De-risking cell and gene therapies with innovative solutions:

A review for leveraging a proven workhorse technology in new ways

AUTHORs: Farzin Farzaneh Ph.D., CSO; Nicholas Ostrout Ph.D., VP Corporate Development & Strategy; Glenda Dickson Ph.D., Senior Principal Scientist, Innovation; and David Darling Ph.D., Senior Principal Scientist, Innovation, ViroCell Biologics

Innovations designed to de-risk and enhance lentiviral manufacturing, and also to achieve better vector gene expression control, are needed to substantially enhance the applicability of gene therapy beyond adoptive cell therapy for cancer treatment and in vivo therapies for inherited genetic disorders.

ViroCell Biologics was founded with the goal of developing solutions in a targeted manner to de-risk vector design and manufacturing, while enabling better control of gene expression, thereby delivering improved clinical outcomes and expanding the applicability of gene therapies.

Projects have included identification of small-molecule additives that boost vector titers, development of a novel serum free, suspension HEK293 cell line that affords improved titers with transient transfection performance, and a stable producer cell line that increases manufacturing efficiencies. Ligand-modified lentiviral vectors (LVVs) enable improved purification and concentration processes and greater cell/tissue targeting.

Additional early-stage work focuses on development of gene regulatory promoter sequences and non-integrating lentiviral vectors that have the potential to dramatically expand the diseases for which gene and adoptive cell therapies is also being developed.

Building better control into viral vectors with revolutionary precision

There is growing recognition across the biopharmaceutical industry that expanding the potential of gene therapies will require increasingly sophisticated ways to control how viral vectors target specific cell types and affect the function of the target cell. While current applications, such as CAR-T cell therapy and rare monogenic disease treatment, have demonstrated the promise of viral vector-mediated genetic delivery, these successes have been enabled by tightly defined use cases and highly selective clinical settings. Moving beyond these boundaries to broader indications — including autoimmune diseases, cardiovascular conditions, and even in vivo CAR-T therapies — demands a new generation of vectors with built-in precision and predictability.

ViroCell Biologics was established in 2021 to address this challenge head-on. Drawing on more than two decades of gene therapy development expertise at King’s College London and King’s College Hospital, the company was founded to address the critical unmet needs in gene delivery — particularly the need for fine-tuned control systems that allow for robust expression where needed and silence where not.

The company is developing programmable lentiviral vectors designed to behave intelligently/intuitively within biological systems. These include computationally derived, machine learning to develop highly selective expression systems driven by combinations of tissue-specific promoters, enhancers, microRNAs, and other regulatory elements that enable tight post-transcriptional and post-translational control. By adjusting these molecular "dials," ViroCell is helping developers to build vectors that can upregulate or downregulate genes in response to cell-specific signals, helping to ensure expression occurs only where biologically appropriate.

This approach holds enormous promise not only for increasing therapeutic efficacy, but also for minimizing off-target effects and mitigating risks such as toxicity or immune activation. The goal is not simply to engineer a gene delivery system, but to design environmentally responsive, self-regulating genetic tools that act with the same precision as a biologic therapy — with fewer unintended consequences.

Rather than introducing wholly new components, ViroCell’s innovation lies in how it recomposes known, well-understood biological elements, combined with recent scientific advancements, into configurations that deliver entirely new capabilities. It is this reimagining of vector design — grounded in the familiar but applied in novel, integrated ways — that enables ViroCell to reduce development risk while opening new therapeutic frontiers.

Rethinking scale, risk, and readiness in gene therapy development

Innovation at contract development and manufacturing organizations (CDMOs) is typically focused on improving scalability and streamlining technology transfer. ViroCell invests deeply in these core capabilities — developing optimized upstream and downstream manufacturing solutions to de-risk the development — but also pursues innovation that extends well beyond platform standardization or incremental improvements in yield and purity.

For example, in transient transfection-based production of viral vectors, ViroCell has demonstrated that the addition of select small molecules can yield a fourfold increase in vector titer. This effectively multiplies manufacturing capacity and significantly reduces the cost of goods. Similarly, the company’s new HEK293 cell line is engineered to tolerate five- to 10-fold greater cell densities before reaching viability limits, further boosting productivity and reducing the cost per unit of vector production run.

Another initiative involves the development of a serum-free suspension-adapted HEK293 cell line capable of producing both lentiviral (LV) and adeno-associated viral (AAV) vectors. While adherent HEK293 cells are often used during early-phase development, suspension processes are far more efficient at scale. ViroCell’s proprietary suspension HEK293 line supports high-titer vector production, as demonstrated by strong yields using transfection with both green fluorescent protein (GFP) and chimeric antigen receptor–GFP (CAR-GFP) plasmids, illustrating the applicability of the cell line for a variety of potential transgenes. These cells are also being used in ongoing studies evaluating the role of small molecule additives in further enhancing titers.

To move beyond the limitations of transient transfection altogether, ViroCell is developing stable packaging and producer cell lines — a technically challenging endeavor owing to the cytotoxicity of certain vector components, like vesicular stomatitis virus glycoprotein (VSV-G). One notable solution involves controlled, reversible expression of VSV-G using an inhibitory small molecule. In this system, VSV-G is fused to a responsive sequence, and in the presence of the inhibitor, its translocation is suppressed. After culture expansion, the inhibitory molecule is removed to induce vector release. This enables dose-dependent expression control and opens the door to long-term, high-yield lentiviral vector production in suspension cultures. Ongoing experiments are evaluating integration efficiency, small molecule dose responsiveness, yield, and genomic stability.

