Title : Cell and gene therapies in models of vascular brain disorders
Abstract:
Cell and gene therapies hold promise for brain repair in disorders of the central nervous system. Here, I will focus on stroke and brain disorders associated with vascular dysfunction, particularly blood-brain barrier (BBB) breakdown.
I will review the basic pathophysiology of ischemic stroke and the types of different stem and progenitor cells that have been studied to promote brain repair after stroke. I will examine recent clinical trials with results using stem cells for treating stroke and preclinical studies using cell therapy for stroke Specifically, I will provide more detailed results from one of our earlier studies showing that 3K3A–activated protein C (APC) stimulates postischemic neuronal repair by human neural stem cells in mice.
APC is a blood protease with anticoagulant activity and cell-signaling activities mediated by the activation of protease-activated receptors 1 and 3. Recombinant variants of APC, such as the 3K3A-APC (Lys191–193Ala) mutant with reduced (>90%) anticoagulant activity, engineered to reduce APC-associated bleeding risk while retaining normal cell-signaling activity, have shown benefits in preclinical models of ischemic stroke, brain trauma, multiple sclerosis, amyotrophic lateral sclerosis and different systemic disorders. 3K3A-APC has advanced to clinical trials as a neuroprotectant in ischemic stroke. I will show that late postischemic treatment of mice with 3K3A-APC stimulates neuronal production by transplanted human neural stem and progenitor cells, promotes circuit restoration and improves functional recovery.
Then, I will examine potential of human iPSC-derived brain pericytes (iPSC-PC) that we have been developing recently as a possible replacement therapy for neurological disorders associated with BBB breakdown and pericyte deficiency such as Alzheimer’s disease and related neurodegenerative disorders. Pericytes maintain BBB, and their loss leads to BBB breakdown and neuronal dysfunction. Thus, replacement of lost pericytes holds potential to restore cerebrovascular and potentially neuronal function. Our quantitative analysis of total proteome and phosphoproteome indicated that human iiPSC-PC share 96% of total proteins and 98% of protein phosphorylation sites with primary human brain pericytes including cell adhesion and tight junction proteins, transcription factors, and different protein kinase families of the human kinome. Functionally, they increase BBB integrity in human and mouse models of BBB, and they home to host brain capillaries in pericyte-deficient mice to form hybrid human-mouse microvessels. They also exert neuroprotective effects in pericyte-deficient mice and clear Alzheimer’s amyloid-b and tau neurotoxins.
Finally, I will discuss our recent work showing that gene therapy directed at restoring lost low-density lipoprotein receptor–related protein 1 (LRP1) at the BBB improves cerebrovascular and neuronal function. LRP1, a cell signaling transmembrane protein, clears proteinaceous toxins at the BBB, but is increasingly reduced in Alzheimer’s disease associated with BBB breakdown and neurodegeneration. I will show that LRP1 inactivation from the mouse brain endothelium results in progressive BBB breakdown, followed by neuron loss and cognitive deficits, which is reversible by brain endothelial-specific LRP1 gene therapy.
Audience Take Away Notes
- The types of different stem and progenitor cells that have been studied to promote brain repair after stroke.
- Recent clinical trials with results using stem cells for treating stroke and preclinical studies using cell therapy for stroke
- Late 3K3A–activated protein C therapy after stroke to stimulate postischemic neuronal repair by transplanted human neural stem cells in mice
- Potential of human iPSC-derived brain pericytes (iPSC-PC) as a possible replacement therapy for neurological disorders associated with blood-brain barrier breakdown such as Alzheimer’s disease and related neurodegenerative disorders
- Gene therapies specifically directed at the blood-brain barrier to improve cerebrovascular and neuronal function due to loss of a lipoprotein receptor
- This research may help other faculty to expand their research and teaching
- The audience will learn about practical solutions used with different types of stem and progenitor cells for stroke and how their survival in brain after transplantation of human neural stem and progenitor cells can be promoted by agents that stimulate neurogenesis and formation of neuronal circuits such as for example 3K3A-APC
- They will learn about potential of iPSC-derived pericytes to improve cerebrovascular and neuronal function and clear Alzheimer’s toxins from brain
- They will also get a better idea that gene therapy directed at the BBB can restore cerebrovascular integrity and slow down development of neurodegenerative and cognitive changes
