The ability to permanently insert large stretches of DNA into the human genome remains one of the central challenges of genetic medicine. While CRISPR-based technologies have transformed genome editing, gene-length insertion remains difficult, particularly when engineering cells directly inside the body rather than extracting, modifying, and reinfusing them.
In a new study published in Cell, researchers at Tessera Therapeutics describe a potential alternative: engineered retrotransposons, dubbed “gene writers,” that can permanently integrate therapeutic DNA sequences into the genome using machinery delivered entirely as RNA.
The research, co-led by Donghui Li, PhD, Alberto De Iaco, PhD, and Kevin C. Ngan, PhD, represents a significant demonstration of Tessera’s long-awaited gene writing platform. Beyond establishing the technology’s molecular capabilities, the team demonstrated functional CAR T-cell generation in humanized mice using targeted lipid nanoparticles (tLNPs), without requiring viral vectors or ex vivo cell engineering.
How are Tessera’s “gene writers” different?
Li, Alberto De Iaco, and Ngan initially surveyed 9,559 retroelements across 452 eukaryotic species, ultimately screening 406 reconstructed candidates for their ability to integrate independently supplied RNA templates into human cells. Several exhibited the desired activity, including compatibility with all-RNA delivery. Through extensive engineering, Tessera was able to create what they call “gene writers”—elements that can insert reporter genes into human cells efficiently and reliably using RNA templates that are introduced in trans.
Unlike conventional CRISPR-Cas9 editing and newer approaches such as base and prime editing, which rely to varying degrees on cellular DNA repair mechanisms to introduce genetic changes, Tessera Therapeutics’ Gene Writing technology uses specialized endonuclease and reverse transcriptase machinery to convert an RNA template into DNA that can be permanently integrated into the genome. Rather than relying on CRISPR-associated enzymes or conventional viral delivery systems, Tessera turned to non-long terminal repeat (non-LTR) retrotransposons, naturally occurring mobile genetic elements that copy RNA into DNA and integrate it into the genome through a process known as target-primed reverse transcription (TPRT).
The approach also differs from emerging programmable insertion systems such as PASSIGE, which combines prime editing with recombinase-mediated DNA integration, and bridge RNA systems, which use programmable RNA-guided recombination. Although these technologies offer potentially greater control over insertion location, Tessera’s approach emphasizes relatively simple molecular machinery and compatibility with RNA-based delivery. A particularly important distinction is that the gene writers identified in the study do not require the poly(A) tails used by LINE-1 retrotransposons or the homology arms associated with previously engineered R2 systems. Instead, they recognize specific untranslated regions flanking their RNA cargo. That specificity could help prevent unintended integration of unrelated cellular RNAs.
The all-RNA advantage
One of the most consequential aspects of the research is its delivery strategy. Tessera’s gene writing approach approach requires only two principal RNA components: a messenger RNA encoding the retrotransposon machinery, or “driver,” and a separate RNA template carrying the genetic cargo. Both can be packaged into lipid nanoparticles. This potentially combines two properties that have historically been difficult to achieve simultaneously: the permanent genomic integration associated with viral gene delivery and the flexibility of nonviral RNA delivery.
The implications extend beyond eliminating viral manufacturing requirements. The tLNPs can be engineered to target particular cell populations, opening the possibility of administering gene writing therapeutics directly to patients. In principle, the strategy could also be adapted to other RNA-compatible genome engineering platforms, although not all editors can accomplish stable gene integration using RNA components alone.
The researchers selected one candidate, Vingi-1_Acar, for further development based on its activity and integration characteristics in human T cells. By engineering its RNA template, including modifications to untranslated regions and RNA structural elements, they achieved approximately threefold improvement in activity.
In vivo CAR T in humanized mice
The most compelling therapeutic proof of concept came in CAR T-cell engineering, an established cancer treatment modality gaining traction in autoimmune disease. All FDA-approved CAR T-cell therapies remain autologous, requiring a complex, individualized vein-to-vein manufacturing process in which patient-derived T cells are collected, genetically modified, expanded ex vivo, and reinfused. Tessera researchers sought to circumvent this logistical and manufacturing burden by using tLNPs to deliver gene writing machinery directly to T cells in vivo, potentially enabling CAR T-cell generation without ex vivo manipulation.
In humanized mice, a single dose generated functional CD19-targeting CAR T cells that sustained B-cell depletion for at least 18 days, with minimal effects on other T-cell populations. To assess the platform’s versatility, researchers also engineered CD20-targeting CAR T cells and compared their performance with transient CAR expression achieved through conventional mRNA delivery. Although mRNA delivery triggered faster initial B-cell depletion, B-cell populations rebounded by day 38. In contrast, gene writer-generated CAR T cells reached approximately 15% of circulating T cells by day 11 and achieved near-complete B-cell depletion by day 18, which persisted through day 38. Cell culture-based experiments also showed sustained anti-tumor activity of gene writer-generated CAR T cells across repeated challenges, unlike transiently engineered cells.
