Penn partnership FAQs

What just happened? What does it mean exactly?

We announced that FAST entered into an agreement with the University of Pennsylvania to develop an investigational adeno-associated virus (AAV) gene therapy for Angelman syndrome (AS). 

Let’s zoom out to explain what this means, and how we got here. 

At FAST, we separate the therapeutic approaches that we support by strategy, or pillars. 

Pillar 1 consists of therapeutic programs that focus on replacing the missing or non-functional UBE3A gene in neurons of individuals living with Angelman syndrome, or “fixing the maternal copy.” One of the programs in that pillar of our pipeline—an investigational adeno-associated virus (AAV) gene therapy for Angelman syndrome—just took a major leap forward. The data now supports the advancement of a human clinical candidate through investigational new drug application (IND)-enabling studies—the last step before hopefully moving into human clinical trials.

The gene therapy program involves delivering a healthy copy of the missing or non-functional UBE3A gene directly into brain cells, called neurons. This allows neurons to make UBE3A protein that is either missing or not functioning properly. Different ways that gene therapies might be delivered  include: an injection into the cerebral spinal fluid (CSF) (e.g., either down in the lower back, via lumbar puncture or up at the base of the skull [ICM or “intra cisterna magna”]; into the fluid deep in the brain called the ventricle [“intraventricular” or ICV]); directly into the tissue of the brain (“intraparenchymal”); or, through a vein (intravenous). Viruses generally don’t cross the blood vessels that surround the brain (blood-brain barrier) very well, so it is necessary to administer this gene therapy directly to the brain or spinal fluid to get to neurons. 

At FAST, we talk a lot about the Valley of Death— the chasm between when a treatment is discovered, which often happens in a university lab, and getting it into the bodies of humans, which is primarily the purview of biotech or pharmaceutical companies. Innumerable treatments, including promising ones, don’t make it over that canyon, for a number of reasons. These can include the drug not being safe or effective, but also issues that have nothing to do with science—like lack of funding or deprioritization because the program isn’t critical for the company. Sometimes companies “kill” a program because they need to cut costs or don’t have the resources to see it through.

This program is promising based on early animal studies, so much so that we want to do everything we can to protect it as it moves across that valley. 

How much is FAST investing here, and in what way? 

FAST is committed to invest approximately $14m based on milestone achievements to advance this gene therapy program through the development and regulatory steps needed to allow it to move forward into a first-in-human clinical trial.

Haven’t we been hearing about a UPenn program for years? What’s new now?

What’s new is that all those years of hard work are finally paying off. 

Starting in 2017, FAST began funding Dr. Jim Wilson to develop a gene therapy for Angelman syndrome. He is a pioneer in the field, and we specifically sought him out to leverage his incredible expertise and knowledge with this platform to work on Angelman syndrome. You can actually watch this specific program develop over the years, via Jim’s talks at our Summit:

2017 | 2018 | 2019 | 2020 | 2021 | 2022

Drug research and development is time-consuming, intricate work. In this case, to begin with, numerous variations of the gene therapy were screened and tested. After a candidate was chosen, it then had to be tested in the AS mouse model for effects, followed by thorough testing in larger animals to assess for any  early signs of toxicity. 

What happened this year is that Dr. Wilson and his team finally settled on a human candidate, the term for a compound for evaluation in humans, that they feel confident about. 

What was seen in the lab now that generated this “go” decision?

In the years since we first started funding this program, a tremendous amount of discovery and pre-clinical research evaluating all different variations on a UBE3A construct was undertaken to find the one that showed positive effects in animal models of Angelman syndrome, while also showing early safety, tolerability and biodistribution throughout the brain of larger animal models. 

 Biodistribution is about seeing which locations throughout the brain are actually receiving the gene therapy and how much is there. This recent biodistribution data was important because it showed evidence of “cross-correction”— which means that it was expressing the UBE3A gene from one cell and positively impacting multiple neighboring cells. This phenomenon is incredibly exciting for AS, as it means that this AAV gene therapy construct could conceivably provide improved biodistribution of UBE3A throughout the brain in cells that get the gene therapy and cells that are neighbors. 

After diligence and care, the team at UPenn and the Scientific Advisory Board at FAST declared the decision on advancing this human candidate a “go.” This next stage of “IND-enabling studies” is required to bring this to a potential first in human clinical trial. 

Can you explain a bit more about “cross correction,” and why it was so exciting here? 

Cross correction is when one cell that receives the gene therapy by AAV makes the UBE3A protein, but this same UBE3A protein made by the gene therapy is also detected in neighboring cells that do not have the virus in it. The UBE3A protein is spreading around to other cells, multiplying its effect. This is an incredibly exciting finding, and strengthened the argument for moving forward. 

We need to get the UBE3A gene to as many neurons as possible. But the amount of virus that can be delivered to the brain will limit the number of neurons that are “transduced,” or which receive the virus carrying the UBE3A gene. If enough cells don’t get access to this copy of UBE3A, it can limit the effect since only a small fraction of the brain is impacted. Since gene therapy is generally considered a single-treatment therapy, or “one and done,” this presents a particular challenge because at present you cannot get another dose to make sure more parts of the brain are transduced.  

Isn’t there talk about gene therapy’s toxicity risks?

This is something that will continue to be carefully assessed in the IND-enabling studies. The early screening for toxicity has already been completed and has shown promising results, which were actually presented to the community last year (see here), and which allowed the program to keep moving forward. 

How is this different from the PTC gene therapy program that was canceled this year, or the work being done at Taysha Gene Therapies and other companies? 

They are each different gene therapy constructs and are using different forms of the UBE3A gene, along with different types of AAV vector for delivery, so we would consider each one to be a different drug.

Over the few months, two gene targeted AS programs were shelved or canceled, and over the past two years, 10 other programs were deprioritized due to tumultuous financial times. Is this the right market environment to be advancing a new pathway?

FAST focuses on great science, promising results, and the potential for a safe and effective path forward for all therapeutic platforms that could positively impact the lives of our loved ones living with AS. We understand that most pharmaceutical companies will never be as passionate about finding these solutions for AS as we are. We live with the reality of this disorder every single day. Our fears are bigger than this or that turn of the stock market. 

The program at Penn has been a robust scientific effort going back to 2017, and the recent data were strong enough to move forward towards a future clinical trial. That’s what we needed to know in order to make the decision to advance it and work hard, together with the team at Penn, to shepherd the program into a first-in-human clinical trial after regulatory review. We do not want to see any program shelved unless the science says it should be. And luckily, FAST is now surrounded by highly experienced advisors and experts, all dedicated to finding potentially transformative treatments for Angelman syndrome. That is, and will always be, our north star. 

What’s next for this to get into clinical trials, and how long will it take? 

Every gene therapy program is different. The next steps here are the ones that will define if and how a clinical trial can proceed. This is where we do all of the studies that the regulatory agency needs to see to give a green light for a clinical trial. We are going to begin these IND-enabling studies and we are optimistic and hopeful that these studies will support a gene therapy clinical trial for Angelman syndrome.