The precision gene therapies being developed at Encoded are capable of potentially targeting specific cell types or levels of expression to address a range of disease mechanisms.
Pediatric central nervous system (CNS) disorders represent a significant proportion of the global burden of disease because they contribute both to premature mortality and lifelong disability. While only a few gene therapies have become approved products, genetic medicine remains an emerging field with virtually limitless potential.
Genetic drivers of pediatric CNS diseases are being identified at an increasing rate, and as their functions are understood, new therapeutic targets will continue to emerge and so will the potential for new gene therapies.
Encoded’s name comes from the epigenetic code in DNA 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 generate best- and potentially first-in-class gene therapies with gene specificity and cell selectivity.
The Potential of Encoded’s Platform
Overcoming Challenges of First-Generation Gene Therapies
A gene therapy construct consists of a therapeutic transgene and regulatory elements, including a promoter, that controls the therapeutic transgene’s expression. First-generation adeno-associated virus (AAV)-mediated gene therapies often use standard regulatory elements, such as ubiquitous promoters, that lead to widespread transgene expression across many cell types. (For more information on how first-generation gene-based medicines work, click here to access educational resources from the Institute for Gene Therapies.)
In contrast to conventional first-generation products, our cell-selective regulatory elements promote robust and precise gene expression in target cells. Because our gene therapy candidates recapitulate natural patterns of gene expression, we expect minimal off-target activity and potentially improved safety profiles.
Our technology platform overcomes key potency and selectivity limitations of first-generation AAV-mediated gene therapies. AAV vectors are not associated with human disease and show minimal integration into the genome; however, they have limited genomic packaging capacity, restricting their application to smaller genes. We can address this limitation by designing gene therapy constructs that utilize smaller regulatory elements to drive expression of the transgene, or alternatively, deliver genetic material that instructs a functioning copy of a gene to upregulate.
Enabling Cell-Selective Targeting and Regulation
Promoters, enhancers and untranslated regions are all examples of regulatory elements, which are non-coding genomic sequences in our DNA. Regulatory elements and transcription factors are among the elements that influence or regulate gene expression. Using genomics-driven screening methods, we test thousands of regulatory sequences from the human genome to specifically identify which drive robust and precise gene expression in target cells.
We then apply machine learning algorithms to these uncovered sequences to identify patterns or motifs that are driving the desired pattern of gene activity. Understanding the “grammar” underlying transcriptional regulation enables us to engineer synthetic regulatory elements that are more selective, potent and smaller in size than those found in naturally occurring genomic sequences. By engineering human regulatory elements, the Encoded research platform allows targeting of specific, disease-relevant cell types to optimize on-target gene expression in organs such as the CNS and minimize off-target effects in organs such as the liver.
Encoded’s programs aim to modulate the function of coding DNA through regulatory elements. Our optimized human regulatory elements can be delivered with any system, including AAV vectors, to control where and when they are expressed and thereby shape the functionality of target cells.
Utilize standard regulatory elements, leading to widespread, non-specific transgene expression across many cell types
The limited cell-selective targeting of these approaches has restricted the number of indications accessible to gene therapy, or resulted in therapeutics with less-than-optimal profiles.
Cell-Selective Targeting and Regulation
Synthetically engineer regulatory sequences to modulate or create desired patterns of gene expression
Leveraging the Encoded Platform to Develop Innovative One-Time Therapies for Pediatric CNS Disorders
Each one of our programs originates at Encoded as a solution to a biological problem. We combine our genomics-driven data with internal CNS biological expertise and access to worldwide thought leaders to employ best-in-class identification of therapeutic targets initially for disorders that are monogenic, which involve a single gene, like Dravet syndrome.
We are focusing on developing our pipeline of one-time gene therapies for pediatric CNS disorders that have significant unmet need and have not been previously addressable by gene therapy. Our precision gene therapies are designed to target specific cell types or levels of expression. We can target a range of loss- or gain-of-function disease mechanisms with the Encoded platform by (1) replacing a gene, (2) upregulating gene expression, or (3) silencing gene expression.
How we can employ the Encoded platform to target a range of disease mechanisms: