Industry Insights: Advances in enzymatic manufacturing, therapeutic pipelines, and regulatory pathways for nucleic acid therapeutics

Summary

Across December 2025 and mid-January 2026, activity in the nucleic acid therapeutics landscape reflected continued investment in manufacturing, expanding clinical pipelines, and multiple regulatory milestones. Alnylam announced a $250 million expansion of its RNA interference (RNAi) manufacturing capacity using enzymatic ligation technology, while GSK entered a partnership with CAMP4 worth up to $458 million to advance antisense oligonucleotide (ASO) therapies targeting regulatory RNAs. Furthermore, several companies reported progress across preclinical and clinical programs, including ASO and small interfering RNA (siRNA) candidates for amyotrophic lateral sclerosis (ALS), cardiovascular disease, and rare neurological disorders, alongside new clinical data presentations at major scientific meetings. Regulatory momentum was also evident, with Breakthrough Therapy designations and new approvals granted for RNA-based medicines across the USA and Canada.

MARKET TRENDS

Alnylam announced a $250 million expansion of RNAi manufacturing using enzymatic ligation technology [1]

Alnylam Pharmaceuticals announced a $250 million investment to expand its RNAi manufacturing facility in Norton, Massachusetts, incorporating its enzymatic ligation–based siRELIS platform to increase siRNA production efficiency. The platform, which has been accepted into the US FDA Emerging Technology Program, assembles siRNA from pre-synthesized nucleotide blocks rather than traditional stepwise synthesis. The expanded site, expected to be operational by late 2027, will support scaling of Alnylam’s pipeline, including candidates such as zilebesiran and nucresiran, amid broader efforts to strengthen US-based pharmaceutical manufacturing.

GSK partnered with CAMP4 on antisense RNA therapies for neuro and kidney diseases [2]

GSK announced a collaboration with CAMP4 Therapeutics focused on developing ASOs targeting regulatory RNAs implicated in neurodegenerative and renal diseases. Under the agreement, CAMP4 will receive $17.5 million upfront and is eligible for up to $440 million in development and commercial milestones, along with tiered royalties. CAMP4 will apply its RAP Platform to identify and validate ASO candidates designed to increase protein expression by modulating regulatory RNAs, while GSK will take responsibility for global development, manufacturing, and commercialization. The deal expands GSK’s growing portfolio of RNA-focused partnerships.

RESEARCH AND DEVELOPMENT HIGHLIGHTS

Aperture advanced an MMP9 (ASO) program for ALS [3]

Aperture Therapeutics announced progress on APRTX-003, a first-in-class ASO targeting matrix metalloproteinase-9 (MMP9) for the treatment of ALS. The program aims to suppress MMP9 at the RNA level to address chronic neuroinflammation and neurodegeneration, key drivers of motor neuron loss in ALS. Using its proprietary platform combining human genetic evidence and machine learning–guided oligonucleotide design, Aperture identified MMP9-targeting ASOs that achieved robust knockdown of MMP9 mRNA and protein and reduced inflammatory biomarkers in human iPSC-derived microglia. The company has also developed a humanized MMP9 knock-in mouse model to support translational studies.

Geron reported new imetelstat data in lower-risk MDS and myelofibrosis at ASH 2025 [4]

Geron Corporation presented new oral and poster data at the American Society of Hematology 2025 Annual Meeting, highlighting clinical and mechanistic findings for imetelstat in lower-risk myelodysplastic syndromes (MDS) and myelofibrosis. Pooled analyses from the Phase 3 IMerge trial suggested early treatment-emergent cytopenias were associated with greater hemoglobin increases and higher rates of red blood cell transfusion independence, supporting an on-target effect of telomerase inhibition. Long-term follow-up showed favorable trends in overall survival and progression-related endpoints, although the study was not powered for statistical significance.

