Current Pipeline

This is the current drug development pipeline for Angelman syndrome:

Each arrow is a different program.

Many of these programs have been, or still are, funded by FAST. But this chart also includes those that aren’t. At FAST, it’s our job to monitor all promising AS programs, and to ensure that the community has a birds-eye view on the entire landscape.

Now, let’s break all of this down.

“Gene therapy” typically refers to replacing the missing gene, UBE3A. This is often accomplished through “viral delivery” or a “viral vector” carrying the missing, or nonfunctional, gene (UBE3A). The UBE3A protein is an enzyme. So you can also replace the missing protein. This is called Enzyme replacement therapy (ERT).  For our purposes, “gene-targeted therapy” can mean either “gene replacement or gene editing” of the mother’s copy or “gene activation” of the father’s copy, which is why we organize our programs according to those broad categories.

Pillar 1 consists of therapeutic programs that focus on replacing the missing or non-functional UBE3A gene, or protein, in the brain of individuals living with Angelman syndrome. There are currently three kinds of strategies being used in this bucket, though different programs use them differently.

Learn more about each program below:

Pillar 2 consists of therapeutic programs that focus on “turning on dad’s gene” by activating the silent paternal (dad’s) copy of the UBE3A gene in neurons. There are currently four kinds of strategies being used in this bucket, though different programs use them differently.

Learn more about each program below:

Pillar 3 consists of therapeutic programs that focus on “downstream targets to treat symptoms” by addressing different molecular pathways and effector proteins impacted by the missing UBE3A protein. These drugs generally aim to improve the communication of neurons at the synapse. There are currently four kinds of strategies being used in this bucket, though different programs use them differently.

Learn more about each program below:

• Exogenous ketone supplements: Use of exogenous ketones to induce ketosis as a way to control seizures and improve cognitive behavior.

• GABAaɑ5 positive allosteric modulator: To restore deficient GABAergic signaling as a way to potentially improve seizures and/or cognition. This program is currently under investigation and in a clinical trial.

• IGF-1, 2 ligands (NNZ-2591): To regulate IGF-1 and 2 availability to correct some of the synaptopathy observed in individuals with AS allowing for improved neuronal communication. This program is currently under investigation and in a clinical trial.

• BDNF: To use a downstream target of UBE3A to regulate learning and memory deficits at the synapse.

There are currently at least 5 different drug candidates in the pipeline, 4 of which are FAST funded. 

Now, let’s look at that pipeline again.

This might seem like the least exciting part of the roadmap, but it’s vital--since it includes all of the work that has to happen around drug development, both before and after, to ensure that it moves safely and quickly. This Pillar encompasses a wide range of work, including:

• Creation of animal models and cell lines for each genotype. No potential therapeutic can be tested in humans without these!

• Angelman Syndrome Biomarker and Outcome Measure Consortium (ABOM) This consortium brings together hundreds of individuals invested in Angelman syndrome including pharmaceutical companies, clinicians, translational research teams, regulatory experts, and patient advocacy groups, in order to achieve advanced endpoints and biomarkers, which are required to accurately measure the effect of a drug has on patients in clinical trials. Learn more about ABOM here.

• Global Angelman Syndrome Registry (GASR). Learn more about GASR here.

• Natural History Study. Learn more about the Natural History Study here.

• Newborn Screening: Screening every baby in a known population will give us the true incidence rate of AS. This rate helps pharmaceutical companies estimate how many individuals could potentially benefit from treatments being developed. In addition, in the future, babies screened for AS at birth could be given these approved therapies immediately, potentially before symptom onset, which could profoundly impact the trajectory of their life, while also encouraging more companies to consider working hard on therapeutic options for AS.

And the jewel in our Pillar 4 crown:

• Rush Pediatric Neuroscience F.A.S.T. Center for Translational Research: Global headquarter for training individuals in how to run neurogenetic clinical trials and deliver innovative interventional therapies. Learn more about the center here. And read about it in the Wall Street Journal.