HarborSite: Precise and Efficient Gene Editing for Next-Generation Gene Therapies

The Problem

An ideal gene therapy should allow for safe and durable expression of large therapeutic gene(s) in a variety of different cell types. Additionally, it should be easily deliverable to target cells and tissues in vivo. To satisfy these criteria, therapeutic genes need to be efficiently integrated into carefully selected genomic locations by highly precise and efficient, yet compact tools that fit into common delivery agents. None of the current gene therapy technologies that are being used in hundreds of clinical trials – from well-established lentiviral therapies to the most advanced CRISPR-based editors – possess all these properties, thus inhibiting the development of gene therapies for a broader range of diseases.

Our Solution

HarborSite overcomes key limitations of existing gene therapies by combining two proprietary genome editing technologies – genomic safe harbors (GSHs) and highly effective recombinase enzymes (recombinases).

GSHs are regions of the human genome that reside outside coding and regulatory sequence elements of the human genome, identified using computational methods. Inserting therapeutic genes into GSHs ensures their safe expression by avoiding potential disruption of coding genes and inadvertent activation of genes associated with cancer development. These concerns are common to lentiviral gene therapies, which rely on random genomic insertions. Importantly, experimentally validated GSHs enable long-term expression of the integrated genes in numerous cell types, ranging from stem cells to their fully differentiated progeny.

HarborSite’s second core technology are recombinases: small enzymes capable of re-arranging large DNA fragments. Exploiting the natural properties of these enzymes allows for precise and highly efficient integration of therapeutic genes with a broad range of sizes into the genome without causing double-stranded breaks, and the involvement of the DNA repair machinery that responds to them, thus opening up opportunities for gene editing in a variety of cell types. The small size of these enzymes allows them to be used with a continuously growing palette of tissue-specific delivery vehicles.

The combined advantages provided by HarborSite allow it to be harnessed for in vivo and ex vivo therapy approaches in which recombinases and therapeutic genes are co-delivered to disease-affected target cells. The enzyme efficiently inserts the therapeutic cargo into carefully selected sites in GSHs for their safe and long-lasting expression.

Impact

The HarborSite approach to gene therapy was conceived by Erik Aznauryan, Ph.D. and Tina Lebar, Ph.D., two members of George Church’s group in the Wyss Institute’s Synthetic Biology platform and Harvard Medical School. Based on its outsized potential for safe and long-lasting next-generation gene therapies in a broad spectrum of disease areas, HarborSite was recognized as a 2022/2023 Wyss Validation Project. The team is currently evaluating the safety and efficacy of their technology in proof-of-concept studies, with computational support by Viktor Horvath, Ph.D. The project is supervised by Jenny Tam, Ph.D., a Synthetic Biology platform lead at the Wyss Institute. The team is pursuing commercialization of the HarborSite technology with Bill Bedell, Ph.D., a business development manager at the Wyss.