FGF18

BOSTON, March 13, 2023 /PRNewswire/ -- Remedium Bio, a gene therapy company developing novel treatments for significant unmet needs, today announced the publication of pre-clinical data demonstrating the safety and chondrogenic activity of RMD1101, its innovative gene therapy for Osteoarthritis. These data are the first to be published from Remedium's ongoing research collaboration with Tufts University studying the approach. The paper, entitled "Adeno-Associated Virus-Delivered Fibroblast Growth Factor 18 Gene Therapy Promotes Cartilage Anabolism" will be published in Volume 14, Issue 1 of the journal Cartilage, and is available OnlineFirst. RMD1101 appears safe and effective at promoting cartilage anabolism Key Points AAV2-FGF18 appears to have a wide therapeutic safety window and is able to induce chondrogenesis at very low, locally administered doses The FGF18 gene therapy appears to induce chondrogenesis by increasing hyaline cartilage associated gene expression and promoting chondrocyte proliferation RMD1101 appears safe and effective at promoting cartilage anabolism in vivo, following a single intra articular injection "Having these results published in Cartilage provides important external validation of their significance" said Frank Luppino, President and CEO of Remedium. "Our findings confirm the chondrogenic mechanism after a single injection of RMD1101 and provide preliminary confirmation for the potential of the gene therapy approach to treating Osteoarthritis." RMD1101 is the only disease modifying gene therapy treatment for Osteoarthritis based on the clinically validated chondrogenic mechanism of FGF18. It is being studied as a single injection treatment for OA in both the human and companion animal markets. "Our results show the promise of treating Osteoarthritis by harnessing the endogenous regenerative power of articular cartilage with a single intra-articular injection FGF18 gene therapy," said Dr. Li Zeng, PhD, Associate Professor of Immunology at Tufts University School of Medicine. Dr. Zeng is a co-author of the publication and an expert in Osteoarthritis and the molecular and cellular mechanisms of the disease. Cartilage is a peer-reviewed, open access journal which publishes articles with a focus on recent discoveries related to the musculoskeletal system and cartilage repair, development, and regeneration. The Sage Publishing group, MEDLINE indexed journal publishes full length original manuscripts covering preclinical and clinical research, and is considered among the top journals in the field of cartilage regeneration. About Remedium Remedium Bio, Inc. is a preclinical-stage biotechnology company developing novel gene therapies for a broad range of highly debilitating diseases. The company's R&D approach focuses on modularly combining proven technologies to treat well-characterized disease pathology, thereby streamlining elements of the product development process. Remedium's pipeline includes a lead candidate first-in-class, single-injection, potentially disease-modifying gene therapy for the treatment of Osteoarthritis and treatments for the management of Diabetes and Stroke. To learn more, visit Contact Remedium: info@remedium-bio.com

Chesnot/Getty Images TrialSpark and Sanofi inked a three-year partnership to expedite drug development for areas with high unmet needs through the licensing or acquisition of six mid-to-late-stage drug candidates. New York-based TrialSpark and Sanofi aim to secure up to six best-in-class Phase II and Phase III drug candidates and develop them for diseases with high unmet needs. TrialSpark noted the deal harnesses its innovative clinical development program, which includes behavioral intervention and digital technologies, in order to deliver better outcomes for patients in need. The partnership was announced Tuesday, but the two companies noted work on this endeavor began in September. The companies did not disclose much about the partnership, only noting they will jointly pursue the six drug candidates together. The companies did not disclose any financial details, nor did they reveal what disease areas they aim to take on through the collaboration. TrialSpark’s own areas of interest include rheumatology, dermatology, CNS and cardiometabolic diseases. Although financing was not included in the announcement, TrialSpark raised $156 million in a Series C financing round last year. When that was announced, the company noted those funds were earmarked for the acquisition or licensing of clinical-stage assets. The funds were also tagged for potential investments in other pharma companies that have promising candidates. The Latest in a String of Collaborations TrialSpark’s business model includes the acquisition of assets considered undervalued by larger pharma and biotech companies. TrialSpark in-licenses and co-develops drug programs either in-house or through joint ventures and new companies launch. That model was on display earlier this year when TrialSpark licensed sprifermin, a potential first-in-class disease-modifying recombinant form of human fibroblast growth factor 18, from Merck KGaA. Sprifermin is being assessed as a potential treatment for osteoarthritis. The Germany-based Merck KGaA had taken the drug through mid-stage development, and TrialSpark intended to build on that with a Phase IIb and Phase III trial. In addition to the licensing, TrialSpark formed a new company, High Line Bio, to develop the drug. In order to rapidly advance drugs through the clinic, TrialSpark employs a ‘hub-and-spoke’ approach. The method aims to improve patient enrollment through establishing relationships with physicians and private practices in areas where trials are being conducted. That increases patient and physician access to research, the company claims. Combined with comprehensive trial management, that approach allows clinical studies to initiate at a faster pace, which speeds up the timeline for top-line data. TrialSpark and Sanofi are no strangers. Last year, Sanofi and TrialSpark partnered to increase the speed and efficiency of clinical trials for potential treatments for chronic obstructive pulmonary disease. Sanofi tapped into TrialSpark’s holistic approach to clinical trials that accelerate patient recruitment and enrollment while improving retention. Additionally, TrialSpark’s approach to recruitment was designed to increase minority participation in the studies, which is essential since many Hispanic and African Americans are challenged by COPD but have not historically been included in clinical research.

