LncRNA Pioneer Song Xu and LingTaiKe Bio Tackle Stability and Extrahepatic Targeting Challenges in Nucleic Acid Therapeutics

In 1999, Song Xu, founder of lncTAC Biotech, was conducting postdoctoral research at Yale University. To demonstrate the association between tissue factor and tumor metastasis, Song designed relevant experiments, only to find that among tumor cell clones overexpressing tissue factor, some exhibited strong metastatic potential while others showed weak metastatic capacity. “At the time, I thought something had gone wrong with the experiment; I never imagined it would later turn out to be such a significant discovery,” Song recalled.

Two decades ago, RNA interference research was just emerging. At that time, the prevailing view held that RNA functioned exclusively through complementarity with other RNA or DNA molecules, and the scientific community largely rejected the notion that RNA could operate through alternative mechanisms. However, Song Xu discovered that long non-coding RNA (lncRNA) regulates tumor metastasis by interacting with proteins, a finding that stood in stark contrast to the conventional wisdom of the era.

Song Xu described the experience as truly “painful” when trying to demonstrate the novel functions of lncRNA, as he could find no relevant clues in any published papers. This situation persisted for a year, with his experiments making little headway. “It was only through a sudden flash of inspiration that I considered whether RNA–protein interactions might be responsible for this phenomenon, and the problem was then readily resolved.”

It was precisely this “accident” that made Song Xu one of the pioneers in the field of lncRNA, and he was among the first internationally to report on the role of lncRNA–protein interactions in the mechanisms underlying tumor initiation and progression.

To date, the lncRNA field has become a hotbed of rapid development. In China, lncTAC, a company focused on lncRNA, has been established for over two years. This stems from Song Xu’s “accident” more than 20 years ago, and even more so from his perseverance.

In the early 2000s, it was difficult for the public to accept this new mechanism because Song Xu’s research findings were inconsistent with the prevailing understanding of lncRNAs in the scientific community at that time. In 2005, Science published a relevant paper reporting that a research team had concluded, based on gene-knockout mouse experiments, that lncRNAs lacked biological function, thereby refuting previously discovered mechanisms and functions of lncRNAs.

Pioneering a new field inevitably means facing widespread skepticism in the early stages. After returning to China in 2006, Song Xu encountered a second wave of doubt. “At that time, many people advised me against working on lncRNA and instead suggested I focus on small RNAs. Similarly, when I founded lncTAC, it was difficult to explain our business model to others because there were no comparable companies internationally. They also advised me not to pursue this path.”

Not until 2008, after *Science*, *Nature*, and *Cell* published reviews on lncRNA, the mechanisms related to lncRNA have gained widespread recognition, and this field has gradually become a hotspot.2021,Globally, there have been successive reports ofFlagship Pioneering、Sanofi Ventures、Inkef Capital、Bristol Myers SquibbLeading incubators and investment firmsInitiating strategic entry into the lncRNA field.

After More Than 20 Years of Waiting, the Era of lncRNA Drugs Has Finally Arrived.

The number of lncRNA projects approved by the National Natural Science Foundation of China surged from 1 in 2007 to 717 in 2018.Extensive research has demonstrated that long non-coding RNAs (lncRNAs) regulate gene expression at multiple levels, including epigenetic modification, transcriptional regulation, and protein translation. They are widely involved in physiological processes such as cell differentiation and organismal development, and are closely associated with the pathogenesis of major human diseases, including cancer. Furthermore, lncRNA-based therapeutics are not constrained by the type or localization of target molecules; potential targets include extracellular, membrane-bound, and intracellular molecules, while DNA, RNA, and proteins all serve as potential target molecules for lncRNA drugs.

lncRNAs are becoming a sustained focus of interest in both basic and applied biomedical research, with extensive studies on their functions and mechanisms of action creating new opportunities for the development of lncRNA-based therapeutics.

"When the industry was still a blue ocean, Song Xu also chose to personally step into entrepreneurship. 'Perhaps by licensing the results to companies, they would move faster in operations, and I would bear relatively less risk.'"However, when it comes to the know-how truly involved in product R&D, the pace of translation may actually be slower without the full-process participation of basic scientists.“Moreover, lncTAC’s current team composition is highly rational, allowing me to remain deeply focused on the scientific translation of lncRNA-related technologies.”

In April 2021, lncTAC was co-founded by Song Xu, Qin Chong, and Ding Lihua. As the first innovative enterprise in China dedicated to the research and development of lncRNA-based therapeutics, lncTAC is also one of the few companies worldwide that have mastered the core technology of multifunctional modular lncRNA drugs.

Benefiting from decades of prior basic research experience in the lncRNA field, Xu Song is currently primarily responsible for R&D and management in the company’s biological direction; Co-founder and CTO Chong Qin is primarily responsible for R&D and management in the company’s chemical direction; Co-founder and CEO Lihua Ding oversees the overall management and operations of lncTAC.

