originally developed as PT3) that can potentially go to brain to do job. Dr Q. Richard Lu is our key contact for all the resources who along with Dr Liu monitored the experimental designs and data interpretation and supervised the whole project. Both of them and Dr Michael P. Jankowski are from Cincinnati Children’s Hospital who also have greatly helped in studies concerning the animal models. Dr Dutta from Cleveland Clinic, Dr Turner from University of Melbourne. Klaus-Armin Nave from the Max Planck Institute contributed knowledge in neurogenetics and multi-omics methods. F.M. Kirby from Harvard Medical School, USA and other scientists collaborated on this paper with their diverse expertise and resources, enabling comprehensive research and robust findings neurobiology and epigenetics.