CLINICAL TRIALS AND RESEARCH

Rona advanced a dual-target siRNA into Phase 1 development [5]

Rona Therapeutics announced the submission of RN5681, a GalNAc-conjugated bi-valent siRNA targeting both PCSK9 and LPA, to the Australian Human Research Ethics Committee, marking its entry into clinical development. The Phase 1 study is expected to begin dosing in Q1 2026. RN5681 is designed to simultaneously lower LDL cholesterol and lipoprotein(a) by silencing two genetically validated cardiovascular risk drivers within a single molecule. The program represents the company’s first clinical candidate from its bi- and multi-target siRNA platform and is intended to address residual cardiovascular risk not adequately managed by existing lipid-lowering therapies.

Amylyx reported early Phase 1 safety data for a novel ASO in ALS [6]

Amylyx Pharmaceuticals presented early safety and tolerability data from cohort 1 of the first-in-human Phase 1 LUMINA trial evaluating AMX0114, an ASO targeting calpain-2, in people with ALS. In cohort 1 (n=12), AMX0114 was generally well tolerated, with no treatment-related serious adverse events or dose-limiting toxicities reported. Based on these findings, the company plans to open enrollment for the second cohort in Canada and the USA. The randomized, double-blind, placebo-controlled trial is assessing safety, pharmacokinetics, pharmacodynamics, and biomarker changes, including neurofilament light chain levels, with initial biomarker data from cohort 1 expected in the first half of 2026.

Biogen and Stoke reported new zorevunersen data in Dravet syndrome [7]

Biogen and Stoke Therapeutics presented new clinical and mechanistic data for zorevunersen, an investigational ASO for Dravet syndrome, at the 2025 American Epilepsy Society Annual Meeting. Long-term Phase 1/2a and open-label extension data has shown durable reductions in seizure frequency, an increase in seizure-free days, and improvements in cognition, behavior, and quality of life when added to standard anti-seizure medicines. A propensity score weighted analysis comparing treated patients with a natural history cohort demonstrated statistically significant seizure reductions and cognitive and behavioral improvements at timepoints aligned with the ongoing Phase 3 EMPEROR study. EEG analyses supported a disease-modifying mechanism of action, alongside accumulating long-term safety data.

TOOLS AND TECHNOLOGIES

Mount Sinai researchers reported a cell-selective mRNA therapy platform [8]

Researchers at the Icahn School of Medicine at Mount Sinai reported the development of a cell-selective modified mRNA translation system (cSMRTS) designed to activate therapeutic gene expression preferentially in targeted cells. Described in Molecular Therapy and demonstrated in mouse cancer models, the platform uses microRNA-responsive control elements to switch mRNA activity on in tumor cells while suppressing expression in healthy tissues. When delivered systemically in lipid nanoparticles, cSMRTS showed markedly higher gene expression in tumors and substantially reduced off-target activity in major organs, leading to significant tumor growth reduction. The approach shifts selectivity from delivery vehicles to the mRNA payload itself and is being explored for broader preclinical development and commercialization.

AI-driven approaches for RNA drug development were outlined in a new review article [9]

A peer-reviewed article recently published in Engineering reviewed how AI could accelerate and reshape RNA drug development. The authors outlined the advantages of RNA-based therapeutics, including shorter development timelines and higher clinical success rates compared with traditional drugs, while highlighting current experimental and computational limitations. The review described three AI-driven strategies – data-driven, learning-strategy-driven, and deep-learning-driven approaches – and discussed their application to RNA design, target identification, and optimization. The authors also proposed an integrated, software-based workflow combining AI model feedback with real-world data to enable personalized RNA drug discovery, automated synthesis, and early biological validation, positioning AI as a key enabler of future RNA therapeutics.

REGULATORY CHANGES AND UPDATES

Ionis received the FDA Breakthrough Therapy designation for zilganersen in Alexander disease [10]

Ionis Pharmaceuticals announced that the FDA granted Breakthrough Therapy designation to zilganersen, an investigational ASO for the treatment of Alexander disease, a rare and often fatal neurological disorder. The designation was supported by topline results from a pivotal Phase 1–3 study showing statistically significant stabilization of gait speed versus control at week 61, with favorable safety and tolerability. Zilganersen also demonstrated consistent benefit across key secondary endpoints. Ionis plans to submit a new drug application in Q1 2026 and is preparing to initiate an Expanded Access Program in the USA. Zilganersen is designed to reduce excess glial fibrillary acidic protein produced by disease-causing variants in the GFAP gene.