For in vivo applications, insertional mutagenesis remains a well-known concern with integrating lentiviral vectors. While integration can offer the benefit of long-term expression, it also raises potential safety questions — particularly of importance in pediatric and large-population indications. In addition, lentiviral vectors can carry a greater payload, over twice the capacity offered by AAVs. Unlike AAVs, lentiviral vectors are not typically associated with liver toxicity, which is an important consideration given the vast quantities of, especially AAV required due to inefficient targeting, making them attractive alternatives if integration risks can be mitigated. 

To address these limitations, ViroCell employs a multipronged strategy to reduce risk while retaining efficacy. This includes the use of non-integrating lentiviral vectors that remain episomally maintained and maintain unchanged, long-term gene expression in non-dividing cells, as well as constructs that target “safe harbor” genomic sites when stable expression is needed. Vectors may also include built-in safety features, such as CRE-inducible suicide genes, designed to trigger apoptosis in the event of uncontrolled proliferation or mutation.

Targeting remains a key challenge for in vivo gene delivery. AAV platforms have gained popularity in part owing to the diversity of available serotypes that allow for tissue-specific delivery. While pseudotyped RNA viruses offer promise in this domain, their use has remained largely experimental and difficult to translate into GMP-compliant platforms. ViroCell is actively working to expand the toolkit of usable pseudotypes — as part of a larger effort aimed at making clinically viable lentiviral targeting a reality.

The potential for gene therapy to address common diseases — from inflammatory conditions to cardiovascular disorders — is enormous. But it will only be realized by taking the necessary first steps to optimize the safety, precision, and manufacturability of vectors, thereby ensuring cost effective and efficient manufacturing approaches to maximize the likelihood of product success through the development process and into commercial delivery. ViroCell is committed to that goal.

At the same time, the company recognizes the pressures many clients face to be first in the clinic. For programs on an accelerated timeline, ViroCell offers a plug-and-play platform capable of manufacturing QP-released vectors in six months or less. For clients with more flexibility, the company can optimize vector design, evaluate multiple permutations, and select the best construct for GMP manufacturing. Whether the priority is speed or sophistication, ViroCell’s platform is built to deliver.

Targeted by design: Enhancing selectivity in viral vector delivery

For gene therapy to realize its full potential, viral vectors must evolve to enable highly selective delivery to specific tissues, minimizing off-target effects while maximizing therapeutic efficacy. This is especially important in the move from ex vivo therapies to in vivo gene delivery, where the vector must navigate the body, target its intended cell type(s), and deliver its payload with efficiency and precision.

ViroCell is advancing two complementary strategies to achieve this goal: ligand-directed targeting and tissue-specific promoter design that results in the expression of the gene of interest only in a specific cell type, or under certain conditions.

In one approach for ligand-directed targeting, viral vectors — both LV and AAV — can be chemically modified using click chemistry to attach ligands that guide the virus to specific tissues. This form of surface engineering allows the viral envelope to recognize and bind selectively to target cell receptors, enabling localized transduction while minimizing uptake by off-target tissues.

This method has several compelling use cases. In in vivo CAR-T cell therapies, the viral vector is delivered systemically via intravenous injection but must only infect a specific subset of T cells or another target cell population. Ligand-directed targeting should ensure that only the intended cells are transduced, reducing the risk of unintended gene modification and improving safety.

Beyond targeting, ligand functionalization also improves downstream processing. Internal studies have shown that modified vectors can be more easily captured, purified, and concentrated, an important advantage when therapies must be administered in ultra-low volumes. This is critical for intracranial injections, inner ear delivery, or ocular gene therapies, where only tens of microliters may be deliverable, as well as for efficiency in large-dose programs. In such cases, every microliter must carry high potency, and the vector must meet stringent purity thresholds. Ligand-mediated purification may further enhance recovery and purity, making these therapies more feasible.

Together, ligand engineering and tissue-specific transcriptional control represent powerful tools for expanding the therapeutic utility of lentiviral and retroviral platforms. ViroCell’s ongoing work in this space is designed not only to broaden the range of treatable diseases, but also to make these next-generation therapies safer and more effective.

The case for a Lentiviral Renaissance

Over the past two decades, the field of gene therapy has largely been shaped by the three viral platforms: AAVs, lentiviral vectors, and large DNA viruses, such as oncolytic viruses. Each has made important contributions, with AAVs dominating in vivo applications and lentiviral vectors serving as the backbone for ex vivo therapies like CAR-T.

At ViroCell, our work has always been vector-agnostic. Whether the goal is to increase vector titers, improve purity, or enhance tissue specificity, we focus on solving technical challenges that apply across platforms. This includes innovations in ligand-directed targeting, stable cell line development, and vector design, all of which can benefit lentiviral vectors, AAV, and even non-viral systems alike.

Non-viral alternatives — such as lipid nanoparticles (LNPs) delivering episomally maintained nucleic acids — also hold promise, particularly for RNA therapies that undergo reverse transcription to DNA in target cells. However, these platforms remain constrained by delivery efficiency, expression duration, and tissue targeting precision.

Looking ahead, however, lentiviral vectors may be poised for broader in vivo use, especially if current limitations can be addressed. Lentiviral vectors offer a mature yet continuously evolving toolkit that, with the right engineering, can unlock applications that other delivery systems struggle to reach. Their proven adaptability and payload flexibility position lentiviral vectors to address complex therapeutic needs that demand more than a single-platform approach. Just as monoclonal antibodies transformed over decades from early promise to a mainstay of modern medicine, lentiviral platforms are poised to expand their impact as next-generation refinements come online.

ViroCell’s goal is to accelerate the lentiviral vector revolution, ensuring that lentiviral vectors remain an essential option in a broader toolkit of delivery solutions, each fit for purpose and optimized for safety, scalability, and clinical success.

July 2025