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IGF-1 Modified NSCs – A Much Awaited Treatment for Alzheimer’s Disease?

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Review of “Human Cortical Neural Stem Cells Expressing Insulin-Like Growth Factor-I: A Novel Cellular Therapy for Alzheimer’s Disease” from Stem Cells Translational Medicine by Stuart P. Atkinson

Alzheimer’s Disease (AD) is a devastating and prevalent neurodegenerative disorder which, unfortunately, lacks an effective treatment strategy. The ever-increasing ageing population will only exacerbate this problem, although the group of Eva L. Feldman (Ann Arbor, Michigan) has set out to counter this growing problem by investigating the merits of cortical neural stem cell (NSC)-based therapeutic interventions. 

Their new study, published in Stem Cells Translational Medicine, describes an exciting new therapeutic option – a cortical NSC line engineered to overexpress IGF-1, an essential trophic factor for neuronal development and normal function [1, 2]. They show that this engineered cell line engrafts and survives within the brain in a mouse model of AD and so may be a viable therapeutic option to address the loss of neurons of the cerebral cortex and hippocampus in humans affected by AD [3].

The stable over-expression of IGF-1 in the human cortical NSC line increased the production and excretion of IGF-1 by 50 fold (to 3–5 ng/ml). The authors observed no significant effects on NSC proliferation or migration (so no pesky transformation) and exogenous IGF-1 expression did not lead to unwanted NSC differentiation. However, upon directed differentiation, IGF-1 expression did increase the number of mature GAD65-positive GABAergic neurons, the major subtype lost in AD (Figure A, B, and E), but did not alter the number of VLGUT-positive glutamatergic neurons (Figure C, D, and F). Additionally, IGF-1 expression also prevented NSC apoptosis in response to amyloid beta (1-42) protein treatment, a commonly used in vitro model of AD-associated toxicity [4], and prevented the death of co-cultured primary cortical neurons (CNs) via a potent paracrine effect.

The final test for these cells involved the transplantation of the modified NSCs into the fimbria fornix (which connects the hippocampus to cortical and subcortical brain structures) in the commonly used APP/PS1 double transgenic mouse model of AD. Encouragingly, the authors noted human cell survival and engraftment at ten weeks and that the NSCs had entered the early stages of differentiation towards becoming mature neurons.

We await further assessments of behavior, memory and learning, as well as cell safety following NSC transplantation; but if the outcome is good, will this become the first approved treatment since 2003 [5]?

References

  1. Anlar B, Sullivan KA, and Feldman EL Insulin-like growth factor-I and central nervous system development. Horm Metab Res 1999;31:120-125.
  2. Russo VC, Gluckman PD, Feldman EL, et al. The insulin-like growth factor system and its pleiotropic functions in brain. Endocr Rev 2005;26:916-943.
  3. McGinley LM, Sims E, Lunn JS, et al. Human Cortical Neural Stem Cells Expressing Insulin-Like Growth Factor-I: A Novel Cellular Therapy for Alzheimer's Disease. Stem Cells Transl Med 2016;5:379-391.
  4. Bruce AJ, Malfroy B, and Baudry M beta-Amyloid toxicity in organotypic hippocampal cultures: protection by EUK-8, a synthetic catalytic free radical scavenger. Proc Natl Acad Sci U S A 1996;93:2312-2316.
  5. Cummings JL, Morstorf T, and Zhong K Alzheimer's disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther 2014;6:37.