Maria I. Olivero-Acosta, PhD 

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Investigator Bio: 

Dr. Maria Olivero-Acosta is a Postdoctoral Fellow in the laboratory of Dr. Xianjun Dong in the Department of Neurology at Yale School of Medicine. She is a recipient of the prestigious J. William Fulbright Award, which supported her PhD training in medicinal chemistry and molecular pharmacology from Purdue University. Her postdoctoral research focuses on the application of human-induced pluripotent stem cell (hiPSC)-derived neuronal models to investigate the mechanisms underlying neurodegenerative diseases. Her research utilizes stem cell-based modeling of Parkinson’s disease (PD) and focuses on the modulation of pathogenic circular RNAs (circRNA) using antisense oligonucleotides and adeno-associated virus (AAV)-mediated delivery of circRNA. Her long-term goal is to develop precision therapies for neurological disorders, leveraging patient-derived models to drive personalized medicine. 

Objectives/Background:

We are studying little-known types of RNA called circular RNAs (circRNAs), which are highly stable and form a closed loop that may play an unrecognized role in PD. These RNAs are abundant in the brain and help regulate nerve cell growth and communication. We have found more than 11,000 types of circRNAs in dopamine neurons, the primary cells affected in PD. Some of these circRNAs are consistently higher in people with PD and in those with early signs of the disease. This project will study the pathological roles of these circRNAs and test whether targeting them with a type of genetic therapy called antisense oligonucleotides (ASOs) can slow or reverse neurodegeneration in lab-grown 3D brain models (organoids) made from human brain cells with a genetic form of PD that causes protein buildup of alpha-synuclein. We will grow these brain models, track changes in the circRNAs over time, and test ASOs for their ability to protect brain cells. 

Methods/Design:

This study uses miniature midbrain structures grown from human stem cells in the lab, confocal microscopy, biological assays, and ASO interventions to explore the role of circRNAs in a PD model, caused by extra copies of the SNCA gene. We will compare healthy brain models with those carrying the SNCA change. At different growth stages, we will track eight specific circRNAs linked to PD. We will test whether lowering these RNAs early improves brain cell health. We will also check the effects over time, focusing on whether lowering these RNAs improves nerve cell function, reduces cell death, and decreases protein buildup. 

Relevance to Diagnosis/Treatment of Parkinson’s Disease:

This study investigates genetic therapy approaches that reduce harmful RNAs found at higher levels in PD. By lowering these RNAs in human brain models, we aim to help brain cells work better and slow damage. This work establishes a new framework for exploring circRNA-based mechanisms and lays the foundation for future personalized therapies.