Novel erythropoietin‐based therapeutic candidates with extra <i>N</i>‐glycan sites that block hematopoiesis but preserve neuroplasticity

Bürgi, Milagros; Aparicio, Gabriela I.; Dorella, Aquiles; Kratje, Ricardo; Scorticati, Camila; Oggero, Marcos

doi:10.1002/biot.202000455

Cited by 7 publications

(3 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…(ii) The effect on cognition by far outlasted any transient effect on hematocrit [ 18 , 20 , 22 , 26 , 31 ]. (iii) Even more compellingly, the above-cited study on transgenic EPO expression in brain [ 29 ] and (iv) non-hematopoietic EPO analogues [ 32 – 37 ] have been further key arguments for EPO actions on brain in absence of blood effects. (v) Moreover, boosted cognition and neuroplasticity of mice expressing constitutively active EPOR in glutamatergic pyramidal neurons [ 38 ], but not in GABAergic interneurons [ 39 ], suggested a central role of these neurons for EPO effects on cognition, independent of hematopoiesis.…”

Section: Separating Epo Effects On Brain From Hematopoiesismentioning

confidence: 99%

Introducing the brain erythropoietin circle to explain adaptive brain hardware upgrade and improved performance

Ehrenreich¹,

Garcia-Agudo²,

Steixner-Kumar³

et al. 2022

Mol Psychiatry

View full text Add to dashboard Cite

PrefaceExecutive functions, learning, attention, and processing speed are imperative facets of cognitive performance, affected in neuropsychiatric disorders. In clinical studies on different patient groups, recombinant human (rh) erythropoietin (EPO) lastingly improved higher cognition and reduced brain matter loss. Correspondingly, rhEPO treatment of young rodents or EPO receptor (EPOR) overexpression in pyramidal neurons caused remarkable and enduring cognitive improvement, together with enhanced hippocampal long-term potentiation. The ‘brain hardware upgrade’, underlying these observations, includes an EPO induced ~20% increase in pyramidal neurons and oligodendrocytes in cornu ammonis hippocampi in the absence of elevated DNA synthesis. In parallel, EPO reduces microglia numbers and dampens their activity and metabolism as prerequisites for undisturbed EPO-driven differentiation of pre-existing local neuronal precursors. These processes depend on neuronal and microglial EPOR. This novel mechanism of powerful postnatal neurogenesis, outside the classical neurogenic niches, and on-demand delivery of new cells, paralleled by dendritic spine increase, let us hypothesize a physiological procognitive role of hypoxia-induced endogenous EPO in brain, which we imitate by rhEPO treatment. Here we delineate the brain EPO circle as working model explaining adaptive ‘brain hardware upgrade’ and improved performance. In this fundamental regulatory circle, neuronal networks, challenged by motor-cognitive tasks, drift into transient ‘functional hypoxia’, thereby triggering neuronal EPO/EPOR expression.

show abstract

Section: Separating Epo Effects On Brain From Hematopoiesismentioning

confidence: 99%

Introducing the brain erythropoietin circle to explain adaptive brain hardware upgrade and improved performance

Ehrenreich¹,

Garcia-Agudo²,

Steixner-Kumar³

et al. 2022

Mol Psychiatry

View full text Add to dashboard Cite

show abstract

“…Moreover, an interesting alternative in epitope masking is the nanopatterning technique, in which polyethylene glycol (PEG) molecules are used instead of glycans ( 43 , 44 ). Finally, glycan masking was also successfully applied to the design of protein-based drugs such as interferon alpha 2 ( 45 ), human coagulation factor IX ( 46 , 47 ) human erythropoietin ( 48 ) and human hormones ( 49 , 50 ). Glycan unmasking, nanopatterning and glycosylated drugs however are out of the scope of this review and thus are not included in our collection.…”

Section: Literature Overviewmentioning

confidence: 99%

Glycan masking in vaccine design: Targets, immunogens and applications

2023

View full text Add to dashboard Cite

Glycan masking is a novel technique in reverse vaccinology in which sugar chains (glycans) are added on the surface of immunogen candidates to hide regions of low interest and thus focus the immune system on highly therapeutic epitopes. This shielding strategy is inspired by viruses such as influenza and HIV, which are able to escape the immune system by incorporating additional glycosylation and preventing the binding of therapeutic antibodies. Interestingly, the glycan masking technique is mainly used in vaccine design to fight the same viruses that naturally use glycans to evade the immune system. In this review we report the major successes obtained with the glycan masking technique in epitope-focused vaccine design. We focus on the choice of the target antigen, the strategy for immunogen design and the relevance of the carrier vector to induce a strong immune response. Moreover, we will elucidate the different applications that can be accomplished with glycan masking, such as shifting the immune response from hyper-variable epitopes to more conserved ones, focusing the response on known therapeutic epitopes, broadening the response to different viral strains/sub-types and altering the antigen immunogenicity to elicit higher or lower immune response, as desired.

show abstract

“…Based on the sialylation-mediated inhibition of clearance of circulating EPO in the liver [ 9 ], rapidly cleared EPO-variants in vivo , such as asialoEPO and Neuro-EPO with decreased or absent sialic acids, have been suggested [ 10 , 11 ]. Recently, EPO-variants having modification or de novo addition on N-linked glycosylation have also been suggested [ 12 , 13 ]. They exhibit an efficient neuroprotective effect without additional erythropoiesis.…”

Section: Introductionmentioning

confidence: 99%

Second-generation non-hematopoietic erythropoietin-derived peptide for neuroprotection

Cho¹,

Yoo²,

Kim³

et al. 2022

Redox Biology

View full text Add to dashboard Cite

Erythropoietin (EPO) is a well-known erythropoietic cytokine having a tissue-protective effect in various tissues against hypoxic stress, including the brain. Thus, its recombinants may function as neuroprotective compounds. However, despite considerable neuroprotective effects, the EPO-based therapeutic approach has side effects, including hyper-erythropoietic and tumorigenic effects. Therefore, some modified forms and derivatives of EPO have been proposed to minimize the side effects. In this study, we generated divergently modified new peptide analogs derived from helix C of EPO, with several amino acid replacements that interact with erythropoietin receptors (EPORs). This modification resulted in unique binding potency to EPOR. Unlike recombinant EPO, among the peptides, ML1-h3 exhibited a potent neuroprotective effect against oxidative stress without additional induction of cell-proliferation, owing to a differential activating mode of EPOR signaling. Furthermore, it inhibited neuronal death and brain injury under hypoxic stress in vitro and in an in vivo ischemic brain injury model. Therefore, the divergent modification of EPO-derivatives for affinity to EPOR could provide a basis for a more advanced and optimal neuroprotective strategy.

show abstract

Novel erythropoietin‐based therapeutic candidates with extra N‐glycan sites that block hematopoiesis but preserve neuroplasticity

Cited by 7 publications

References 49 publications

Introducing the brain erythropoietin circle to explain adaptive brain hardware upgrade and improved performance

Introducing the brain erythropoietin circle to explain adaptive brain hardware upgrade and improved performance

Glycan masking in vaccine design: Targets, immunogens and applications

Second-generation non-hematopoietic erythropoietin-derived peptide for neuroprotection

Contact Info

Product

Resources

About