Professor Qin Chong, a renowned expert in the field of protein degradation and a doctoral supervisor at Ocean University of China, has successfully developed the most potent BET protein degrader reported to date, exhibiting activity 100–5,000 times greater than that of comparable BET degraders.

Mr. Ding Lihua boasts over 20 years of executive experience in multinational corporations, having served as Director of the Prescription Drug Division at Xi’an Janssen Pharmaceutical Ltd., General Manager of Abbott Laboratories’ China operations, and General Manager of Fresenius Kabi Huari Pharmaceutical (China), where he was also a core member of the Asia-Pacific management team. Additionally, he has extensive experience in domestic innovative enterprises, spanning from market development to comprehensive corporate management. His achievements include restructuring the China team of Hong Kong-based Qianfan Pharmaceutical and serving as its General Manager for China, establishing the marketing headquarters of Hisun Pharmaceutical (a listed company) and serving as its General Manager, and building the business unit structure of Yikang Pharmaceutical Group while serving as the Group’s Executive President.

In addition to the three founders’ interdisciplinary and industrial backgrounds, lncTAC is overall an R&D-driven, multidisciplinary team. Its members possess expertise spanning oncology, biology, chemistry, immunology, and related fields, with more than 50% holding master’s or doctoral degrees.

Benefiting from three founders with complementary expertise, lncTAC is developing in a focused and efficient manner in the field of lncRNA.

But wantNeedIn the field of nucleic acid therapeutics, one must confront the common pain points in development: instability and delivery challenges. Stability determines the therapeutic efficacy, dosing interval, and cost of the product. Meanwhile, extrahepatic delivery technology dictates the future market size of nucleic acid drugs; solving targeted delivery to each specific organ represents a market opportunity worth tens of billions of U.S. dollars.

Resolving these two issues can significantly improve the success rate of drug development.According to BIO（Biotechnology Innovation Organization）、Informa Pharma Intelligence、A report jointly released by QLS shows：2011–2020，The average success rate of drug development projects from Phase I clinical trials to obtaining U.S. FDA approval for market launch is only7.9%. Meanwhile, Alnylam, the siRNA leader, has increased the overall success rate of drug development to64.3%, its success is primarily attributed to siRNA stabilization technology and liver-targeting technology.

Compared with other nucleic acid drugs, lncRNA-based therapeutics exhibit superior stability and are not constrained by the type or location of the target molecule.

Song Xu introduced,“You can think of mRNA drugs as one-dimensional molecules that primarily function through sequence-encoded proteins; small nucleic acid drugs are like two-dimensional molecules that mainly function by targeting RNA; while lncRNAs are three-dimensional molecules that primarily rely on their spatial structures to exert their effects. Based on these three-dimensional structures, we can develop more functionalities, but we must also establish a technological platform entirely distinct from those currently used for nucleic acid drugs.”

Moreover, lncRNAs naturally possess abundant stability modules, delivery modules, functional modules, and target modules. Leveraging this characteristic, lncTAC has spent two years refining its globally leading platforms for nucleic acid stabilization, delivery, and functionality.

It is worth mentioning that lncTAC’s stability technology can be used not only to stabilize lncRNA therapeutics, but also small nucleic acid drugs such as siRNA, ASO, and mRNA.According to assessments conducted by third-party CRO companies, lncTAC’s stability technology platform not only enhances the stability of ASO drugs but also improves their knockdown efficacy by dozens of times.

Furthermore, lncTAC has developed a series of extrahepatic targeted delivery technologies for various organ tissues and cells. These delivery modules are capable of delivering not only nucleic acid therapeutics but also various other molecules, including small-molecule drugs, radiopharmaceuticals, and toxins.“How can we gain external recognition for our delivery technology? It’s simple: we can conduct a live demonstration to let everyone witness whether we can achieve extrahepatic delivery.”

In terms of product portfolio strategy, lncTAC also differs from most international lncRNA companies. While the majority of lncRNA firms focus on developing drugs with lncRNAs as therapeutic targets, lncTAC adopts a modular approach to lncRNAs for innovative drug development, rather than merely treating them as targets. Based on human tissues and organs, lncTAC has screened and identified a comprehensive set of targeting modules capable of directing therapeutics to cells in various extrahepatic organs and tissues. Leveraging these modules, lncTAC is currently developing oncology drugs targeting extrahepatic sites.

Currently, lncTAC has completed preclinical candidate (PCC) selection for two projects, validating its lncRNA modular drug discovery platform, and is expected to enter the investigational new drug (IND) stage next year.

Regarding future development, Song Xu stated, “In the next 3 to 5 years,lncTAC will accelerate the commercialization of its products through in-depth collaborations with domestic and international enterprises and licensed market development.“If we merely provide a large number of collaborative pipelines, our stability technology platform and extrahepatic delivery technology platform have yet to deliver their maximum value to the industry. We hope to seize more opportunities in the future to help enterprises across the upstream and downstream of the industrial chain address pain points in delivery and stability, thereby jointly advancing the development of the industry.”