Saeed Anwar

At least 27 dead, mostly children, in Bangladesh air force jet crash At least 88 people, including children, are being treated in hospital. The government announced a day of mourning, with flags at half-mast and special prayers at all places of worship.

I can't take it!

My heartfelt prayers go out to everyone affected by the tragic plane crash in Dhaka. Deepest condolences to the families of the victims.

27 fatalities with over 100 injured, most of whom are young kids, when an Air Force training jet crashed into a school campus yesterday.

Third death from a Sarepta gene therapy A third patient, a 51 year-old in a Phase I study of SRP-9004 for Limb-Girdle muscular dystrophy Type 2E, has died from a Sarepta gene therapy.Like two dea...

This is so deeply saddening.

This brings the total toll from AAV-based gene therapies to 9 lives, with other serious adverse effects also emerging.

Clearly, the field is at a crossroads. The call for safer, more precise, and cost-effective delivery systems has never been louder.

Deeply saddened to learn about the tragic incident involving Air India flight AI171.

My thoughts and prayers are with the passengers, crew, and their families. Heartfelt wishes for a quick recovery to those injured and want to offer strength and love to everyone affected.

#apaperaday Today’s oligonucleotide themed pick is from molecular therapy nucleic acids by anwar et al on exon skipping for dysferlin doi 10.1016/j.omtn.2024.102443.
Dysferlinopathies cause progressive muscle weakness in the limb girdle muscles.

Thanks, Dr. Aartsma-Rus, for featuring our study and providing a great breakdown of the work! Really appreciate your thoughtful comments.

One small clarification: we did include a mock-PMO treated control to account for non-specific effects.

The use of mRNA in medicine is growing quickly. This study further emphasizes the necessity of understanding how these particles travel in vivo and interact with the immune system to advance precision medicine.

For me, as someone working with LNPs to deliver synthetic genetic materials, this study backs an important reality—we need better delivery strategies. Whether for vaccines, gene therapies, or RNA therapeutics, refining LNP design is key to maximizing efficacy and minimizing unintended effects.

This study demystifies how mRNA vaccines spread in the body, confirming that LNPs effectively reach immune hubs while avoiding major off-target accumulation. But at the same time, it leaves critical gaps unanswered.

LNP behaviour is known to be species-dependent, yet most biodistribution studies rely on rodent models. While rhesus macaques offer a closer parallel, how well do these findings translate to humans?

I would love to see comparative studies of IM vs. IV administration, as they could be essential to understanding these dynamics.

For gene addition and editing, IV delivery is often the most feasible. However, systemic circulation can significantly affect LNP biodistribution, leading to:
→ Increased liver accumulation
→ Potential cardiac exposure
→ Differential immune engagement, like spleen uptake vs. lymphatic processing

While this study offers important insights into intramuscular (IM) mRNA vaccine delivery, it raises bigger questions for gene therapy applications, particularly those requiring intravenous (IV) delivery.

This aligns with existing knowledge, the study doesn’t explore whether different LNP formulations alter which immune cells preferentially take up nanoparticles. Would tweaking lipid composition change cellular tropism? This could be crucial for boosting immune targeting or reducing inflammation.

Once inside the lymph nodes, LNPs are primarily taken up by antigen-presenting cells (APCs):

→ Dendritic cells → Key for presenting antigens to T cells

→ Monocytes & neutrophils → Early responders influencing inflammation

I guess this is a major consideration, especially as LNPs are being investigated for chronic treatments like gene therapies.

Actually, liver accumulation isn’t surprising—hepatic clearance is a known clearance pathway for LNPs—but what does this mean for long-term safety? Could repeated dosing in therapeutic applications lead to immune modulation or hepatotoxicity?

...that there was minimal off-target distribution, but the liver remains a wildcard!

→ Little to no LNP accumulation in the heart, lungs, or brain (great!)
→ Noticeable LNP presence in the liver, albeit lower than in lymph nodes (not good)

One of the most pressing concerns with LNP-based drug delivery is off-target accumulation. Ideally, LNPs should stay localized to muscle and lymph nodes, ensuring a strong immune response without unnecessary systemic exposure. They found...

So, could this (partially) explain why vaccine efficacy sometimes fluctuates between recipients?

This finding is both reassuring and concerning. It confirms that LNPs effectively reach key immune sites. But it also raises questions about stochastic lymphatic drainage, a factor that could introduce variability in immune response across individuals.

They report that LNPs rapidly reach immune hubs, but transport is variable:
→ Deltoid injections targeted the axillary, apical, and pectoral lymph nodes
→ Quadriceps injections reached the iliac lymph nodes

This study tackled these questions by radiolabeling LNPs and tracking their movement post-injection. They found that just in 4 hours, a big portion had already drained into lymph nodes (dLNs)—indicating that passive lymphatic transport, rather than active immune cell uptake, plays the dominant role.

Since the global rollout of LNP-based COVID-19 mRNA vaccines, LNP-based drug delivery has gained traction, but there are still major knowledge gaps in their in vivo behaviour, particularly regarding systemic circulation, clearance, and immune cell interactions.

Visualizing lipid nanoparticle trafficking for mRNA vaccine delivery in non-human primates Buckley and colleagues report a strategy for in situ imaging of mRNA-lipid nanoparticle vaccines in live animals. Lipid nanoparticles were observed in muscle tissue and draining lymph nodes, with stoc...

This @moltherapy.bsky.social paper by Dr. Darrell Irvine's team at @mitdeptofbe.bsky.social reports real-time visualization of lipid nanoparticle (LNP) biodistribution in rhesus monkeys using PET-CT imaging.

Lifetime of ground conformational state determines the activity of structured RNA - Nature Chemical Biology Biomolecules morph between conformations with distinct lifetimes essential for function. This study reveals the cores of flaviviral RNAs stay stable up to ten million times longer than canonical base ...

RNAs are not necessarily druggable in the same way that proteins are. If you plan to target RNAs, avoid project designs that are particularly suited for protein-targeting approaches.

Antisense oligonucleotide-mediated exon 27 skipping restores dysferlin function in dysferlinopathy patient-derived muscle cells Dysferlinopathy is a progressive muscular disorder caused by the deficiency of dysferlin, a protein crucial for muscle membrane repair. Until now, there has been no effective treatment, significantly ...

Dr. Naoki Suzuki wrote a commentary on our recent paper on DYSF exon 27 skipping for dysferlinopathies! Dr. Suzuki of Tohoku University is a leading expert in the neuromuscular diseases field.

Read below, the expert perspective on our work!

Great thanks to Dr. Suzuki for this insightful piece!

Huge thanks to all my co-authors and collaborators for making this happen! I especially wish to thank my PI, Dr. Toshifumi Yokota, for providing me with the guidance and all the freedom to work on this project as I wanted to!

Apart from that, this is the first proof-of-concept showing that DYSF lacking exons 26–27 retains dysferlin function in patient-derived muscle cells.
Key insights:
→ In vitro functional recovery
→ Cellular improvements
→ Safety of exon-skipping therapy in dysferlinopathy

In vitro, this looks great—but how about in vivo?
But, there’s no existing animal model to test these antisense oligos in vivo.
So, developing a suitable animal model will be crucial to evaluate long-term efficacy, biodistribution, and safety before advancing to preclinical and clinical development.