Dr. Liu Guangzhi of Beijing Anzhen Hospital: Antigen-Specific Immunotherapy for Multiple Sclerosis Shows Promise, with Ex Vivo Treg Expansion Emerging as a Key Technological Frontier

Beyond Leading the Future of Medicine, the Rare Disease Market for Multiple Sclerosis Is Also an Untapped Gold Mine.

First, in terms of returns,As a lifelong condition, multiple sclerosis requires patients to take medication long-term, resulting in substantial medical costs. Consequently, developers can achieve significant revenue after product launch. Taking teriflunomide tablets as an example, if not covered by insurance, one box costs RMB 7,896. With a dosage of one tablet per day for 28 days, the average daily cost amounts to RMB 280.

Secondly, in the global multiple sclerosis treatment market,From 2022 to 2030, the global multiple sclerosis (MS) patient population is projected to grow at a compound annual growth rate (CAGR) of 2.8%, with the total market size reaching $28.09 billion. This has naturally attracted major pharmaceutical companies to compete in the MS market, with industry leaders such as Biogen, Novartis, Roche, and Sanofi holding significant shares in the multiple sclerosis drug market.

Finally, in terms of R&D status,As of 2019, there were 28 marketed drugs for multiple sclerosis, 14 in the registration phase, 4 in the pre-registration phase, and 24 in Phase III clinical trials. Furthermore, in 2021, two new multiple sclerosis treatments from Biogen—dimethyl fumarate enteric-coated capsules (Tecfidera™) and fampridine sustained-release tablets (Fampyra™)—were officially launched in China, ushering in a new era for multiple sclerosis treatment in the country.

Although, from an overall perspective,China's Multiple Sclerosis Pharmaceutical Market Is Still in Its Early Stages, but the favorable policy trends have also spurred a surge in domestic investment and R&D.

Since multiple sclerosis was officially included in the First Batch of Rare Diseases Catalogue in 2018, policy barriers have been gradually dismantled. In particular, after China joined the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), various standards have largely aligned with international norms. In May 2020, multiple sclerosis was included in the national medical insurance reimbursement negotiations.

This is undoubtedly a significant impetus for the market access of multiple sclerosis drugs in China. Under this positive signal, high-value medications for multiple sclerosis are unleashing their market potential and becoming increasingly attractive.

In 2011, "antigen-specific CD4⁺“The Preclinical Research Project on Regulatory T Cell Injection Therapy for Multiple Sclerosis” was officially launched, and to date, the R&D work of Liu Guangzhi’s team has spanned 11 years.

Over the course of 11 years of research, observation, and reflection, Liu Guangzhi identified a problem, namelyCurrently available treatments for multiple sclerosis are non-specific and are associated with numerous side effects upon long-term use.

Based on this, the team began to extract initial T cells from the patient's blood and conducted parallel studies with the patient's B cells. After sequential stimulation with cytokines, it was found that CD4⁺ Studies on the mechanism of regulatory T cells (Tregs) in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) suggest that they may serve as a novel therapeutic target, which has subsequently been confirmed in multiple animal experiments.CD4+ regulatory T cells (Tregs) can significantly alleviate the clinical severity of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS).

However, the team did not stop there; after identifying an effective and specific therapy, they began to explore ways to further enhance its efficiency.

Summarizing the experience from multiple previous studies, Liu Guangzhi also discovered that patients with multiple sclerosis exhibit functional defects in regulatory T cells (Tregs). To address this challenge, the team attemptedIsolation of Functionally Competent Tregs via In Vitro Culture。

This process is specifically divided into five steps: Step 1 involves isolating B cells from EAE model mice using immunomagnetic beads, followed by activation induced by sCD40L; Step 2 entails isolating naïve T cells using the same method and co-culturing them with the activated B cells; Step 3 utilizes flow cytometry sorting to isolate CD4⁺CD25^highCD127^lowregulatory T cells; the fourth step involves injecting the sorted Treg cells into EAE model mice (2×10⁴ per mouse), and observing initial symptom improvement through body weight and clinical scoring; finally, peripheral blood mononuclear cells (PBMCs) are harvested, B cells are isolated using immunomagnetic beads, activated with sCD40L to acquire antigen-presenting function, and CD4⁺Naïve T cells co-cultured with activated B cells.

Results from extensive experiments indicate:In Vitro Induction and Expansion of Mouse Myelin Oligodendrocyte Glycoprotein (MOG) by sCD40L-Activated B Cells_35-55Specific CD4⁺CD25⁺Tregs, and for the first time, they were injected to treat EAE mice, with efficacy and safety assessments meeting the required standards.

Furthermore, to further amplify human myelin basic protein (MBP)_85-99Specific CD4⁺CD25⁺Treg, the team also establishedHumanized NSG Mouse EAE Model, the cells were injected into the model to evaluate efficacy and safety, providing a basis for subsequent clinical trials and laying the foundation for specific immunomodulatory clinical therapies targeting multiple sclerosis.

Liu Guangzhi revealed that, currentlyNo in vitro induction and expansion of MBP has been observed._85-99Antigen-Specific CD4⁺CD25⁺Tregs and Reports on Their Use in the Treatment of EAE, nor have there been reports of intervention studies similar to those for multiple sclerosis. In short, in vitro culture technology represents the team’s most notable innovation.

It is reported that the project’s animal experiments are currently nearing completion.

In the next phase of plans, the team will also launchStudies in Large Animals (e.g., Non-Human Primates), Treg cell injections were administered to their EAE models to evaluate efficacy and safety. Meanwhile, as one of the national clinical research institutions for stem cells, the team is also preparing to launch a multicenter clinical trial of Treg therapy in MS patients, enrolling 30 cases to assess the efficacy and safety following Treg cell injection, with translation into clinical application if feasible.

In fact, each step—from mouse studies to primate trials, and ultimately to applying for clinical trial approval and conducting human trials—requires substantial financial support. Liu Guangzhi stated that the team is eager to attract investors with a R&D background to provide funding and jointly advance the research and development efforts.

“From bench to bedside.” Liu Guangzhi, who regards saving lives as his sacred duty, is equally committed to identifying clinical problems, addressing them through technical research, and refining solutions based on patient feedback. Only through this iterative cycle can true translational success be achieved, and throughout this entire process, Liu Guangzhi has consistently adhered toPrioritize R&D activities above all else.

In fact, steady R&D is a form of translation, but translation is not limited to R&D. Therefore, as a scientific researcher, Liu Guangzhi also pays special attention to the following four points:

First, cultivate patience and perseverance in scientific research, maintaining steadfastness until breakthroughs emerge. Second, adjust your mindset to withstand setbacks; remain optimistic about tackling critical bottlenecks in research and be well-prepared to address them. Third, do not treat publications as the ultimate goal of research; instead, foster a developmental perspective in technical studies to promote the horizontal expansion of research topics. Fourth, maintain a strong awareness of translation, consciously applying ideas to clinical practice.