Roche and Neurocrine Biosciences (NASDAQ: NBIX) are co-developing an AAV-based gene therapy delivering full-length [SCN1A](/entities/scn1a) for [Dravet syndrome](/diseases/dravet-syndrome). This program represents a direct gene replacement approach — as opposed to the ASO (STK-001) or CRISPRa (ETX101) strategies employed by Stoke and Encoded — and is currently in IND-enabling studies.
Partnership Background
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Executive Summary
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Roche and Neurocrine Biosciences (NASDAQ: NBIX) are co-developing an AAV-based gene therapy delivering full-length [SCN1A](/entities/scn1a) for [Dravet syndrome](/diseases/dravet-syndrome). This program represents a direct gene replacement approach — as opposed to the ASO (STK-001) or CRISPRa (ETX101) strategies employed by Stoke and Encoded — and is currently in IND-enabling studies.
Partnership Background
In 2021, Roche and Neurocrine entered into a strategic collaboration for the development of gene therapies targeting severe neurological diseases. Neurocrine's expertise in CNS drug development and delivery, combined with Roche's global clinical infrastructure and diagnostics capabilities, positions this program as a significant competitive entry in the [Dravet syndrome](/diseases/dravet-syndrome) gene therapy landscape.
Key partnership terms:
Neurocrine leads development and commercialization activities
Roche provides global infrastructure and biomarker capabilities
Shared development costs and profits
Neurocrine retains US commercial rights; Roche handles ex-US
Technical Approach
Gene Replacement Strategy
Unlike [STK-001 (Stoke Therapeutics)](/clinical-trials/stk001-dravet-syndrome-phase-1-2) which uses ASO-based NMD inhibition to boost endogenous [SCN1A](/entities/scn1a) expression, and [ETX101 (Encoded Therapeutics)](/clinical-trials/etx101-encoded-therapeutics-dravet-syndrome) which uses CRISPRa to activate the wild-type allele, the Roche/Neurocrine program delivers a functional copy of the [SCN1A](/entities/scn1a) gene directly via AAV.
Technical considerations for SCN1A delivery:
[SCN1A](/entities/scn1a) coding sequence is ~6 kb, approaching the AAV packaging limit of ~4.7 kb
Solution: Engineered mini-gene or regulatory element optimization to reduce cargo size while preserving functional activity
Alternatively: Dual-vector approach (split-intein or trans-splicing) to package the full gene across two AAV vectors
Delivery route: Likely intracerebroventricular (ICV) or intraparenchymal for optimal CNS distribution
AAV Serotype
The program uses an engineered AAV capsid optimized for CNS penetration. Specific serotype identity is not publicly disclosed, but given Roche's investment in next-generation capsid platforms (including engineered AAV9 variants), the program likely builds on PHP.eB or similar CNS-tropic capsid technology.
Expression cassette design
Promoter: Neuron-specific promoter (e.g., Synapsin-1 or Mecp2) for selective expression in neurons
Regulatory elements: Woodchuck hepatitis virus post-transcriptional regulatory element (WPRE) for enhanced expression
PolyA signal: Bovine growth hormone polyadenylation signal
Safety elements: Inverted terminal repeats (ITRs) from AAV2 for genome packaging