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Celldom to Tackle Single-Cell Analysis Sector With Integrated Genotyping, Phenotyping Platform


NEW YORK (GenomeWeb) – Fresh off receiving a $1.5 million Small Business Innovation Research grant from the National Institutes of Health earlier this month, Celldom aims to engage the oncology, stem cell, and immunology research markets with its single-cell analysis platform.

The Durham, North Carolina-based firm is developing a two-part platform, called TrapTx, that integrates cell sorting and image-based analysis to isolate and track cell growth, migration, and interaction with single-cell gene expression analysis. The company's first assays will be for detecting rare drug-resistant leukemia cells, but Celldom hopes to eventually market the platform to academic and pharmaceutical researchers for use in a number of personalized medicine applications.

The single-cell analysis market is currently bustling with several companies offering their own novel methods to examine a variety of cell types. Celldom's most direct competitor will likely be Fluidigm, which arguably helped shape the current market with its C1 single-cell genomics system for preparing single-cell templates for mRNA sequencing, DNA sequencing, epigenetics. or miRNA expression. In addition, Fluidigm markets the Hyperion imaging platform, which can profile proteins in hundreds of single cells while retaining their spatial and structural context in a tissue sample.

Researchers can also use flow cytometers the likes of those sold by Becton Dickinson to flow sort single cells into multi-well plates for further phenotypic and genotypic analysis. In addition, recent market entrants Berkeley Lights and Cell Microsystems enable higher throughput tools to genotype cells through light-based and magnetic-based platforms, respectively. However, both firms' platforms require exporting desired cells into single tubes. Firms such as WaferGen — now part of Takara Bio — and Cellular Research — acquired by BD in 2015 — also offer single-cell sorting tools that use sedimentation to populate single cells into an array of microwells.

Celldom, which was founded in 2016 by Duke University engineering professor Benjamin Yellen, CEO Zachary Forbes, and Chief Science Officer Kris Wood, is taking what it believes to be a different approach to single-cell analysis.

Forbes explained that the TrapTx platform comprises a tissue-box sized apparatus that holds the firm's microfluidic chip. Using a fluid pumping system timed to deliver media through the chip, the tool pushes individual cells into their own "apartments." The platform can scale "from hundreds to 100,000 cells in individual compartments or wells," each marked by their own unique DNA barcode.

The tool then uses specialized software that drives auto-imaging and analysis of the chips using the DNA barcode attached to the bottom of each well. The software improves the workflow's efficiency by taking an image of each compartment to confirm if the researcher has a single cell, double, triplet, or empty compartment.

"Each compartment has a molecular address, with the DNA barcode, affiliated with the software," Forbes said. After sequencing the cells, for instance, "researchers can use the software to instantly register the sequencing data to the corresponding apartment."

Forbes highlighted that the TrapTx platform "offers researchers the flexibility on an open platform to determine how they want to preserve cells and track them."

According to Forbes, the platform then uses a customized workflow for lysing cells while in their apartments for reverse-transcriptase PCR and amplification, then "pooling molecules out of the chip outlets to prepare libraries for sequencing."

While the assay time depends on the volume of cells on the chip, and sample size, Forbes said that the platform "on average" can produce results in about two hours and that the firm will try to reduce that. He noted that the tool can examine both adherent and in-suspension cancer cells, T cells, as well as cells from heterogeneous samples such as whole blood.

"It takes about as much time required for one to grab a flask of cells from the incubator, do a count, prepare a suspension, turn on the machine, pop a chip in the slot, introduce cells, and image them," Forbes said. "We have a little device that the chip is in, which goes into the [user's] incubator, providing a fresh media and gas exchange at a calculated rate to optimize provisions for the cells."

Forbes noted that the TrapTx system will be able to perform several aspects of the cell analysis workflow, including: arraying cells into individual compartments; live automated imaging for a confirmatory check of arraying efficiency; imaging as needed across multi-hour or multi-day assays; and an on-chip genomic workflow to pool samples for library preparation.

Because the TrapTx system does not integrate incubation, Forbes argued that it frees up the tool for multiple experiments in a single day, rather than monopolizing the device for one experiment. In the future, the firm aims to develop much larger production scale systems that incorporate incubation and additional features.

While he declined to discuss specific details, Forbes said that Celldom has filed multiple patents for its single-cell analysis tool, and that the company has "a number of active funnels for ideas." Celldom has exclusively licensed the technology from Duke to develop a single-cell analysis workflow.

Forbes acknowledged that the main challenge his team has encountered so far has been "doing everything on our own, in terms of the experiments," rather than outsourcing the work to external labs. He also noted raising funds to develop the technology has also been challenging.

In addition to the SBIR Phase II grant awarded last week, Celldom previously received a $250,000 SBIR Phase I grant in 2017. Forbes explained that the firm received the grant because it showed that it could keep the cancer cell lines alive up to two weeks in the TrapTx's compartments.

As part of the SBIR II grant, Forbes and his team aim to demonstrate that the TrapTx platform can use a FLT-3 inhibitor on acute myeloid leukemia cells and detect resistant colonies growing in the wells. Forbes noted that the grant will help complete the development of a "single-cell-based high-throughput drug screening platform, capable of identifying rare drug-resistant cells."

Celldom also raised an undisclosed number of convertible notes during a friends and family funding round that closed in January.

Celldom estimates that more than 500 NIH-funded laboratories focus on understanding the biology and seeking solutions to issues such as cancer and immune disease. Forbes said that Celldom will therefore focus on a bottom-up approach, "starting with academic customers" for its first set of leukemia-focused drug-resistance assays and a "pipeline of chips and workflows for other deadly cancers."  

Celldom then plans to move upward to the biopharmaceutical industry as it gains acceptance among early adopters, seeking to penetrate drug-discovery and development R&D sectors and eventually companion diagnostics for personalized precision medicine. Forbes believes the platform has the potential to reduce waste in the drug-discovery pipeline by "credentialing drug candidates for resistance at an earlier preclinical stage."

According to Forbes, Celldom previously partnered with an undisclosed cancer therapeutics company to examine potential drug development and clinical trials. The partner was interested in using the TrapTx instrument to test a group of patients' cancers against a variety of drug doses to qualify them for a potential trial, and then to sample them just prior to beginning the medication to coordinate phenotypic response cellularly to real-world response.

"Since we are interested in the product finding impact at target discovery through lead optimization into qualifying clinical trials and eventual companion diagnostics, [we believe] that it was a good bootcamp at the time," Forbes noted.

Discussing potential competitors, Forbes argued that the throughput on Fluidigm's C1 platform — 800 cells per chip — is too small to identify rare cellular events. He believes that the large volume sizes of 384-well plates used in flow sorting approaches can lead to high cost in reagents and incubator space, in addition to the tool not being conducive to prompting cell-to-cell interactions.

In contrast, Forbes claims that Celldom's cell trapping architecture is significantly denser, enabling 10x to 100x more cells to be handled in the same unit area.

While Forbes did not disclose the estimated cost of the platform or initial assays, he noted that Celldom does not aim to undercut the competition by offering a dramatically lower price.

Once Celldom can demonstrate that its platform can smoothly integrate isolation, stimulation, phenotyping, and genomic analysis of cloned cells in a combined workflow, Forbes claims that the firm's products will be "the only platform on the market capable of connecting complex phenotypes to expression profiles of single cell clones in massively parallel format[s]."