RARE - Rachele Rossi

In this episode of RARE, Laura Hulley speaks with Rachele Rossi, a translational medicine director with more than 15 years of experience advancing gene and genetic therapies for rare neuromuscular and neurodegenerative diseases. With a career spanning academia and biotech, Rachele has dedicated much of her work to understanding and treating Duchenne Muscular Dystrophy (DMD), one of the most studied yet still deeply complex rare diseases.

Drawing on her scientific expertise and years of translational research, Rachele shares why DMD remains such a compelling area of focus, the challenges that continue to slow therapeutic progress, and why the field needs to look beyond drug delivery alone to unlock more effective treatments.

 

A Career Shaped by Rare Disease Research

Rachele’s journey into rare diseases began by chance during her PhD and internship at the University of Ferrara in Italy, where she worked in a medical genetics unit focused on rare neurodegenerative and neuromuscular disorders.

Her early research centered on collagenopathies and dystrophinopathies, laying the foundation for a career that has now spanned over 15 years. During her PhD, she also spent time at KTH Royal Institute of Technology, before moving to University College London approximately seven years ago to join the renowned Dubowitz Neuromuscular Centre.

Although she now works in biotech, Rachele maintains an honorary contract with UCL and continues to lead translational grants focused on DMD.

 

Why Duchenne Muscular Dystrophy Remains a Scientific Passion

DMD has been what Rachele describes as “one of the red threads” running throughout her career.

Her motivation is both personal and scientific. Because the DMD community is relatively small and highly engaged, researchers are able to connect directly with patients and families. This close connection provides a powerful reminder of the real-world impact of research.

Scientifically, Rachele is fascinated by the extraordinary complexity of the DMD gene, one of the largest genes in the human genome at approximately two million base pairs.

“It’s around 41 years since the DMD gene was discovered, and still there are so many things we don’t know.”

Her research focuses particularly on the gene’s RNA transcripts and how they are processed, spliced, and translated into dystrophin protein.

 

The Promise and Limitations of Antisense Oligonucleotide Therapies

One of the most promising therapeutic approaches in DMD is exon skipping using antisense oligonucleotides (ASOs). These therapies are designed to restore the reading frame of the DMD gene, enabling production of a shortened but functional dystrophin protein.

Rachele has worked extensively in this field and acknowledges the progress made so far. Four exon-skipping therapies have been approved by the U.S. Food and Drug Administration.

However, she emphasizes that current therapies still have significant limitations.

They restore relatively low levels of dystrophin protein. The clinical benefit remains modest. Collectively, they target only about 27% of the DMD population.

“They are not able to restore enough protein to make a significant change in the life of patients.”

These limitations highlight the need for deeper biological understanding and more effective approaches.

 

Challenges in Rare Disease Research

Rachele identifies challenges on several levels.

Scientific Complexity: DMD is a genetic disorder that requires precise correction of DNA or RNA to create lasting therapeutic effects.

Limited Patient Populations: As with many rare diseases, small numbers of patients make it difficult to conduct large studies with strong statistical power.

Funding Constraints: Rare disease research often receives less funding compared with more common conditions.

The Need for Strategic Planning: Researchers must design studies carefully and use resources efficiently to maximize impact.

 

An Under-Discussed Issue: Transcript Imbalance

One of the most compelling parts of the discussion focused on what Rachele believes is an overlooked challenge in DMD therapy.

When discussing DMD treatment, many experts emphasize a single issue: delivery.

Rachele recalled hearing a prominent researcher say that the three main challenges in DMD are “delivery, delivery, delivery.”

While she acknowledges that getting therapies into muscle cells is critically important, she argues that delivery is only one piece of a much larger puzzle.

Her research highlights a phenomenon known as transcript imbalance, first described in 1996, in which the beginning of the DMD transcript is expressed more strongly than the later portions of the gene.

This means that even if an antisense therapy successfully reaches the cell and induces exon skipping, not all corrected RNA molecules are ultimately translated into dystrophin protein. This biological bottleneck may help explain why high exon-skipping efficiency does not always translate into substantial protein restoration.

 

A Call for Broader Scientific Exploration

Rachele hopes that more research groups and pharmaceutical companies will expand their focus beyond delivery technologies to investigate transcriptional and translational mechanisms that influence treatment outcomes.

Her recent review, co-authored with colleagues in Leiden and Versailles, emphasizes the importance of understanding these underexplored biological processes.

The central message is clear: to develop truly effective DMD therapies, the field must address every stage between gene correction and protein production.

 

Key Takeaways

• Rachele Rossi has spent more than 15 years advancing translational research in rare neuromuscular diseases.
• DMD remains both scientifically fascinating and personally meaningful because of its complexity and close-knit patient community.
• Current exon-skipping therapies represent important progress but restore limited amounts of dystrophin and benefit only a subset of patients.
• Rare disease research faces challenges including small patient populations, limited funding, and complex biology.
• Collaboration across academia, charities, and industry is essential.
• Transcript imbalance is a critical but under-recognized factor that may limit the effectiveness of current therapies.
• Future advances will require looking beyond delivery to better understand RNA processing and protein translation.

 

Rachele Rossi’s insights offer a powerful reminder that meaningful progress in rare disease research depends not only on technological innovation, but also on a willingness to question assumptions and explore overlooked biology. Thank you to Rachele for taking the time to feature and sharing her thoughts.