Induced neural stem cells and RNA nanotechnology: a combinatorial approach to spinal cord injury
Funded in: 2016, 2017, 2018
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Problem: Inflammation causes a hostile microenvironment for transplanted stem cells thus limiting their therapeutic potential
Target: Amelioration of the inhospitable nature of the injury site through the use of RNA nanotherapeutics
Goal: Demonstrate the potential merits of multi-modal approaches (nanotherapeutics and stem cells) to spinal cord injury therapy
Neural stem cell transplantation has demonstrated considerable promise as a potential therapeutic avenue in the treatment of spinal cord injury. However, some of these encouraging results have been largely restricted to very early interventions, thus limiting their clinical utility. The low survival/integration rate of stem cell transplants has been ascribed, in part, to the hostile injury microenvironment. Furthermore, there is a number of practical and/or ethical concerns regarding the acquisition of stem cells suitable for transplantation. Here we will investigate a combinatorial approach employing two complementary technologies with the intent of circumventing most of these limitations, and enhancing the efficacy and clinical potential of stem cell therapies.
We will start from the amelioration of the inhospitable nature of the injury site through the use of RNA nanotherapeutics designed to down regulate the expression of the neuroinflammatory protein Lipocalin 2 (Lcn2). Lcn2 is secreted by reactive astrocytes and mediates inflammation by enhancing reactivity in surrounding astrocytes and infiltrating immune cells, as well as by having a toxic effect on surviving neurons (and, potentially, transplanted stem cells). By decreasing the release of Lcn2 we aim at reducing inflammation and increasing the survival of transplanted stem cells.
Our approach is also designed to validate a convenient new source of autologous neural stem cells for transplants: induced neural stem cells (iNSCs). These stably expandable cells can be generated directly from skin cells obtained from the intended recipient, resolving potential ethical and compatibility concerns. iNSCs exhibit properties very similar to their natural analogues, including the ability to differentiate into all neural cell types, therefore suggesting similar therapeutic potential.
In vitro work with anti-Lcn2 RNA nanotherapeutics, looking at their ability to reduce the reactivity of astrocytes and immune cells while enhancing the survival of neurons, will be followed by in vivo trials in animal models of contusion spinal cord injury, comparing and contrasting combinatorial nanotherapeutics + iNSC therapy with the individual treatments, with an eye towards anatomical and functional recovery.
It is our hope to demonstrate the potential merits of multi-modal approaches to spinal cord injury therapy.