Engineered BDNF producing cells as a potential treatment for neurologic disease

Abstract

Introduction Brain-derived neurotrophic factor (BDNF) has been implicated in wide range of neurological diseases and injury. This neurotrophic factor is vital for neuronal health, survival, and synaptic connectivity. Many therapies focus on the restoration or enhancement of BDNF following injury or disease progression. Areas covered The present review will focus on the mechanisms in which BDNF exerts its beneficial functioning, current BDNF therapies, issues and potential solutions for delivery of neurotrophic factors to the central nervous system, and other disease indications that may benefit from overexpression or restoration of BDNF. Expert opinion Due to the role of BDNF in neuronal development, maturation, and health, BDNF is implicated in numerous neurological diseases making it a prime therapeutic agent. Numerous studies have shown the therapeutic potential of BDNF in a number of neurodegenerative disease models and in acute CNS injury, however clinical translation has fallen short due to issues in delivering this molecule. The use of MSC as a delivery platform for BDNF holds great promise for clinical advancement of neurotrophic factor restoration. The ease with which MSC can be engineered opens the door to the possibility of using this cell-based delivery system to advance a BDNF therapy to the clinic.

Preclinical translation of exosomes derived from mesenchymal stem/stromal cells

“…4 There are likely several reasons for such differences observed between MSC preclinical and clinical studies such as potency, consistency and scale-up manufacturing issues which have been reviewed elsewhere. 4,5 MSCs' therapeutic effects are generally thought to be mediated through the secretion of a variety of factors including canonical secretory proteins such as cytokines and growth factors, as well as exosomes [6][7][8][9][10] (Figure 1). MSCs act as a localized delivery system by secreting such factors, which then in turn affect the physiology of both adjacent and distant responder cells.…”

An update on stem cell therapy for neurological disorders: cell death pathways as therapeutic targets

“…Recent studies by this research group also alluded to the potential of stem cells for stroke and other neurological disorders. For example, the potential of MSCs is discussed as a delivery platform for bioactive factors such as brainderived neurotrophic factors, BDNF [4] and as a foundation to enhance treatment of neurologic diseases, specifically Huntington's disease [5,6]. The present review article and the authors' recent studies also demonstrate how the transplanted MSCs successfully migrate to the area of infraction and induce angiogenesis, neurogenesis, and neurite outgrowth through neuroprotective factors.…”

The Transcription Factor XBP1 in Memory and Cognition: implications in Alzheimer’s Disease

“…However, an important aspect to consider, besides proving a therapeutic concept in animal models and generating a drug to effectively translate that concept to clinics, is the challenge to efficaciously deliver a molecule to the brain due to constraints of bioavailability and the blood-brain barrier. In that regard, nanoparticle-based drug engineering (234) and/or MSC-based therapy (200), if proved efficient, could help overcome a rampant problem encountered in the pharmaceutical industry in general and lead to clinical trials with more positive outcomes. Hence, XBP1 and downstream pathways (see Figure 1) merit aggressive and thorough exploration as genuine therapeutic targets that could pave the way for more effective disease-modifying therapies in AD pathology.…”

“…More recent approaches utilizing human mesenchymal stem cells (MSCs) that have been genetically engineered to produce BDNF have shown beneficial outcomes in a Huntington disease model (199). Importantly, some pharmaceutical companies, namely Atherys, SanBio and Brain Storm Therapeutics, finalized several MSC therapy-based phase II clinical trials involving ischemic stroke and amyotrophic lateral sclerosis patients and reported no adverse effects whatsoever (200). Furthermore, modulating the IRE1α-XBP1 pathway with small-molecule compounds could be a promising approach for disease therapy (201), since various studies have reported that XBP1 protects against oligomeric forms of prion protein or α-synuclein (167,(202)(203)(204).…”