RNA therapeutics represents a new class of modern medicine for targets considered undruggable. The RNA based drug targets remain hidden inside the cells within the cytosol of the cell. Nanoparticle based platforms efficiently enter inside cells through the process of endocytosis, they remain sequestered within the membrane-derived vesicles which prevents cytosolic delivery of RNA. Our lab has two major long term goals:

  1. Gain fundamental insights onto the intracellular delivery of novel drug delivery systems and identify mechanisms of endosomal escape.
  2. Engineer efficient delivery platforms based on mechanistic insights gained through dissecting the gateways of cellular entry and endosomal escape.

Our primary focus is to deliver messenger RNA for the treatment of various disorders, of particular interest is lysosomal storage disorder based rare disorders and novel cancer therapeutics.

We believe that through insights generated through fundamental know how of nanoparticle processing through endocytosis, we will begin to answer some central questions in drug delivery. e.g. 1. Can we deliver new molecules to hard to transfect cell populations? 2. Can we improve potency and reduce toxicity through improved cytosolic delivery? 3. Can we target our nanocarriers to selective tissues that bear different endosomal machinery? 4. What are the mechanisms of endosomal escape and how does this insight help in designing new nanocarriers.

Project 1

Overcoming endosomal barriers

The deployment of molecular to microscale carriers for intracellular delivery has tremendous potential for biology and medicine, especially for in vivo therapies. The field remains limited, however, by a poor understanding of how carriers gain access to the cell interior. Furthermore, intracellular delivery into the cytosol remains the biggest hurdle for drugs to reach its target. Our current understanding of endosomal escape comes through pertinent examples from the cell biology of how viruses, bacteria, non-viral vectors and their effectors can enter cells and escape endosomal confinement. To decode the mechanisms of endosomal escape and improve cytosolic drug/gene delivery, our lab is currently developing methods 1. That allows rapid analysis of pathways of intracellular delivery and escape for multiple carriers 2. That enhances cytosolic delivery and efficacy of nucleic acids, especially modified messenger RNA for therapeutic production of proteins.

Project 2

Therapies for Lysosomal Storage Disorders (LSDs)

LSDs constitute a group of approx. 50 rare inherited metabolic disorders. Currently, our lab focuses on development of therapeutics for Niemann Pick Type C-1 (NPC1) based lipid storage disorder. NPC1 is 13-membrane trans-membrane protein that is present on the surface of late/endosome lysosomes and is responsible for cholesterol recycling. Absence of NPC1 leads to large accumulation of cholesterol in enlarged late endosome/lysosomes. NPC1 deficiency leads to neurodegeneration and hepatotoxicity. Our previous work demonstrates that lipid based nanoparticles preferentially accumulate in late endosome/lysosomes and our retained in these structures, thus these carriers our very effective in delivery of nucleic acids and or drugs.

Our lab has developed a potent liposomal formulation that delivers 2-Hydroxy propyl β cyclodextrin, a cholesterol scavenger at extremely doses. 2-Hydroxy propyl β cyclodextrin has shown effective treatment in preclinical NPC1 animal models but clinical trials in NPC1 patients, shows severe toxicity due to large dose that is being administered. Our technology (patent pending) has shown ca. 20 fold improvement in drug delivery in NPC1 deficient cells.

We are developing novel carrier mediated delivery vectors for delivery of mRNA/DNA/proteins for intracellular delivery of different LSDs.

Project 3

New technologies for drug delivery for cancer and other devastating diseases

We are currently working with different research labs and companies to engineer non- viral vectors based on polymers/lipids or bioinspired materials for delivery of different nucleic acids for drug/gene delivery for treatment of cancer, infectious diseases and rare genetic disorders These technologies are based on our deep understanding of the endo/lysosomal pathways. (Stay tuned for more).