The 17th Global Science Summit brought together over 1,000 in-person and virtual attendees from 55 countries around the world!
We were honored to have our translational research and pharmaceutical partners share their updates and insights to the community. In addition, we had an abundance of insightful educational talks for families and caregivers to better understand drug development, their role in supporting our mission, and how they can help get involved in the future.
You can watch all of the presentations on the FAST YouTube Channel!
Also, FAST’s Science Team has summarized highlights below. If you have questions after watching the recordings or reading below, please reach out to science@cureangelman.org!
Friday
Pillar 1 Highlights
Dr. Barb Bailus – Keck Graduate Institute
Focus: Developing cell-penetrating peptides (CPP), or “Backstage Passes,” to help deliver functional UBE3A across the blood-brain barrier.
2024 Milestones: Achieved successful delivery of functional UBE3A protein in mouse and human neuronal cells using a novel CPP approach.
Looking Ahead: Planning mouse behavioral rescue studies in 2025.
Chris Luthers – UCLA
Focus: Hematopoietic stem cell gene therapy using a lentiviral vector to enable UBE3A expression.
2024 Milestones: Demonstrated full behavioral rescue in the mouse model of Angelman syndrome including areas of learning, memory, motor skills, and EEG metrics.
Looking Ahead: Anticipating to initiate IND-enabling studies required to get to human clinical trials.
Dr. Nadav Ahituv – UCSF
Focus: Using CRISPR activation to target the non-UBE3A genes on the paternal allele which are missing on the maternal allele in individuals with large maternal deletions.
2024 Milestones: Developed a construct capable of upregulating five critical genes simultaneously.
Looking Ahead: Preparing to test the construct in both cell and animal models.
Pillar 2 Highlights
Dr. Dave Segal – University of California, Davis
Focus: Developing two innovative approaches to activate the paternal UBE3A gene:
CRISPR-based strategy (Cas13)
Artificial Transcription Factor (ATF)
2024 Milestones:
Demonstrated success with Cas13-based CRISPR in both mouse and human cells, along with behavioral rescue in an AS mouse model.
Validated the efficacy of a previously successful ATF approach delivered via AAV, showing promising results in mouse and human cells and behavioral improvements in an AS mouse model.
Looking Ahead: Preparing for head-to-head testing of these two therapeutic strategies to evaluate their efficacy and safety in animals to potentially define a human therapeutic candidate.
Drs. Jiangbing Zhou and Yong-hui Jiang - Yale University
Focus: Developing a gene editing platform using a novel innovative delivery platform, which is a non-viral approach for delivering a gene editor to the neurons of the brain for paternal unsilencing.
2024 Milestones: STEP-RNPs demonstrated over 90% UBE3A reactivation in human iPSC cells with a human candidate editor. In mouse brains, UBE3A reactivation reached up to 76% or neurons, accompanied by significant improvements in all phenotypes tested in the animal model including both motor and cognitive tasks.
Looking Ahead: Focused on completing dose range studies in mice and non-human primates for the studies required to get to human clinical trials. In addition, they are rigorously conducting comprehensive on/off-target assessments to ensure the safest constructs are advanced.
Pillar 3 Highlights
Dr. John Marshall - Brown University
Focus: This work focuses on two compounds, Syn3 and D-Syn3 that work to mitigate impaired brain derived neurotrophic factor (BDNF) signaling. BDNF signaling helps to regulate the communication between two neurons, along with something called synaptic plasticity. When this is impaired, as observed in an AS mouse model, learning and memory deficits are seen.
2024 Milestones: Use of D-Syn3 in a mouse model of AS was found to improve learning and memory and seizure susceptibility.
Looking Ahead: Next steps include evaluating blood brain barrier dynamics, looking at the effect of D-Syn3 on EEG, and analyzing toxicity as a part of a pre-IND enabling package for a potential future human clinical trial.
Pillar 4 Highlights
Dr. Xiaona Lu - Yale University
Focus: Developing AS patient-derived iPSC cell lines for screening potential therapeutics.
2024 Milestones: Nearing completion of depositing all patient-derived iPSC cell lines at EBiSC, a vendor that will make the cell lines available to all parties globally to advance AS therapeutic development.
Looking Ahead: The timing on the availability of these cell lines will be officially announced in 2025.
Saturday
Clinical Trial Highlights
Pillar 1: GTP-220
Speaker: Dr. James Wilson, CEO of Gemma Biotherapeutics, formerly at University of Pennsylvania (UPENN)
IND Enabling studies are complete and the data on the investigational gene therapy, GTP-220, supports continued development into a Phase 1/2 clinical trial.
Pillar 2: ETX201
Speaker: Dr. Sirika Pillay, Encoded Therapeutics
Vectorized miRNA approach to potentially treat Angelman syndrome by unsilencing the paternal UBE3A gene using a single treatment approach with AAV9 delivery.
Multiple data points support further development of ETX201 toward IND-enabling studies.
Pillar 2: Ionis: ION582
Speakers: Drs. Becky Crean and Lynne Bird
Phase 3 Trial Name: Reveal (Drug: ION582)
Ionis detailed information on their planned global, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of ION582 in approximately 200 male and female participants ages 2-50.
Genotypes: Deletion and Mutation
Pillar 2: Ultragenyx: GTX-102
Speaker: Dr. Kimberly Goodspeed
Phase 3 Trial Name: Aspire (Drug: GTX-102)
Ultragenyx detailed information on their planned global, randomized, double-blind, sham controlled, study evaluating the efficacy and safety of GTX-102 in approximately 120 male and female participants ages 4-17
Genotypes: Deletion
There will be an additional study in 2025 named “Aurora” to study other children who do not qualify for the Aspire study, such as those with non-deletion genotypes and those in age ranges outside of those in Phase 3 Aspire.
Pillar 2 & 3: Roche: Rugonersen (Pillar 2) and Alogabat (Pillar 3)
Speaker: Shady Sedhom & Dr. Joerg Hipp
Phase 1 / 2 Trial Name: TANGELO (Drug: rugonersen)
Study was completed Sept 2024
Data indicates that rugonersen was generally safe with preliminary evidence of changes on the Bayley scale of infant and toddler development (BSID) as well as changes seen on the EEG.
Currently the process of identifying a potential external partner to continue the development of rugonersen in AS is underway
Phase 2 Trial Name: Aldebaran (Drug: alogabat)
Phase 2a Proof of Mechanism recruitment is still open for children and adolescents with AS deletion genotype
Plan to recruit last patient by mid-2025
Pillar 3: Neuren: NNZ-2591
Speaker: Liza Squires
Phase 2 Trial Name: NNZ-2591
NNZ-2591 was safe and well tolerated, saw improvements in important aspects of AS, including communication, behavior, cognition, and motor abilities based on an Angelman specific CGI scale.
Have not announced plans for a Phase 3 trial at this time.