UCLA researchers in the Department of Molecular and Cell & Developmental Biology have developed novel therapeutic strategy to treat intellectual disability disorders discovered via a screening platform for drug discovery in a human model of brain development. BACKGROUND: Rett syndrome is an X-linked genetic neurological disease associated with loss of function mutations in the gene MECP2, which was originally identified as encoding a methylated DNA binding protein. Rett syndrome strikes all racial and ethnic groups predominantly in females, and occurs worldwide in 1 of every 10,000 births. Currently, there is no drug approved for Rett syndrome, and the disease symptoms (i.e. breathing disorder, seizure) are often managed by off-label drugs. There is an unmet need for developing treatments for Rett syndrome and other intellectual disability disorders, such as KAT6A syndrome.
INNOVATION: UCLA researchers led by Professor William Lowry have developed a state of the art screening platform for drug discovery in a human model of brain development and have identified novel therapeutics to treat intellectual disability disorders. Based on a previously described in vitro human model system derived from iPSCs (UCLA Ref: 2017-432-1), the researchers further developed a model system generated from brain organoids, or mini-brain-like structures that represent the human fetal brain at early-mid gestational ages. The researchers found that loss of MECP2, as commonly found in Rett patients, resulted in a nearly complete loss of inhibitory neuron function, P53 induction and senescence initiation, leading to loss of appropriate neuronal network activity and induction of aberrant synchronized spikes that are reminiscent of epileptic activity observed in Rett patients. Using the drug-screening platform based on brain organoids, the researchers identified a potent inhibitor of senescence that restored normal inhibitory neuron function. They further modified the compound to increase activity and blood-brain barrier (BBB) permeability as well as decrease toxicity. These inventions provide not only a potential clinical path for Rett Syndrome and other intellectual disability syndromes that show similar etiology (KAT6A syndrome, among potentially many others), but also provide a screening platform for drug discovery in a human model of brain development.
POTENTIAL APPLICATIONS: • Novel treatment for Rett syndrome and other intellectual disability disorders • State-of-art screening platform for drug discovery in a human model of brain development
ADVANTAGES: • Compounds were synthesized with increased activity, low toxicity, and BBB permeability • Novel drug-screening platform that recapitulates the human brain development as well as disease phenotypes associated with intellectual disability disorders
DEVELOPMENT-TO-DATE: This invention has been developed and tested in brain organoids.
Related Papers (from the inventors only) Ohashi M, Korsakova E, Allen D, et al. Loss of MECP2 Leads to Activation of P53 and Neuronal Senescence. Stem Cell Reports. 2018;10(5):1453–1463. doi:10.1016/j.stemcr.2018.04.001
Category Keywords: Medical > Therapeutics Medical > Disease > Central Nervous System Medical > Disease > Genetic Diseases and Dysmorphic Syndromes Life Sciences > Therapeutics & Vaccines > Genetic disease
Technology-related keywords: Rett syndrome, MECP2, P53, iPSC, drug screening, brain organoid, intellectual disability disorders, drug discovery, autism, x chromosome-linked genetic disorder, genetic disease