SUMMARY:
An interdisciplinary group of UCLA researchers have developed and validated a library of compounds that alleviate symptoms of Rett Syndrome and hold enormous therapeutic potential for the long-term treatment of other intellectual disability syndromes.
BACKGROUND:
Intellectual disability (ID) affects more than 100 million people globally and imposes a heavy economic burden of $14.7 billion annually on families and health systems. IDs, including Rett syndrome, Down syndrome and fetal alcohol syndrome, are caused by mutations in epigenetic regulatory proteins. Recently the mutations have been implicated in causing the premature aging, or senescence, of neurons, the primary location of which are in the brain. However, drug development to treat such disorders has been significantly hindered by the difficulty in developing therapeutic compounds that are able to reach neurons in the brain. This is because of a tightly regulated cellular barrier that divides the vascular system from the central nervous system called the blood-brain barrier (BBB). Therefore, towards the development of curative drugs for IDs, crossing the blood-brain barrier (BBB) is of crucial importance. While the global market for ID therapeutics was $7.3 billion in 2013, currently prescribed drugs such as the antipsychotics risperidone and aripiprazole can only treat moderate behavioral symptoms. For most patients, treatment further necessitates speech, physical, behavioral, and occupational therapy in tandem with drug therapies. Therefore, an effective long-term or curative therapy that targets the root cause of ID, and efficiently crosses the BBB, is highly desired.
INNOVATION:
UCLA researchers led by Dr. William Lowry in the Department of Molecular, Cell, and Developmental Biology and Dr. Michael Jung in the Department of Chemistry and Biochemistry have together discovered a library of compounds with the potential to reverse neuronal senescence and treat ID. Focusing on Rett syndrome for their studies, they developed Rett-derived human organoid models that allow screening of senescence inhibitors in the context of ID. Using these models, they screened 45 molecules for senescence inhibition and identified 14 that successfully inhibited senescence, promoted dendritic branching, and restored brainwaves. Of those molecules, one novel compound was found to effectively penetrate the BBB in vivo in murine models. These results indicate that compounds that reverse neuronal senescence and penetrate the BBB could be effective for treating Rett syndrome. While other ID syndromes are caused by mutations in different epigenetic regulatory proteins, they all present with similar types of neuronal stress and similar neurological phenotypes. Therefore, the compounds identified here that reverse neuronal stress in models of Rett Syndrome could also alleviate ID syndrome symptoms in a wide variety of disorders. Additionally, the UCLA researchers provide a strategy to develop a high-throughput drug screening platform to assess ID therapies in human organoids.
POTENTIAL APPLICATIONS:
● Novel long-term therapy for ID
● Human organoid models can be utilized in high-throughput platforms to develop novel therapeutic strategies for ID and broader CNS diseases
● High therapeutic value of anti-senescence drugs towards treating age-related diseases such as Alzheimer’s or atherosclerosis
ADVANTAGES:
● Compounds directly target the root cause of ID by reversing senescence
● Compounds serve an untapped therapeutic market with no currently approved treatment
● Organoids are physiologically relevant in vitro models
DEVELOPMENT-TO-DATE:
Researchers have successfully identified a compound that successfully reverses neuronal senescence in vitro in human organoid models and penetrates the BBB in vivo in murine models.