These findings suggest that permanent gene integration could enable longer-lasting CAR T therapies while reducing the need for complex cell manufacturing and potentially repeated dosing.
Safety, precision, and remaining challenges
The study also examined insertional mutagenesis, a key safety concern for genome-integrating therapies, in which DNA integration can disrupt essential genes or activate oncogenic pathways. Unlike lentiviral vectors, which preferentially integrate within transcriptional units, Gene Writers exhibited broadly distributed integration profiles, with no significant enrichment near oncogenes or tumor suppressor genes under the conditions tested.
Vingi-1_Acar also induced relatively modest, transient DNA damage responses. Li, De Iaco, and Ngan observed approximately 1% aneuploid cells, comparable to the experimental delivery control, and detected no large chromosomal rearrangements in six analyzed induced pluripotent stem cell clones. However, these findings do not establish long-term safety. Integration remains largely random rather than precisely programmable, leaving potential risks of insertional mutagenesis. Li, De Iaco, and Ngan demonstrated preliminary retargeting of Vingi-1_Acar toward the TRAC locus using a Cas9 nickase fusion and homology-containing templates, but efficiency remained too low for therapeutic applications.
Another challenge is incomplete integration. Depending on the gene writer and cargo, a substantial proportion of insertion events were truncated or otherwise nonfunctional. The CD19 CAR template, for example, yielded only 22.8% functional integrations in the relevant sequencing analysis. These limitations will become increasingly important as Tessera pursues larger therapeutic cargos, more demanding cell types, and applications beyond CAR T therapy.
Moreover, the in vivo experiments were conducted in humanized mice, not nonhuman primates or patients. Integration-site safety profiles characterized in cultured cells still require validation in vivo, alongside longer-term studies of persistence, immune responses, and potential genotoxicity.
Broader platform opportunity
Although CAR T cells provided the first therapeutic proof of concept, the platform’s potential extends to other applications requiring durable expression of therapeutic genes, including genetic diseases in which replacing or supplementing a defective gene could provide lasting benefit. The diversity of naturally occurring retrotransposons also suggests opportunities to develop different gene writers optimized for particular cargos, cell types, or genomic integration characteristics. The tLNP work has broad applicability beyond this program. Tessera has long expressed interest in tLNPs, and with genetic medicine delivery companies such as Mirai Bio operating within the Flagship Pioneering ecosystem, the effort raises the possibility of a broader push toward developing and manufacturing scalable genetic medicines in-house.
The study nevertheless leaves several commercial and scientific questions unanswered, including how readily the platform can be adapted to other tissues, whether its delivery system can scale beyond T cells, and how Tessera’s intellectual property and underlying technology differentiate it from competing genome insertion platforms. Ultimately, the significance of Tessera’s work is not that it has solved every challenge associated with permanent genome engineering. Rather, it demonstrates that a previously underexplored class of naturally occurring genetic elements can be engineered into a functional delivery-compatible platform for inserting therapeutic genes directly into cells in vivo.
Whether gene writers can achieve the precision, efficiency, and safety required for clinical use remains to be seen. But the research introduces another potentially powerful modality into an increasingly crowded genome engineering landscape—one that could complement, rather than simply replicate, existing technologies.
The “copy cat” criticism
The findings also arrive against a backdrop of controversy over Tessera’s claims of technological originality. For years, the Flagship Pioneering-backed company has faced accusations that aspects of its gene writing platform closely resemble prime editing, pioneered by David Liu, PhD, and Andrew Anzalone, PhD, and commercialized by Prime Medicine. The dispute became particularly public in 2024, when Prime Medicine’s former chief scientist, Jeremy Duffield, MD, PhD, remarked at a scientific conference that Tessera appeared to be doing prime editing under another name.
Tessera’s limited peer-reviewed disclosures had further fueled skepticism about its differentiation. The new Cell study offers a substantive response, demonstrating a mechanistically distinct approach based on engineered retrotransposons capable of permanently integrating genes through all-RNA delivery. While it does not resolve questions surrounding Tessera’s other technologies or intellectual property, the work provides tangible evidence that its broader gene writing ambitions extend beyond repackaging existing editing tools.
The publication also comes during a period of significant organizational change. In January, Tessera laid off 90 employees, approximately 35% of its workforce, as it streamlined operations and prioritized clinical development, including its partnership with Regeneron to advance a potential treatment for alpha-1 antitrypsin deficiency. The restructuring was followed by a leadership transition in July, when former Merck executive Joseph Romanelli succeeded Michael Severino, MD, as president and CEO. Severino, who previously held senior roles at AbbVie, Amgen, and Tessera, was subsequently named president and CEO of Sarepta Therapeutics, replacing longtime chief executive Doug Ingram roughly five months after he announced his departure.
Against this backdrop, the new study represents more than a scientific milestone. It provides a timely demonstration of Tessera’s technological differentiation as the company navigates a leaner operating model and a renewed focus on clinical execution. Whether that distinction translates into meaningful clinical and commercial advantages remains an open question.
