Findings on Optical Coherence Tomography in Malignant Infantile Osteopetrosis.

Malignant infantile osteopetrosis is a rare inherited disorder with neurological complications and a shortened life expectancy. Vision loss is typically attributed to osseous compression of the optic nerves at the level of the optic canal. Fundus imaging is reported, as well as the first optical coherence tomography and optical coherence tomography angiography in this rare condition. Imaging revealed optic nerve pallor, subfoveal ellipsoid zone disruption, and an enlarged foveal avascular zone. These results provide insight regarding other potential mechanisms of vision loss in these patients. [Ophthalmic Surg Lasers Imaging Retina 2022; 53:398-402.].

Long-term outcomes after gene therapy for adenosine deaminase severe combined immune deficiency.

Patients lacking functional adenosine deaminase activity have severe combined immunodeficiency (ADA SCID), which can be treated with ADA enzyme replacement therapy (ERT), allogeneic hematopoietic stem cell transplantation (HSCT), or autologous HSCT with gene-corrected cells (gene therapy [GT]). A cohort of 10 ADA SCID patients, aged 3 months to 15 years, underwent GT in a phase 2 clinical trial between 2009 and 2012. Autologous bone marrow CD34+ cells were transduced ex vivo with the MND (myeloproliferative sarcoma virus, negative control region deleted, dl587rev primer binding site)-ADA gammaretroviral vector (gRV) and infused following busulfan reduced-intensity conditioning. These patients were monitored in a long-term follow-up protocol over 8 to 11 years. Nine of 10 patients have sufficient immune reconstitution to protect against serious infections and have not needed to resume ERT or proceed to secondary allogeneic HSCT. ERT was restarted 6 months after GT in the oldest patient who had no evidence of benefit from GT. Four of 9 evaluable patients with the highest gene marking and B-cell numbers remain off immunoglobulin replacement therapy and responded to vaccines. There were broad ranges of responses in normalization of ADA enzyme activity and adenine metabolites in blood cells and levels of cellular and humoral immune reconstitution. Outcomes were generally better in younger patients and those receiving higher doses of gene-marked CD34+ cells. No patient experienced a leukoproliferative event after GT, despite persisting prominent clones with vector integrations adjacent to proto-oncogenes. These long-term findings demonstrate enduring efficacy of GT for ADA SCID but also highlight risks of genotoxicity with gRVs. This trial was registered at www.clinicaltrials.gov as #NCT00794508.

Identification of a protein that interacts with the golli-myelin basic protein and with nuclear LIM interactor in the nervous system.

The myelin basic protein (MBP) gene encodes the classic MBPs and the golli proteins, which are related structurally to the MBPs but are not components of the myelin sheath. A yeast two-hybrid approach was used to identify molecular partners that interact with the golli proteins. A mouse cDNA was cloned that encoded a protein of 261 amino acids and called golli-interacting protein (GIP). Database analysis revealed that GIP was the murine homolog of human nuclear LIM interactor-interacting factor (NLI-IF), a nuclear protein whose function is just beginning to be understood. It is a member of a broad family of molecules, found in species ranging from yeast to human, that contain a common domain of approximately 100 amino acids. Immunocytochemical and Northern blot analyses showed co-expression of GIP and golli in several neural cell lines. GIP and golli also showed a similar developmental pattern of mRNA expression in brain, and immunohistochemical staining of GIP and golli showed co-expression in several neuronal populations and in oligodendrocytes in the mouse brain. GIP was localized predominantly in nuclei. GIP co-immunoprecipitated with golli in several in vitro assays as well as from PC12 cells under physiologic conditions. GIP was the first member of this family shown to interact with nuclear LIM interactor (NLI). NLI co-immunoprecipitated with GIP and golli from lysates of N19 cells transfected with NLI, further confirming an interaction between golli, GIP, and NLI. The ability of GIP to interact with both golli and NLI, and the nuclear co-localization of GIP and golli in many cells, indicates a role for the golli products of the MBP gene in NLI- associated regulation of gene expression.

Expression of soma-restricted proteolipid/DM20 proteins in lymphoid cells.

A new family of the myelin proteolipid protein (PLP/DM20) gene products, srPLP/DM20, has been identified recently in thymus and brain. In the central nervous system, srPLP/DM20 products are not localized in the myelin membrane, unlike their classic PLP/DM20 counterparts. In the immune system, the classic PLP/DM20 products appear to be expressed predominantly in thymic cortical epithelium. In this study, we examined the cellular expression of sr-PLP/DM20 proteolipids in lymphoid tissues and cells by immunohistochemistry, FACS analysis and RT-PCR. We found that in contrast to the classic PLP/DM20 products, sr-proteins are mainly expressed in developing thymocytes in thymus and in T- and B-lymphocytes in spleen. These results are of importance in our further understanding, not only the different role of these new PLP gene products in central and peripheral tolerance, but also the function of such products in lymphocyte biology.