Multifaceted preclinical studies for the treatment of Batten Disease

Batten Disease is a group of rare childhood disorders consisting of mutations in one of many related genes, which produce similar hallmarks of disease that greatly affect the development and function of the central nervous system.  Our lab has set up strategies to rapidly screen a variety of therapeutics aimed at alleviating disease burden pertaining to these disorders. RNA modulating compounds, stem cell therapies, gene therapies, repurposed pharmaceuticals, small molecule therapies, and natural compounds are all areas the lab is currently investing efforts in.

Antisense Oligonucleotides (ASO’s), a form of RNA modulating compounds, have shown promise for many diseases, including those relating to the CNS.  In collaboration with a leading ASO investigator from Rosalind Franklin University, Michelle Hastings, we have designed ASO’s for treating mutations in CLN1, CLN2, CLN3, and CLN6.  These compounds are designed to “skip” certain parts of the gene which are not functioning properly, in order to restore function to the remaining portion.

Stem cells have the potential to treat a wide range of diseases. Among the different types of stem cells, a particular subset of adult stem cells, named Mesenchymal stem cells (MSCs), has emerged as the most investigated stem cell to date. MSCs can be isolated from virtually any adult tissue, and pre-clinical data strongly supports their safety. In addition, MSC transplantation can be done without adverse immune response. There have been 540+ clinical trials ongoing or registered involving the use of MSC according to clinicaltrials.gov. Previous studies have shown robust glial activation throughout the CNS in Batten disease thus we are exploring MSC as a potential treatment for neuroinflammation.

Gene therapies have progressed quite well in the past decade, including numerous clinical trials. Many factors limit their utility in the CNS, but recent advances in delivery have avoided such pitfalls.  Gene therapies have the ability to reintroduce a functional gene in cases which the patient does not have one.  With a close collaboration with the Brian Kaspar’s lab from Nationwide Children’s Hospital, we are designing and performing preclinical testing to reintroduce a functional gene via adeno-associated viruses for several different forms Batten Disease.

High content screening and high throughput screening are methods to rapidly screening small molecules, repurposed pharmaceuticals, and natural products while monitoring multiple readouts.  This process is initiated by testing these compounds on cell lines of patients, including iPSC, with known gene mutations and monitoring disease at a cellular level.  Therapeutics which show promise in alleviating the disease can then be progressed efficiently into preclinical trials using mouse models of disease.