Our Science

The Potential

Encoded’s name comes from the epigenetic code that controls when and where genes are expressed. To that end, we are identifying and optimizing human regulatory elements targeted to specific organs, starting with the brain, that can be harnessed to develop gene therapies with potentially unprecedented selectivity.

The brain is the most complex organ in the body with thousands of cell types and trillions of connections called synapses. Most drugs available today affect all cell types, with limited means to selectively target specific cell types or circuits that are dysfunctional in disease. This can lead to side effects and toxicity, which limit the number of drugs that reach patients.

Zhao Z, Ukidve A, Kim J, Mitragotri S. Targeting Strategies for Tissue-Specific Drug Delivery. Cell. 2020;181(1):151-167.

Encoded differentiates from current AAV approaches through advanced vector engineering

High throughput NGS screening platforms and computational modeling optimize payload and regulatory element design.

AAV: Adeno-Associated Virus;
NGS: Next-Generation Sequencing;
UTR: Untranslated Region

How it works

A gene therapy construct consists of a therapeutic gene, or transgene, and regulatory elements that control its activity, or expression. These include promoters, enhancers and untranslated regions (UTRs). Encoded engineers these regulatory elements to precisely target specific cell types relevant to disease.

Using genomics-driven screening methods, we screen thousands of naturally-occurring regulatory sequences in the human genome that drive robust and precise gene expression. We then apply machine learning algorithms to these uncovered sequences to identify patterns or motifs that are driving the desired pattern of gene activity.

This enables expression in specific cell types within the brain while minimizing expression in off-target cell types or tissues, for example the dorsal root ganglion, where expression could cause undesirable effect.

AAV: Adeno-Associated Virus;
UTR: Untranslated Region.

Engineered Cassette and Payload

Regulatory Elements: Optimized promoters, enhancers, and 3’UTRs drive cell selective and potent expression and reduce off-target activity

Neuron-Specific Expression: Potent and selective neuronal targeting promotes robust gene expression in a cell type implicated in a broad range of neurological and neurodegenerative disorders

GABA Cell-Selective Expression: Selective targeting of GABAergic cells unlocks a broad range of neurological disorders characterized by GABA pathway dysfunction, including epilepsy and autism spectrum disorders.

Dorsal root ganglion (DRG) de-targeting: Transgene expression in the DRG can cause dose-limiting toxicity. 3’UTR DRG de-targeting elements are designed to reduce expression in the DRG with no impact on expression in the brain.

Payload: Engineered protein coding genes, transcription factors, or RNA modulators for diverse gene targeting and modulation.

Engineered transcription factors (eTFs) are designed to increase endogenous gene expression to activate a biological pathway that is deficient in disease states. For this approach, a healthy copy of the gene must be present.

RNA modulators, such as miRNAs, are designed to drive robust and precise knockdown of pathological gene expression, a common disease driver in neurodegenerative disorders.

Opportunities

Encoded’s platform has delivered critical innovations to establish an industry-leading CNS pipeline supporting monogenic and common CNS disorders.