The CD22-IGF2R interaction is a therapeutic target for microglial lysosome dysfunction in Niemann-Pick type C

Abstract

An oligodendrocyte-derived protein in cerebrospinal fluid impairs microglial lysosome function.

NPC1 Deficiency Contributes to Autophagy-Dependent Ferritinophagy in HEI-OC1 Auditory Cells

“…Recent studies have reported that ferroptosis contributes to the impairment of cochlear hair cells that relate to sensory hearing (Hu et al, 2020;Zheng et al, 2020). Moreover, some previous studies of NPCD have reported that NPC1 deficiency leads to metal dyshomeostasis (Hung et al, 2014) and lysosome dysfunction (Pluvinage et al, 2021;Roney et al, 2021) in multiple organelles. We thus hypothesize a possible mechanism of genetic hearing loss related to NPCD, that is, NPC1 deficiency causes outer hair cells (OHCs) loss or damage in the cochlea by inducing ferroptosis.…”

Associations of plasma soluble CD22 levels with brain amyloid burden and cognitive decline in Alzheimer’s disease

“…As shown in Fig. 2F, plasma sCD22 levels were positively correlated with brain A burden as reflected by 11 C Pittsburgh Compound B-positron emission tomography (PiB-PET) standard uptake value ratio (SUVR) (r = 0.338, P < 0.001) in the AIBL cohort after adjustment for age, sex, and APOE 4 genotype.…”

“…Soluble CD22 (sCD22) is generated by the cleavage of the extracellular domain of CD22. Several studies indicate that sCD22 may be a marker of inflammation and microglial dysfunction (11)(12)(13). Thus, questions arise as to whether CD22 is involved in the pathogenesis of AD and whether the level of sCD22 changes pathologically in AD.…”

Targeting Human CD22/Siglec-2 with Dimeric Sialosides as Novel Oligosaccharide Mimetics

“…CD22 (Siglec-2) is a sialic acid recognizing protein and belongs to the family of the Siglecs (sialic acid recognizing immunoglobulin like lectins). − CD22 is highly expressed on B-cells where it is an important evolutionarily conserved inhibitory co-receptor of the B-cell receptor (BCR). − CD22 binds to α-2,6-linked sialic acids, which are abundantly expressed on the B-cell surface, and cis binding to these ligands regulates the inhibitory function of CD22. , CD22 is expressed as well on cell types other than B-cells, but CD22 expression on other cell surfaces is usually low and the functional relevance remains often underexplored. − CD22 research focused predominantly on B-cells, and several CD22-specific antibodies and antibody drug conjugates (ADCs) entered into clinical trials for B-cell lymphomas and leukemias, as well as autoimmune diseases leading to two currently approved ADCs. , One important regulatory and targeting motif is the extracellular sialoside binding pocket of CD22. ,, Preclinical proof-of-principle (PoP) studies for several modes of action (MOAs) targeting the CD22 sialoside binding site with synthetic ligands and various conjugates of them as new therapeutic modalities exist over a range of disease areas and indications, e.g., B-cell malignancies, neurodegeneration, cellular therapies, anti-drug antibodies and autoimmunity, − transfusion, and vaccinations . Additional functional studies provide strong evidence of potential therapeutic benefits for the abovementioned areas ,− as well as additional therapeutic areas, e.g., gastrointestinal inflammation , and transplantation. , The different therapeutic modalities targeting CD22, like low-molecular-weight compounds, ,− low-molecular-weight bispecific compounds, , protein conjugates, , polymers, , nanoparticles, , or surface modified cells,…”

“…15,16 One important regulatory and targeting motif is the extracellular sialoside binding pocket of CD22. 5,7,17 Preclinical proof-of-principle (PoP) studies for several modes of action (MOAs) targeting the CD22 sialoside binding site with synthetic ligands and various conjugates of them as new therapeutic modalities exist over a range of disease areas and indications, e.g., B-cell malignancies, 18 neurodegeneration, 19 cellular therapies, 20 anti-drug antibodies and autoimmunity, 21−23 transfusion, 24 and vaccinations. 25 Additional functional studies provide strong evidence of potential therapeutic benefits for the abovementioned areas 17,26−32 as well as additional therapeutic areas, e.g., gastrointestinal inflammation 33,34 and transplantation.…”