Isha Srivastava

All Publications

• A Novel Mouse Model for Cerebral Inflammatory Demyelination in X-Linked Adrenoleukodystrophy: Insights into Pathogenesis and Potential Therapeutic Targets. Annals of neurology Hashemi, E., Srivastava, I. N., Aguirre, A., Yoseph, E. T., Kaushal, E., Awani, A., Ryu, J. K., Akassoglou, K., Talebian, S., Chu, P., Pisani, L., Musolino, P., Steinman, L., Doyle, K., Robinson, W. H., Sharpe, O., Cayrol, R., Orchard, P. J., Lund, T., Vogel, H., Lenail, M., Han, M. H., Bonkowsky, J. L., Van Haren, K. P. 2024

  Abstract

  X-linked adrenoleukodystrophy (ALD) is caused by mutations in ABCD1, a peroxisomal gene. More than half of males with an ABCD1 mutation develop inflammatory cerebral demyelination (cALD), but underlying mechanisms remain unknown and therapies are limited. We sought to develop and characterize a mouse model of cALD to facilitate study of disease mechanisms and therapy development.We used immunoassays and immunohistochemistry to assess novel (interleukin 18 [IL-18]) and established molecular markers in cerebrospinal fluid (CSF) and postmortem brain tissue from cALD patients. We generated a cALD phenotype in Abcd1-knockout mice using a 2-hit method that combines cuprizone and experimental autoimmune encephalomyelitis models. We then used magnetic resonance imaging (MRI) and immunohistochemistry to assess the fidelity of cALD molecular markers in the mice.Human and mouse cALD lesions shared histologic features of myelin phagocytosis, myelin loss, abundant microglial activation, T and B-cell infiltration, and astrogliosis. Compared to wild-type controls, Abcd1-knockout mice displayed more cerebral demyelination, blood-brain barrier disruption, and perivascular immune cell infiltration. This enhanced inflammatory response was associated with higher levels of fibrin deposition, oxidative stress, demyelination, and axonal injury. IL-18 immunoreactivity co-localized with perivascular monocytes/macrophages in both human and mouse brain tissue. In cALD patients, CSF IL-18 levels correlated with MRI lesion severity.Our results suggest loss of Abcd1 function in mice predisposes to more severe blood-brain barrier disruption, cerebral inflammation driven by the infiltration of peripheral immune cells, demyelination, and axonal damage, replicating human cALD features. This novel mouse model could shed light on cALD mechanisms and accelerate cALD therapy development. ANN NEUROL 2024.

  View details for DOI 10.1002/ana.27117

  View details for PubMedID 39467011

• Consensus guidelines for the monitoring and management of metachromatic leukodystrophy in the United States. Cytotherapy Adang, L. A., Bonkowsky, J. L., Boelens, J. J., Mallack, E., Ahrens-Nicklas, R., Bernat, J. A., Bley, A., Burton, B., Darling, A., Eichler, F., Eklund, E., Emrick, L., Escolar, M., Fatemi, A., Fraser, J. L., Gaviglio, A., Keller, S., Patterson, M. C., Orchard, P., Orthmann-Murphy, J., Santoro, J. D., Schöls, L., Sevin, C., Srivastava, I. N., Rajan, D., Rubin, J. P., Van Haren, K., Wasserstein, M., Zerem, A., Fumagalli, F., Laugwitz, L., Vanderver, A. 2024

  Abstract

  Metachromatic leukodystrophy (MLD) is a fatal, progressive neurodegenerative disorder caused by biallelic pathogenic mutations in the ARSA (Arylsulfatase A) gene. With the advent of presymptomatic diagnosis and the availability of therapies with a narrow window for intervention, it is critical to define a standardized approach to diagnosis, presymptomatic monitoring, and clinical care. To meet the needs of the MLD community, a panel of MLD experts was established to develop disease-specific guidelines based on healthcare resources in the United States. This group developed a consensus opinion for best-practice recommendations, as follows: (i) Diagnosis should include both genetic and biochemical testing; (ii) Early diagnosis and treatment for MLD is associated with improved clinical outcomes; (iii) The panel supported the development of newborn screening to accelerate the time to diagnosis and treatment; (iv) Clinical management of MLD should include specialists familiar with the disease who are able to follow patients longitudinally; (v) In early onset MLD, including late infantile and early juvenile subtypes, ex vivo gene therapy should be considered for presymptomatic patients where available; (vi) In late-onset MLD, including late juvenile and adult subtypes, hematopoietic cell transplant (HCT) should be considered for patients with no or minimal disease involvement. This document summarizes current guidance on the presymptomatic monitoring of children affected by MLD as well as the clinical management of symptomatic patients. Future data-driven evidence and evolution of these recommendations will be important to stratify clinical treatment options and improve clinical care.

  View details for DOI 10.1016/j.jcyt.2024.03.487

  View details for PubMedID 38613540

• A Novel Mouse Model for Cerebral Inflammatory Demyelination in X-Linked Adrenoleukodystrophy: Insights into Pathogenesis and Potential Therapeutic Targets Annals of Neurology Hashemi, E., Srivastava, I., Aguirre, A., Yoseph, E. T., Van Haren, K. P. 2024

  View details for DOI 10.1002/ana.27117

• Immunotherapy in Autoimmune Encephalitis: So Many Options, So Few Guidelines. Neurology Srivastava, I., Van Haren, K. 2023

  View details for DOI 10.1212/WNL.0000000000208026

  View details for PubMedID 37879941

• A Novel Mouse Model of Cerebral Demyelination in X-Linked Adrenoleukodystrophy Highlights NLRP3 Activation in Lesion Pathogenesis Srivastava, I., Van Haren, K., Hashemi, E., Kaushal, E., Han, M., Lund, T., Bonkowsky, J., Yoseph, E. WILEY. 2022: S174

  View details for Web of Science ID 000867884200308

• The NLRP3 Inflammasome as a Link Between Metabolic Failure and Cerebral Demyelination in X-linked Adrenoleukodystrophy Aguirre, A., Cayrol, R., Srivastava, I., Vogel, H., Van Haren, K. OXFORD UNIV PRESS INC. 2020: 675

  View details for Web of Science ID 000538796100089