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Dr. Barbara Bailus received the 2021 C.U.R.E.-AS Advisory in Excellence award at the FAST Forward Together Global Gala

Hello FAST Family and Friends,

What an amazing and inspiring year 2021 has been, concluding with a wonderful in-person Global Summit and Gala! The FAST Forward Together Global Summit and Gala was in Austin, Texas this year and it was a fantastic host city. I and a few others managed to snag some pretty amazing tacos, BBQ, and see dueling piano players while out on the town. It was wonderful seeing old friends and meeting new ones, many of who I had previously known just through Facebook, yes I spend too much time on this platform. I think everyone that attended both in person and virtually can agree the science was sensational and the future for AS is so hugely optimistic.

A couple of highlights: for the first year ever, FAST had to split the academic and university research and the industry updates into TWO days. This is amazing news. It means there is so much research and clinical trial work being done on AS that we couldn’t fit it all in one day. 

On day one, the academic research was presented and what really stood out to me was realizing how FAST is absolutely leading the way, not just for AS but for so many other neurodevelopmental disorders in general. FAST is asking and answering the type of questions that the whole neurological field is grappling with: what is the best way to deliver a gene therapy, where exactly does the therapy need to go, how much is enough, how much is too much, what about different genotypes, what about different ages, is there a critical window for therapeutics, how can we best predict a successful therapy using mouse and rat models.

We heard about progress being made in different ways to deliver the gene therapy from Drs. Jan Nolta and Joe Anderson, using a patient’s own modified blood cells a new version of the UBE3A gene could be shuttled into the brain and neurons could take up this UBE3A construct and use it where it is needed. This method, when used in the AS adult mouse model, showed full recovery of motor, balance, cognition and anxiety. The group at UC Davis is now taking this into IND-enabling studies, which means clinical trials are coming soon! Also, from UC Davis we received updates on the amazingly successful infrastructure project that enables ALL AS researchers to test potential treatments at a state-of the art rodent behavioral facility, helping speed the process toward clinical trials.

We heard updates from Jim Wilson’s team at UPenn on multiple gene therapy approaches, including miRNAs, CRISPR, a novel hUBE3A replacement and UBE3A cDNA, all using the state-of-the-art delivery methods in AAV, which have been successfully used in many gene therapies, including diseases like SMA.

Dr. Jiang provided an update on the progress for the first-ever bank of AS stem cells that includes numerous examples of EVERY genotype, including large deletion, small deletion, UPD, ICD, UBE3A gain of function, UBE3A loss of function and sibling controls, and how these lines will be globally available for sharing as soon as they are each produced, which has already resulted in numerous collaborations. This will transform our basic understanding of AS and hopefully help us to better tailor treatments for each genotype. These lines will then be transformed into brain organoids for more sophisticated drug screening.

We listened to Dr. Keung, who is making these organoids from the AS stem cells to create the most relevant human cell model possible to better understand AS and screen for future therapies and understand the differences between different genotypes, including ICD-Mosaic. The research being presented showcased amazing progress and robust collaborative efforts. The entire FAST scientific team is working together, out of their own silos, and supplying one another with materials and insights, making it possible to fast forward toward a cure, TOGETHER. 

On day two, we heard from industry about current ongoing, and future human clinical trials. Dr. David Segal gave the keynote address and highlighted just how far the field of gene therapy has come and how AS is right at the forefront of this field, far surpassing his expectations when he entered this space over a dozen years ago.

We heard about some of the Angelman Syndrome Biomarker and Outcome Measure (ABOM) initiatives, like the communication measure called the ORCA and the gait assessment called the Actimyo, that supported some of the endpoints being evaluated in a current Natural History Study that just launched out of the UK under the guidance of Dr. Laurent Servais. These measures are now being implemented in multiple clinical trials and other neurological disorders.

Dr. Emil Kakkis, from Ultragenyx Pharmaceuticals, updated us on the challenges and successes of clinical trials, using the GeneTx trial as an example. He explained very eloquently how participants showed some objective improvements, despite the severe adverse events seen, and how there is renewed hope for a potentially effective path forward with a new dosing regimen.

Drs. Stromatt and Berry-Kravis expanded upon the GeneTx trial, KIK-AS, and shared some impressive Vineland-3, Bayley-4, CGI-I-AS, ORCA, Actimyo and EEG Data in the first five patients enrolled. The data shows a trend toward improvement in activities of daily living, fine motor skills, gross motor skills, communication, and sleep, to name a few.

Roche provided an update on enrollment in their trial called TANGELO, an antisense oligonucleotide (STOP the STOP/reactive paternal UBE3A). They are now enrolling the younger cohorts. They did not share any clinical data at this point. Still, they did share there are some adverse events seen, including fever, vomiting, and some other ailments that seem to be short-lived.

Ionis gave a promising update on their HALOS trial, which is expected to start in early 2022. This is another ASO. This means that in 2022, there will be THREE ASO trials for AS! 

Another promising technology in the pipeline for 2022 is a small molecule drug from Neuren Pharmaceuticals that focuses on improving several of the symptoms of AS and has shown promise in a rodent model.

Taysha Gene Therapies also presented an update on their strategies for AS, including a dual isoform gene replacement approach and an shRNA paternal activation approach. They are advancing 2 programs in parallel!

The overall message was one of hope, determination, and possibilities. One that made me believe that 2022 is going to be an amazing year, as one of the speakers put it, “FAST is going to get the cure and then this event will be just a reunion meeting.” Better Days Are Coming, and 2022 is just the start. From the perspective of a scientist, I can attest that FAST has come so far and is an inspiration to the entire field of neurodevelopmental disorders. It is an honor to work with this community. The 2020s are finally the right decade to be a human with Angelman Syndrome because the transformative treatments are coming, and they are coming FAST. So, let’s get ready to change the tagline to #curedAngelman!

Barbara Bailus, Ph.D., FAST Scientific Advisory Board Chair