RARE Daily

Harvard Spinout Hopes to Increase Efficiency of Vector Production for Cell and Gene Therapy

November 17, 2020

Rare Daily Staff

64x Bio has emerged from stealth to describe its proprietary VectorSelect platform for developing screening technologies that can dramatically increase the efficiency of viral vector production.

The spinout of Harvard’s Wyss Institute says its fundamental advances will enable the delivery of lifesaving cell and gene therapies to patients by reducing the cost and complexity of manufacturing, which is a critical bottleneck of this multi-billion dollar market.

Spun out of Harvard by a former postdoctoral fellow in George Church’s lab, 64x was accepted into Y Combinator, and featured as a top 10 startup on Demo Day. The company ultimately closed a $4.5 million seed round led by First Round Capital, Fifty Years, and Refactor Capital. Additional co-founders include Pam Silver, professor of Biochemistry and Systems Biology at Harvard Medical School and Jeffrey Way, staff scientist at the Wyss Institute.

Viral vectors are engineered viruses that deliver a genetic payload to cells and are a critical component of most cell and gene therapies, a market that is projected to triple by 2024. Current vector manufacturing is incredibly inefficient, driving costs upwards of hundreds of thousands of dollars per dose, and barely meeting demand even for small-scale orphan disease trials. Demand will only continue to expand as gene therapies enter the market and new trials grow in number, requiring a supply of vector that simply cannot be manufactured today.

One of the biggest inefficiencies is that many cell lines used for vector production are not optimized for the task, resulting in poor manufacturing yield and quality.

“Engineering purpose-built cell lines is essential to solving the manufacturing bottleneck,” says Lex Rovner, CEO and co-founder of 64x. “Viruses are a product of cellular gene expression, so there is no reason their production cannot be systematized in the same way antibody and enzyme production has been, yet attempts at discovering better cell lines through genetic mutation and screening have fallen short.”

The challenge is that cells have “evolved to minimize virus production,” said George Church, co-founder of 64x, and professor of Genetics at Harvard Medical School. Thus, mutations that confer high vector yield are rare and their discovery requires testing hundreds of millions of mutant cells. As current screening technologies measure yield from individual cells one at a time in multi-well plates, hundreds of thousands of multi-well plates would be required to screen at this scale—a practical impossibility. Furthermore, the linear scale up costs of most screening platforms place further limitations on this process.

64x Bio’s VectorSelect platform leverages leading-edge DNA library synthesis and next generation sequencing to dramatically increase experimental throughput and permit screening of several orders of magnitude more mutants in a single experiment than is possible in a multi-well format, enabling discovery of cell lines with otherwise unattainable and radically improved productivities.

The key innovation involves a proprietary genetic barcoding method that connects information on viral vector productivity back to the parent cell which produced it, enabling massively parallelized genetic screens of millions of candidate production cell lines simultaneously, a feat that has been impossible until now. 64x further utilizes machine learning on their expanding cell database to filter trillions of possible solutions into millions of screenable genetic combinations, increasing the speed and efficacy of cell line discovery.

64x develops optimized cell lines for pharmaceutical and biotechnology companies. The platform is compatible with any viral vector, cell line, and process, enabling its application toward a wide range of cell and gene therapies.

The company says its cell lines will decrease manufacturing cost and time for its partners, enabling pursuit of multiple otherwise unattainable indications, and ultimately, more cell and gene therapies to come to market. Owing to the platform’s broad applicability, 64x also plans to grow into broader biologics markets, such as vaccines and oncolytic therapies.

Photo: Lex Rovner, co-founder and CEO of 64X

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