Investigators at Brigham and Women’s Hospital and collaborating institutions evaluated the dual-therapeutic effect of gene therapy in a clinically relevant model for common type of bone cancer.

With a worldwide incident rate of three.4 cases per million people per 12 months, osteosarcoma is one of the vital common bone cancers affecting children and adolescents. The present gold standard treatment option requires extensive surgical intervention and chemotherapy that results in a poor prognosis and decreased quality of life. Attributable to the aggressive nature of the disease, the surgical intervention normally involves total reconstruction of the limbs or, usually, amputation. Researchers at Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, in collaboration with investigators at University College Dublin (UCD), Massachusetts Institute of Technology (MIT), and Trinity College Dublin (TCD), have identified a possible therapeutic goal and developed a singular delivery system to treat osteosarcoma. In a preclinical study, the team found that using microRNA nanoparticles delivered locally using a hydrogel suppressed osteosarcoma growth while concurrently decreasing bone damage. Results are published in Advanced Materials.

“The usual-of-care treatment plan today isn’t any different in comparison with when first introduced almost 50 years ago,” said lead creator Fiona Freeman, PhD, an assistant professor at UCD School of Mechanical and Materials Engineering and Fellow at UCD Conway Institute, who accomplished the study during her Marie Skłodowska-Curie Global Fellowship within the Artzi lab on the Brigham and MIT. “Nearly one third of patients relapse and want latest interventions. This unmet clinical need prompted us to deal with the possible use of microRNA therapy in osteosarcoma, and specifically on a genetic goal called miR-29b.”

Of their study, the researchers explored the therapeutic potential of miR-29b, a microRNA they hypothesized could block osteosarcoma tumor growth. MicroRNAs are a family of molecules that help control certain activities in cells like growth and development. They’re showing promising leads to the treatment of cancer and viral infection. The team developed a formulation of miR-29b nanoparticles that were delivered via a hyaluronic-based hydrogel delivery system on to the tumor site. The hyaluronic-based injectable delivery system turned to gel on the goal area of the body in a matter of minutes and allowed for local and sustained delivery of the miR-29b to the first tumor site.

“This work seeks to reply a crucial basic science query, as to the balance between with the ability to regenerate damaged bone in order that these young patients is not going to lose their limbs while stopping tumor reoccurrence,” said senior creator Natalie Artzi, PhD, of the Brigham’s Department of Medicine.

Our study demonstrates the facility of local delivery—the miR-29b loaded nanoparticles improve the therapeutic potential of chemotherapy and suppress tumor growth, while concurrently aiding within the repair of the encircling damaged bone even while the patient is undergoing chemotherapy treatment.”

Natalie Artzi, PhD, Senior Writer, Brigham’s Department of Medicine

Along with evaluating whether the gene therapy approach could decrease tumor growth, the investigators also assessed whether the therapy could normalize the dysregulation of bone growth. Each chemotherapeutics and osteosarcoma tumors have been shown to disrupt bone’s ability to repair following surgical intervention.

In a mouse model of osteosarcoma, the researchers compared the addition of the hydrogel gene therapy with chemotherapy to chemotherapy alone. The team found that when miR-29b was delivered together with systemic chemotherapy, the therapy provided a major decrease in tumor burden, a rise in mouse survival, and a major decrease within the destruction of the bone attributable to the tumor. The research team also validated the therapeutic potential using two predictive models of the disease; a 3D co-culture spheroid model; and an orthotopic metastatic murine model.

This work highlights the importance of leveraging biomaterials to reinforce the therapeutic window of therapies that will not give you the chance to achieve the goal site in adequate amounts due to premature degradation or systemic toxicity.  By doing so, the mechanisms related to the therapy could be studied and the fitting drug combination and timed release could be realized. The team’s approach may enable, in the long run, the delivery of immune modulating agents that could be leveraged to coach the immune system to stop cancer reoccurrence—a serious problem in osteosarcoma patients.

The research team is committed to constructing on this research and advancing this technology towards clinical application. Studies like this multi-institutional collaboration show the promise of gene therapy for treating conditions like osteosarcoma and other difficult-to-treat cancers. Mass General Brigham recently launched its Gene and Cell Therapy Institute to assist translate scientific discoveries made by researchers like Artzi, Freeman and colleagues into first-in-human clinical trials and, ultimately, life-changing treatments for patients.

This project was conducted within the Artzi lab in collaboration with researchers inside the laboratory of Daniel Kelly at Trinity College Dublin, Ireland. Freeman spent three years between these two laboratories conducting a Marie Skłodowska-Curie Global Fellowship.

“Fiona’s findings have the potential to revolutionize cancer treatment and improve outcomes by providing vital information that may inform the design of future combination therapies for these young patients,” said Kelly, a professor in Tissue Engineering at Trinity College Dublin and Amber principal investigator, who was co-author of the paper.

Source:

Brigham and Women’s Hospital

Journal reference:

Freeman, F. E., et al. (2023). Localized Nanoparticle‐Mediated Delivery of miR‐29b Normalises the Dysregulation of Bone Homeostasis Attributable to Osteosarcoma Whilst Concurrently Inhibiting Tumour Growth. Advanced Materials. doi.org/10.1002/adma.202207877