Early Career Researcher Interview: Developing a receptor-mediated targeted ASO therapy for severe neuromuscular disorders, Biologics TIN

In this interview as part of the Early Career Researchers series, recognising the amazing translational work being done by postdocs and non-tenured researchers at  UCL, Dr Sara Aguti highlights her Biologics Therapeutic Innovation Network (TIN) Pilot Data Scheme awarded project, developing a novel approach to treat severe neuromuscular disorders. 

What is the title of your project and what does it involve?

The title of my project is: “Preclinical development of a targeted antisense oligonucleotide delivery for collagen VI- related congenital muscular dystrophy”.

This project aims to enhance the delivery of antisense oligonucleotide (ASO) therapies in muscle fibroblasts which represents the major bottleneck for ASO therapy development in collagen VI-related congenital muscular dystrophy.

What is the motivation behind your project/therapeutic? What is the unmet medial need?

Collagen VI-related congenital muscular dystrophies (COL6-CMDs) are a group of severe neuromuscular disorders for which there is currently no cure. In the past years, we identified ASO sequences able to correct common dominant mutations in fibroblasts cultured from COL6-CMD patients. We showed that ASO therapy represents a potential therapeutic approach for COL6-CMDs, however, in vivo studies using naked ASOs have shown poor ASO uptake in the target cells which are muscle interstitial fibroblasts (MIFs).

Hence, our proposed solution to tackle the existing bottleneck is the development of a receptor-mediated targeted ASO therapy. We plan to conjugate our ASO sequences with peptides capable of targeting a receptor predominantly expressed in MIFs, rather than in other muscle cells. This strategy aims to enhance the biodistribution and in vivo uptake of ASOs in MIF cells, thereby expediting the clinical translation of ASOs for COL6-CMD patients.

Why did you want to apply to the Biologics TIN Pilot Data Scheme?

The TIN Pilot Data Fund offers an outstanding opportunity for early-career researchers for two key reasons. Firstly, it allows you to take the lead as the principal investigator on the project, and secondly, it enables you to generate the preliminary data needed for applying for larger grants or fellowships. Such funds are essential for advancing your project and gaining valuable experience in leading your own research.

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How did you find the process for the TIN Pilot Data Scheme? What did you learn?

The application process was straightforward. Through this application, I acquired valuable skills in efficiently summarizing and being concise while explaining the project’s aims and work plan. Additionally, they provided opportunities to participate in training workshops and receive pitch training before the interview. I highly recommend taking advantage of these types of training opportunities.

What do you hope to achieve in the 6 months duration of your project?

During the duration of my project, I aim to establish that the conjugation of our ASO sequences with specific peptides capable of binding to a receptor predominantly expressed in muscle fibroblasts will significantly enhance delivery when compared to naked ASO in vitro experiments. If successful, these findings will allow to move this study to animal models, enabling us to investigate ASO biodistribution in vivo.

What are your next steps from now?

My next step for this project is to utilize the data generated from TIN and apply for a larger grant to assess these new delivery methods in vivo using mouse models. If this targeted ASO-peptide delivery proves effective in enhancing ASO uptake in target cells in vivo, it will have a positive impact not only on COL6-CMDs but also on various other diseases where targeting fibroblasts is desirable. This will enable me to expand my work to address a broader range of disorders.

About Dr Sara Aguti

Sara Aguti is a Senior Research Fellow at the Genetic Therapy Accelerator Centre directed by Professor Francesco Muntoni at the UCL Institute of Neurology. She completed her PhD in Neuroscience and subsequently spent four years as a postdoc with a primary focus on developing ASO therapies for collagen VI-related myopathy. Following her postdoctoral work, she transitioned from academia to the industry, joining MiNA Therapeutics to explore another aspect of RNA therapy: RNA activation by directly targeting DNA. She then returned to UCL as a senior research fellow.

Her current work is focused on developing RNA therapies using different strategies, such as antisense oligonucleotide (ASO) for splicing modulation or silencing approaches, small interfering RNA (siRNA), and small activating (saRNA), to correct mutations in both neurological and neuromuscular disorders. Additionally, Sara is keen on advancing the delivery of RNA therapies to specific tissues or cell lines, with a focus on targeting particular cell types in muscle and brain.