A New Interest in Autism Genomic Therapy Development

Several biopharmaceutical enterprises are starting to target autism spectrum disorder (ASD), with Roche being the latest with its balovaptan therapy. Unfortunately, Roche stopped developing that therapy from a Phase III study. However, that has not stopped other biopharmaceutical enterprises from pursuing a treatment in ASD. Genomic medicines company Sangamo Therapeutics and Novartis have recently announced a partnership focused on developing a genomic therapy for ASD. Sangamo executives, Melita Sun Jung, SVP and Head of Business Development, and Amy Pooler, PhD, VP and Head of Neuroscience, will discuss the future of genomic medicines for these types of targets.

MA: Why are biopharmaceutical companies interested in earlier developed treatments (i.e., Preclinical and Phase I data) rather than the common interest in moving towards collaborating at a later stage (i.e., Phase II or IIb data, moving into Phase III)?

Melita Sun Jung

MSJ: Since we have interacted with many biopharmaceutical enterprises in the industry, our experience suggests there is a certain type of balance you always want in your portfolio, and that includes advancing and having later-stage assets. However, it’s imperative to keep that innovative “scientific funnel” open and to generate new ideas to fill in that early-stage pipeline. I wouldn’t call this a new trend; in fact, we have seen a tremendous amount of deal and partnership activity around preclinical research stage deals even during this time of COVID-19.

MA: Why is there a target on ASD right now, and what are the benefits of targeting neurodevelopmental disorders using genomic therapies?

Amy Pooler

AP: Genomic medicine goes beyond the current approach of treating symptoms of neurological disorders, and it can target even these complex neurodevelopmental disorders at the DNA level. We believe that this approach can have a profound and meaningful impact.

It is early-stage research, and there is a clear need for more research to understand neurodevelopmental disorders better. What we do know, though, is that in some cases, there are mutations or deletions of specific genes that cause too little of the gene to be expressed. This can result in improper communication between brain cells and alterations of what we call “connectivity” in the brain. With zinc finger protein technology (ZFP), we aim to restore the expression of those genes to healthy levels specifically. What this means for patients and their families is the potential for a new genomic medicine designed to target their specific form of the disorder.

MA: It looks like some other pharma companies have gone into autism. I'm curious to know why you target ASD and why target that particular indication, and what potential challenges do you see in targeting that indication?

AP: I think that's the power of the genomic medicine platforms to intervene not at the symptomatic level, but to fundamentally change the disease at the DNA level. I can tell you a little bit more about the zinc finger protein transcription factor (ZFP-TF) platform that we're working with, as it can also help to understand how these specific types of diseases are a great fit for the technology that we have in house.

A key point about the zinc finger protein transcription factors is that they are essentially using specifically designed versions of what cells in our brain already make to regulate genes. We pair zinc finger proteins with transcription factor domains that are functional, enabling us to activate or up-regulate, or suppress or down-regulate expression of a gene. This is an approach that we're using to address an array of neurological diseases. We use the engineered ZFPs to act as a GPS to precisely guide that tethered functional domain to the gene of interest anywhere in the nuclear or mitochondrial genome, so it gives us a lot of flexibility. Gene regulation is different from genome editing approaches – it doesn't cut or modify the target DNA. What it's designed to do is enable precise and long-term repression or activation, following a single administration of the AV vector that encodes the ZFP. So far, we’ve seen some great potential with early preclinical results. For example, in our neurodegenerative programs, we can see specific, potent, and even tunable repression of genes. When I say tunable, I mean that the ZFPs can be designed to precisely modulate the level of expression to varying extents of the targeted genes. We had a beautiful paper last year in Nature Medicine from scientists at Sangamo, demonstrating the repression of the gene involved in Huntington’s disease. Because we’re able to have such a targeted approach, even for complex neurodevelopmental disorders, I think there’s a real opportunity to leverage the strengths of our platform for treatments of these disease.

MA: Could you tell me about the science behind what particular gene you are targeting for autism and how the mechanism of action is going to address that?

AP: There has been much work over the past couple of decades using genome-wide association studies to identify the genes that may be involved in autism. There have been some genes where specific mutations or deletions cause this deficiency or too little, of that gene to be expressed. By using ZFP technology, we can target those specific genes to restore their expression to a healthy level.

MA: Why did Novartis approach Sangamo for this collaboration?

MSJ: We had incredible amounts of inbound interest, so we were in the enviable position of being able to select our partners from a wide range of options. We believe ZFPs can offer several advantages for genetic medicines, as previously mentioned, and we are in a unique position to bring these strengths to bear for our partners, as well as for our programs. It’s a potent platform, and, from the interest, we’ve been receiving, there is a belief in the promise of our technology to address these challenging targets.

Novartis is an industry leader in neuroscience drug development and commercialization, and we are partnering with them because they not only have a deep understanding of the disorder biology, but they have much experience in neuro drug development. They’ve marketed genomic medicines, and they have the intellectual horsepower and the financial resources to take these candidates forward. So, this collaboration will expand our pipeline into therapeutic areas that we wouldn’t have otherwise been able to pursue. There is a great deal of excitement around accelerating the development of new therapeutic options in challenging neurodevelopmental conditions.

AP: Seeing the development of genomic medicine recently has me so excited for therapies that go beyond targeting symptoms and are targeting disorders at the DNA level. I am excited to see these new technologies accelerating towards the clinic, where I think they’ll make a profound impact on the course of ASD and the lives of patients.

Moe Alsumidaie, MBA, MSF, is a thought leader and expert in the application of business analytics toward clinical trials, and Editorial Advisory Board member for and regular contributor to Applied Clinical Trials.