Novartis has agreed to license Sangamo Therapeutics’ zinc finger protein transcription factors (ZFP-TFs) to develop gene regulation therapies for neurodevelopmental disorders that include autism spectrum disorder and intellectual disability, the companies said, through a collaboration that could generate more than $795 million for Sangamo.

Through Sangamo’s ZFP-TFs, the companies plan over three years to develop treatments addressing three target genes associated with neurodevelopmental disorders, by upregulating the expression of key genes that are inadequately expressed in individuals with certain neurodevelopmental disorders.

“The goal is to create new gene regulation therapies that act at the genomic level, moving us beyond the symptom focused treatments of today and toward therapies that can address some of the most challenging neurodevelopmental disorders,” Jay Bradner, president of the Novartis Institutes for BioMedical Research, said in a statement. “This collaboration with Sangamo is part of our commitment to pioneering the next generation of neurodevelopmental treatments.

Sangamo’s ZFP-TF genome regulation technology, now delivered via adeno-associated viruses (AAVs), is designed to selectively repress or activate the expression of specific genes to achieve a desired therapeutic effect, at the DNA level.

While AAVs have many advantages that make them well-suited for gene therapy, Novartis says, they also have one disadvantage: They can’t carry large genes. The collaboration is designed to enable the companies to target diseases caused by mutations in one copy of a large gene.

“The gene for a ZFP-TF is small enough to fit inside an AAV,” Ricardo Dolmetsch, head of neuroscience at the Novartis Institutes for BioMedical Research, explained in a post on the company’s blog. “We can use it to increase the production of a large gene in someone who still has one intact copy of the gene. This dramatically expands the range of diseases that we can potentially target with gene therapy because many diseases are caused by the loss of a single copy of a gene.”

Each of Sangamo’s ZFP-TFs is engineered to bind to a target region of genomic DNA in a highly specific and selective manner. They can be designed to precisely modulate the expression of targeted genes to varying extents. After identifying its target, the ZFP-TF recruits other proteins that help switch genes on or off.

“The zinc finger nuclease technology is remarkable,” Macrae told GEN in January. “It’s one of the commonest transcripts in the body. It’s natural and human, and it’s very, very adaptable. The individual units are modular, so one is always able to come up with a solution for any part of the genome.”

“Hundreds” of potential targets

For its part, Sangamo reasons that it can engineer zinc finger proteins to address virtually any genomic target.

“We are building a broad pipeline of wholly owned and partnered programs with the goal to bring our genomic medicines to patients,” stated Sangamo CEO Sandy Macrae. “In the case of the central nervous system, there are potentially hundreds of neurological disease gene targets that may be addressable by our zinc finger platform.”

For Sangamo, the collaboration with Novartis is the second signed this year that focuses on applying ZFP-TFs toward treating neurological disorders. In February, Sangamo launched a potentially more than $2.7 billion partnership to develop and commercialize Sangamo gene regulation therapies. The collaboration included ST-501 for tauopathies including Alzheimer’s disease, ST-502 for synucleinopathies including Parkinson’s disease, a third treatment targeting an undisclosed neuromuscular disease target, and additional treatments for up to nine additional undisclosed neurological disease targets over five years.

In its latest partnership with Novartis, the Swiss pharma giant will have exclusive rights to ZFP-TFs targeting the genes, which are undisclosed, during the three-year collaboration period.

Novartis also has the option to license Sangamo’s AAVs. Sangamo has agreed to oversee specified research and associated manufacturing activities, all of which will be funded by Novartis—while Novartis agreed to oversee additional research activities, investigational new drug-enabling studies, clinical development, related regulatory interactions, manufacturing, and global commercialization.

Novartis agreed to pay Sangamo a $75 million upfront “license fee” within 30 days, plus up to $720 million tied to achieving development and commercial milestones—consisting of up to $420 million in development milestones and up to $300 million in commercial milestones.

Sangamo is also eligible to receive from Novartis tiered high single-digit to sub-teen double-digit royalties on potential net commercial sales of products arising from the collaboration.

“Partnering Sangamo’s proprietary technology with Novartis’ deep experience in neuroscience drug development is a powerful combination which expands Sangamo’s pipeline and allows us to tackle challenging neurodevelopmental conditions,” Macrae added.

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