Developing a Broadly Applicable Therapeutic Strategy to Reverse Symptoms of Neurodevelopmental Disorders

Key Words: Neurodevelopmental disorders, Targeted therapy, FLT3 kinase inhibitors, MEF2C, SCN2A, Reversal of disease symptoms

One in six children in the US is afflicted by Neurodevelopmental disorders (NDD), such as Autism, Down syndrome, and cerebral palsy. In these NDD patients, genetic sequencing has discovered mutations in a number of NDD risk genes. Interestingly, it has been demonstrated in lab mice that using a gene therapy approach to replace mutant NDD risk genes can largely alleviate symptoms in adults, which suggests that the brain abnormalities in NDD caused by genetic mutations may be reversible even after disease onset. Although there is an ongoing effort to develop gene therapy clinical trials aiming to replace or correct mutations in NDD risk genes in patients to treat disease symptoms, such gene therapies cannot be applied to the majority of NDD patients who carry a broad range of mutations in one or multiple NDD risk genes. Moreover, currently there is no effective drug therapies to treat such devastating disorders.

In order to effectively treat a meaningful number of patients in a cost-effective way, my team and I are devising a new therapeutic strategy combining the benefits of both drug and gene therapies, which can be standardized and applied to a broad range of NDD patients. Our group recently made a surprising discovery that a number of drugs originally developed for treating non-brain diseases such as leukemia could be repurposed into broadly applicable NDD therapeutics. Applying candidate drugs to human brain cells and mouse models of Rett syndrome, a severe form of NDD, corrected abnormalities in gene expression and reduced epileptic seizure that is commonly associated with many subtypes of NDD, suggesting these drugs’ exciting therapeutic potential.

We plan to further examine how our candidate drugs, originally designed to treat non-brain diseases, exert therapeutic benefits on brain cells. We will also test whether our candidate drugs can alleviate symptoms in a number of preclinical NDD models carrying different risk gene mutations. Our vision is to develop broadly applicable therapeutics that relieve NDD symptoms regardless of the complexity or uncertainty of the causes, similar to the way a pair of eyeglasses can improve vision in many myopia patients.