Tumor protein encoding [negatively charged] RNA-nanoparticles induced robust anti-tumor response

This week journal Nature published study that showed that negatively charged [cancer antigen encoding] RNA-nanoparticles are selectively take up by antigen-presenting cells in lymphoid tissues and induced robust type I IFN driven anti-tumor immune response to all tumors tested.

In earlier studies for in vivo delivery of RNA/DNA nucleic acids into antigen-presenting cells scientists have used positively charged [cationic] nanoparticles. However, such particles were mostly trapped within lungs rather than lymphoid tissues where most antigen-presenting cells, such as dendrtic cells, reside. Surprisingly, here the authors showed that negatively charged RNA-nanoparticles selectively accumulated in spleen within antigen-presenting cells after in vivo injection.

Strangely, accumulation of RNA-nanoparticles were reduced when mice were depleted of conventional DCs (cDCs) after diphtheria toxin injection (CD11-DRT BM chimera mice), even though these mice retain both plasmacytoid DCs (pDCs) and macrophages which can themselves capture RNA-nanoparticles.

RNA-nanoparticle injection was associated with rapid IFN-α secretion in a manner that depended on TLR7 expression.

In addition, RNA-nanoparticles induced robust priming of antigen-specific adaptive immune response.

More importantly, injection of tumor protein encoding RNA-nanoparticles delivered incredibly robust prophylactic and therapeutic anti-tumor effect (article has some preliminary  results from phase I study showing T cell priming in cancer patient after RNA-nanoparticle delivery).

In summary, the authors of this study believe that they found universal antigen delivery RNA-nanoparticle construct that induces robust adaptive immune response.

There is one thing that is puzzling about this study which the authors did not tried explain: in mice depletion of cDCs eliminated RNA-nanoparticle uptake and T cell priming. However, pDCs are not depleted in CD11c-DTR chimera mice and the data showed that pDCs are themselves could capture RNA-nanoparticles and are the main source of type I IFNs. So, the question then is why cDCs depletion has such disproportional effect?

David Usharauli

Immunotherapy of Alzheimer-like cis-tauopathy after repetitive head injury

Alzheimer's disease is a neurodegenerative disorder of unknown etiology. Currently there is no cure. One reason is that we don't know much about its pathophysiology. Two major hypotheses dominate the field: β-amyloid and tau hypothesis. In both models, aggregation and deposition of suspected proteins (β-amyloid or tau) causes neuronal death leading to loss of cognitive functions.

A new paper published in journal Nature belongs to tau model. In this research article, the authors showed that cis, but not trans form of phospho-tau (P-tau) protein contributes to development of Alzheimer-like tauopathy during traumatic brain injury that could be reversed by anti-cis antibody immunotherapy.

Here, using mouse model of traumatic head injury, the authors showed that chronic repetitive head injury caused widespread cis P-tau appearance in the brain.

Next, the authors showed that brain lysates prepared from chronically injured brain tissue could induce in vitro neuronal death that could be prevented by anti-cis antibody.

Similarly, the authors showed anti-cis antibody could reverse neuronal cell death following hypoxia or serum deprivation.

More importantly, mice treated in vivo with anti-cis antibody showed significant reduction of tau protein expression in brain tissue after brain injury.

Mechanistically, the authors hypothesized that anti-cis antibody are taken up by neurons via Fcγ receptors, internalized and interact with intracellular FcR TRIM21 that leads to tau protein detection and its elimination by proteasomal degradation.

However, it is not clear how anti-cis antibody is able to reach neurons, to begin with. BBB is not easily accessible to antibodies.

David Usharauli