Arrowhead received FDA Breakthrough Therapy designation for plozasiran in severe hypertriglyceridemia [11]

Arrowhead Pharmaceuticals announced that the FDA granted Breakthrough Therapy designation to plozasiran, an investigational RNAi therapeutic, as an adjunct to diet for adults with severe hypertriglyceridemia. The designation is based on preliminary clinical evidence suggesting substantial improvement over existing therapies. Plozasiran targets apolipoprotein C-III to reduce triglyceride-rich lipoproteins and lower serum triglyceride levels. Arrowhead is conducting multiple Phase 3 trials, including SHASTA-3, SHASTA-4, and MUIR-3, with completion expected in mid-2026, and plans to submit a supplemental new drug application to the FDA by the end of 2026, followed by additional global regulatory filings.

Alnylam received Health Canada approval for vutrisiran in ATTR cardiomyopathy [12]

Alnylam announced that Health Canada granted a Notice of Compliance for AMVUTTRA^® (vutrisiran) for the treatment of cardiomyopathy in adult patients with wild-type or hereditary transthyretin-mediated amyloidosis. The approval expands the drug’s existing indication in Canada, making vutrisiran the first RNAi therapeutic authorized for both ATTR cardiomyopathy and polyneuropathy. The decision was based on results from the Phase 3 HELIOS-B trial, which showed significant reductions in all-cause mortality and recurrent cardiovascular events compared with placebo, with a safety profile similar to placebo. Vutrisiran targets transthyretin mRNA to reduce production of both variant and wild-type TTR and limit amyloid deposition.

References

1. Alnylam Pharmaceuticals. Alnylam to invest $250 million to add enzymatic ligation platform to US manufacturing facility to meet growing global demand for RNAi therapeutics. Dec 17, 2025.

2. CAMP4 Therapeutics and GSK. CAMP4 and GSK enter strategic collaboration to advance RNA-based therapeutic discoveries. Dec 18, 2025.

3. Aperture Therapeutics. Aperture Therapeutics announces first-in-class MMP9 antisense oligonucleotide program for ALS. Jan 6, 2026.

4. Geron Corporation. Geron Corporation presents new data at ASH 2025 highlighting the relationship between treatment-emergent cytopenias and clinical benefit of RYTELO (imetelstat) in lower-risk MDS. Dec 8, 2025.

5. Rona Therapeutics. Rona Therapeutics unveils the global first bi-valent PCSK9–LPA siRNA into clinical development for cardiovascular risk reduction. Dec 17, 2025.

6. Amylyx Pharmaceuticals. Amylyx Pharmaceuticals announces new safety and tolerability cohort 1 data of AMX0114 in ALS from first-in-human LUMINA trial. Dec 5, 2025.

7. Biogen Inc. and Stoke Therapeutics. Biogen and Stoke Therapeutics present data that further support the disease-modifying potential of zorevunersen in Dravet syndrome. Dec 5, 2025.

8. Żak MM, Yoo J, Utrero-Rico A et al. A tumor-selective mRNA system enables precision cancer treatment. Mol. Ther. 2025; published online Nov 15. Link

9. Yan Y, Wu T, Li H, Tang Y, Qian F. The future of AI-driven RNA drug development. Engineering. 2025; 55, 21–23. Link

10. Ionis Pharmaceuticals. Ionis receives US FDA Breakthrough Therapy designation for zilganersen for Alexander disease. Dec 2, 2025.

11. Arrowhead Pharmaceuticals. Arrowhead Pharmaceuticals receives US FDA Breakthrough Therapy designation for plozasiran in severe hypertriglyceridemia. Dec 2, 2025.

12. Alnylam Pharmaceuticals. Alnylam announces Health Canada approval of AMVUTTRA^® (vutrisiran), the first and only RNAi therapeutic for the treatment of cardiomyopathy in adult patients with ATTR amyloidosis. Dec 16, 2025.