近日，北京大学生命科学学院、北大-清华生命科学联合中心胡家志课题组在 Nature Communications期刊发表了题为：Comprehensive assessment of miniature CRISPR-Cas12f nucleases for gene disruption 的研究论文。该研究应用了PEM-seq技术对领域内多种CRISPR-Cas系统的编辑活性、脱靶效应以及对基因组稳定性的影响进行了横向比较，重点描绘了CRISPR-Cas12家族编辑工具的特征。编辑活性：作者首先利用GFP荧光报告系统以及PEM-seq技术对领域内四种新型的Cas12f核酸酶（Un1Cas12f1_ge4.1, CasMINI, CasMINI_ge4.1, AsCas12f1），两种Cas12e核酸酶（PlmCas12e及其优化版本PlmCas12e-R1-v2）以及SpCas9、AsCas12a、LbCas12a的编辑活性进行了详细比较。作者发现了新型的Un1Cas12f1、两种CasMINI及PlmCas12e-R1-v2编辑工具在HEK293T细胞中展现了相对有效的编辑活性，尽管其效率普遍低于Cas9或Cas12a；而AsCas12f1及PlmCas12e在大多数位点的编辑效果不佳（图一A-B）。这与之前研究人员猜测AsCas12f1嗜热酶的特性使得其在人类细胞中很难实现最佳的切割活性相吻合3。该研究进而分析了在有效编辑活性下这些不同CRISPR-Cas系统产生的小规模插删（small insertions and deletions，indels）产物的序列特征。作者发现，与Cas9相比，Cas12核酸酶编辑基因组后更倾向于产生缺失产物，并且其碱基缺失的长度与Cas12核酸酶不对称切割两条DNA链所产生黏性末端的突出（overhang）长度相关（图一C），暗示了Cas12编辑更适用于某些需要对特定DNA片段进行删除从而实现治疗效果的临床疾病。相应地，Cas12大大降低了碱基插入的比例，包括在SpCas9编辑产物中频繁出现的1-bp插入。这些结果暗示了不同断裂末端对基因编辑产物的影响。图一. 通过EGFP沉默实验和PEM-seq技术评估微型Cas12核酸酶的编辑能力。A. 不同CRISPR-Cas系统在HEK293T-d2EGFP细胞系的编辑效率检测流程图。B. 在指定靶位点不同Cas酶的GFP基因破坏效率。C. 不同CRISPR-Cas系统编辑产生的碱基缺失长度的模式图。脱靶活性：进一步，该研究发现Cas12f核酸酶具有相对更高的编辑特异性，尽管这种高特异性可能是由于其与Cas9和Cas12a核酸酶相比而言，整体较低的编辑活性。在研究者检测的大多数位点上，都几乎检测不到Cas12f的脱靶位点，而与之共享靶向序列的SpCas9却能够检测到大量的脱靶位点，说明了Cas12f具有较低的脱靶活性（图二A）。这可能是由于Cas12f对于PAM的识别特异性较高，或者其相对较低的编辑活性所导致。染色体结构变异：该研究随后利用PEM-seq分析方法详细比较了各种CRISPR-Cas系统所产生的基因编辑副产物。作者发现了染色体易位、染色体大片端缺失这些有害的基因编辑副产物普遍存在于各个CRISPR基因编辑系统中，但Cas12f核酸酶可以相对有效地抑制这些副产物的产生，这可能与Cas12f编辑酶切割基因组后产生的黏性末端影响了DNA修复途径相关。具体而言，在该研究所检测位点上，SpCas9平均产生了占编辑事件3.6%的染色体易位，1.9%的染色体大片段缺失副产物；而四种Cas12f产生的染色体易位比例处于1.2%-1.6%之间，产生的染色体大片段缺失比例处于0.5%-1.2%之间（图二B-C）。虽然这些染色体结构异常的发生频率相对较低，但常常与癌症的发生相偶联，是基因编辑过程中值得注意的副产物。外源DNA片段插入：值得警惕的是，作者在靶向位点也发现了大片段的DNA插入事件，通过与递送质粒序列进行比对，发现了这些片段来源于递送载体，外源DNA片段的插入会影响插入位点附近其他基因的表达情况甚至引发细胞癌变，为基因编辑带来了不确定性。SpCas9平均产生了占编辑事件5.2%的外源DNA片段插入副产物，而Cas12f切割所导致的的外源DNA片段插入事件的比例可降至1.1-2.2%之间（图二D）。图二. PEM-seq全面评估各种CRISPR-Cas编辑系统的基因编辑副产物。A. 不同编辑工具在FGF18位点所产生的脱靶位点的数目与分布。B-D. 不同Cas酶在基因编辑中所产生的染色体易位事件（B），染色体大片段缺失（C），外源DNA片段插入（D）的比例。总体而言，该工作利用PEM-seq技术系统地比较了各个CRISPR-Cas编辑系统编辑过程中的DNA修复产物，揭示了不同断裂末端影响各类编辑产物的潜在机制，也为新型Cas12f基因编辑工具的临床应用做出了前瞻性的指导。该工作也证实了PEM-seq技术方法用于描绘基因编辑工具特征的广谱适用性、全面性与高灵敏性。但目前Cas12f仍存在着总体编辑活性较低的问题，保持其安全性的同时并进一步提高其编辑效率，将极大地推动微型基因编辑工具的广泛应用。胡家志团队之前将核酸外切酶与Cas9相偶联生成Cas9TX的思路，为这些新型编辑工具的优化提供了方向。论文链接：https://www.nature.com/articles/s41467-022-33346-1