Authors: Xiaona Lu, Ying Xie, Youmei Bao, Jiang Yu, Zefeng Wang, Jiali Fan, Wendy C. Sheu, Gretchen Long, Zewei Tu, Jie Tong, Garret Manquen, Yichao Li, Varun Katta, Ryan Chow, Binfan Chen, Zhouqi Meng, Ying-hong Ma, Caihong Qiu, Sidi Chen, Shengdar Q. Tsai, Bony De Kumar, Caroline E. Hendry, Yong-hui Jiang, Jiangbing Zhou
Yale University, St. Jude Children’s Research Hospital, Hospital of the University of Pennsylvania
Overview
A new platform for brain-wide genome editing called STEP-RNP has been developed as a potential treatment for Angelman syndrome.
When AS mice of all ages (newborn, juvenile or adult/adolescent) were treated with STEP-RNP, results showed significant improvements in performance on all neurobehavioral tasks including motor, coordination, seizures, and cognition.
STEP-RNP for Angelman syndrome represents a completely new potential treatment option: permanent gene editing without using a virus for delivery. This has the potential to restore UBE3A throughout the brain with a single treatment. While it’s still early, it offers real hope for a long-lasting approach that targets the root cause of Angelman syndrome, rather than just the symptoms. The technology has the potential transform brain delivery of genetic medicines, to not only help individuals with Angelman syndrome, but to be applied to many other neurogenetic disorders.
About the Study
A FAST-funded research team, Drs. Yong Hui Jiang and Jiangbing Zhou, are exploring a new way to turn on the silent paternal UBE3A gene using a technology called STEP-RNP, which has the potential to be more efficient than other delivery methods for genetic medicines. This approach works like a neuronal escort that carries gene-editing tools into brain cells, called neurons, and then is quickly eliminated after the edit occurs. It has an affinity for neurons and can move throughout the brain, get into neurons, and permanently edit the genome, after a single spinal-fluid–based injection, without relying on viruses or the need for frequent repeat treatments.
Angelman syndrome is a great genetic candidate to test this technology due to its eloquent genetics. In AS there is a healthy working copy of the UBE3A gene on the paternal allele (father’s copy); it’s just switched off. While the maternal allele (mother’s copy) is either missing, not working, or silenced. This STEP-RNP can “unsilence” the part of the genome that controls this paternal silencing, allowing that gene to turn back on. STEP-RNP was delivered as a one-time treatment to AS mice, and it was found to distribute across the brain and reactivate the Ube3a gene for months.
Newborn, juvenile and adult AS mice treated with the STEP-RNP all showed significant improvements in tests of motor coordination, memory, and cognitive function, when compared to untreated animals. In most assessments, AS mice treated with STEP-RNP performed similarly to wild-type mice. An examination of the brains of STEP-RNP treated mice showed that the treatment was distributed widely across the entire brain, and there were no observed off-target effects. In addition, the STEP-RNP delivery was found to leave the brain within 24 hours, showing the “hit-and-run” affect, limiting the chronic risk of editing seen with viral delivery. Human neurons and brain organoids derived from AS deletion patients, thanks to the previous fundings of the Yale lab, also showed strong reactivation of paternal UBE3A expression, supporting the method’s potential between species.
FAQ
How far away is a clinical trial for this approach?
This research is still in the preclinical stage, meaning it has only been tested in AS mouse models and in human cells grown in the lab, not in people. The research team has NIH funding support to run the next studies needed to evaluate whether this approach could be ready for clinical development.
Before a first-in-human trial can begin, researchers still need to complete additional animal studies, manufacturing scale-up, and regulatory review. Those steps take time and results can change the path, so it is too early to offer a timeline for a clinical trial just yet.
What does this mean for your loved one living with AS today?
This research does not change clinical care or available treatments today. It’s an encouraging step, but it still needs to be tested further and evaluated for long-term safety and benefit in people.
What it does add is another genetic, targeted option in the Angelman syndrome drug development pipeline: a potential brain-wide, one-time editing strategy designed to restore UBE3A by unsilencing the paternal copy of the gene. In this study, researchers reported meaningful improvements in an Angelman mouse model when the approach was tested at different stages of life, including adulthood. More broadly, it reinforces something important for families: several different gene-targeted strategies are being advanced in parallel, including ASOs, viral gene therapy, gene editing, and now non-viral editing platforms like STEP-RNPs. Having multiple paths moving forward at once increases the odds that one approach, or a combination of approaches, could eventually translate into real, meaningful improvements for people living with Angelman syndrome.
How This Fits FAST’s Funding Strategy
This project is part of our Pillar 2: Turn on Dad’s UBE3A, therapeutic programs that focus on activating the silent copy of the paternal UBE3A gene in the brain. What makes STEP-RNPs especially relevant to FAST’s strategy is that it tackles one of the field’s hardest problems: how to deliver a genetic therapy broadly across the brain.
This work was supported by FAST, NIH, and AS2Bio, combining nonprofit and federal funding with biotech development support. FAST’s role is to help de-risk early, high-impact approaches so the strongest ideas can move from proof-of-concept toward the development steps required before human testing is possible.
This is how FAST accelerates progress: by investing not only in scientific ideas, but in the delivery, tools, and translational work that determine whether an approach can keep moving forward.
Help Fund the Next Steps
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