A Humoral Immune Response Alters the Distribution of Enzyme Replacement Therapy in Murine Mucopolysaccharidosis Type I

Le, Steven Q.; Kan, Shih Hsin; Clarke, Don; Sanghez, Valentina; Egeland, Martin; Vondrak, Kristen N.; Doherty, Terence M.; Vera, Moin; Iacovino, Michelina; Cooper, Jonathan D.; Sands, Mark S.; Dickson, Patricia I.

doi:10.1016/j.omtm.2017.09.008

Cited by 16 publications

(16 citation statements)

References 26 publications

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“…In long-term administration trials with RTB-enzyme fusions, anti-RTB and anti-cargo enzyme immunoglobulin levels in terminal serum have been measured by ELISA. Consistent with data for infusions with recombinant mammalian-cell-derived enzyme [66][67][68], elevated levels of total IgGs reacting against the cargo were detected in the respective KO mice treated with enzyme:RTB. In contrast, ELISA using recombinant RTB as a capture molecule shows no antibody response against the RTB lectin carrier [63,69].…”

Section: Immunogenicity Of Rtb-mediated Treatmentsupporting

confidence: 82%

Targeting Macromolecules to CNS and Other Hard-to-Treat Organs Using Lectin-Mediated Delivery

Acosta

Cramer

2020

IJMS

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The greatest challenges for therapeutic efficacy of many macromolecular drugs that act on intracellular are delivery to key organs and tissues and delivery into cells and subcellular compartments. Transport of drugs into critical cells associated with disease, including those in organs protected by restrictive biological barriers such as central nervous system (CNS), bone, and eye remains a significant hurdle to drug efficacy and impacts commercial risk and incentives for drug development for many diseases. These limitations expose a significant need for the development of novel strategies for macromolecule delivery. RTB lectin is the non-toxic carbohydrate-binding subunit B of ricin toxin with high affinity for galactose/galactosamine-containing glycolipids and glycoproteins common on human cell surfaces. RTB mediates endocytic uptake into mammalian cells by multiple routes exploiting both adsorptive-mediated and receptor-mediated mechanisms. In vivo biodistribution studies in lysosomal storage disease models provide evidence for the theory that the RTB-lectin transports corrective doses of enzymes across the blood–brain barrier to treat CNS pathologies. These results encompass significant implications for protein-based therapeutic approaches to address lysosomal and other diseases having strong CNS involvement.

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Section: Immunogenicity Of Rtb-mediated Treatmentsupporting

confidence: 82%

Targeting Macromolecules to CNS and Other Hard-to-Treat Organs Using Lectin-Mediated Delivery

Acosta

Cramer

2020

IJMS

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“…The poor and inconsistent anti-IDUA humoral response described in MPS-I mice was previously demonstrated, and it was independent of the amount of injected enzyme: high doses of enzyme also failed in promoting a homogeneous immunity in treated mice. 24 Moreover, the percentage of Ab-positive mice was shown to be higher when ERT was applied in adult compared to newborn MPS-I mice. 25 However, the ex vivo HSC GT required the treatment of mice at 4 weeks of age, thus limiting the use of ERT as a model for dissecting the role of pre-existing anti-IDUA immunity on GT.…”

Section: Discussionmentioning

confidence: 98%

Targeting a Pre-existing Anti-transgene T Cell Response for Effective Gene Therapy of MPS-I in the Mouse Model of the Disease

et al. 2019

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Mucopolysaccharidosis type I (MPS-I) is a severe genetic disease caused by a deficiency of the alpha-L-iduronidase (IDUA) enzyme. Ex vivo hematopoietic stem cell (HSC) gene therapy is a promising therapeutic approach for MPS-I, as demonstrated by preclinical studies performed in naive MPS-I mice. However, after enzyme replacement therapy (ERT), several MPS-I patients develop anti-IDUA immunity that may jeopardize ex vivo gene therapy efficacy. Here we treat MPS-I mice with an artificial immunization protocol to mimic the ERT effect in patients, and we demonstrate that IDUA-corrected HSC engraftment is impaired in pre-immunized animals by IDUA-specific CD8 + T cells spared by pre-transplant irradiation. Conversely, humoral anti-IDUA immunity does not impact on IDUA-corrected HSC engraftment. The inclusion of lympho-depleting agents in pre-transplant conditioning of pre-immunized hosts allowes rescue of IDUA-corrected HSC engraftment, which is proportional to CD8 + T cell eradication. Overall, these data demonstrate the relevance of preexisting anti-transgene T cell immunity on ex vivo HSC gene therapy, and they suggest the application of tailored immune-depleting treatments, as well as a deeper immunological characterization of patients, to safeguard the therapeutic effects of ex vivo HSC gene therapy in immunocompetent hosts.

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“…With continued nurturing and support, she has now obtained multiple grants and published several manuscripts, and has taken a compound to clinical trials. [1][2][3][4] • A senior, highly successful basic scientist requested a consultation to discuss her application when it was not awarded upon her first submission. Following the consultation and being steered toward a translational application for her project, she was awarded on a subsequent submission.…”

Section: The Core Voucher Program Actively Promotes Translational Resmentioning

confidence: 99%

Describing the dynamic translational science landscape through Core Voucher utilization

Liclican

Filler

Kaye

et al. 2019

J. Clin. Trans. Sci.

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Introduction:Core facilities play crucial roles in carrying out the academic research mission by making available to researchers advanced technologies, facilities, or expertise that are unfeasible for most investigators to obtain on their own. To facilitate translational science through support of core services, the University of California, Los Angeles Clinical and Translational Science Institute (UCLA CTSI) created a Core Voucher program. The underlying premise is that by actively promoting interplay between researchers and core facilities, a dynamic feedback loop could be established that could enhance both groups, the productivity of the former and the relevance of the latter. Our primary goal was to give translational investigators what they need to pursue their immediate projects at hand.Methods:To implement this system across four noncontiguous campuses, open-source web-accessible software applications were created that were scalable and could efficiently administer investigator submissions and subsequent reviews in a multicampus fashion.Results:In the past five years, we have processed over 1400 applications submitted by over 750 individual faculty members across both clinical and nonclinical departments. In total, 1926 core requests were made in conjunction with 1467 submitted proposals. The top 10 most popular cores accounted for 50% of all requests, and the top half of the most popular cores accounted for 90% of all requests.Conclusion:Tracking investigator demand provides a unique window into what are the high- and low-priority core services that best support translational research.

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A Humoral Immune Response Alters the Distribution of Enzyme Replacement Therapy in Murine Mucopolysaccharidosis Type I

Cited by 16 publications

References 26 publications

Targeting Macromolecules to CNS and Other Hard-to-Treat Organs Using Lectin-Mediated Delivery

Targeting Macromolecules to CNS and Other Hard-to-Treat Organs Using Lectin-Mediated Delivery

Targeting a Pre-existing Anti-transgene T Cell Response for Effective Gene Therapy of MPS-I in the Mouse Model of the Disease

Describing the dynamic translational science landscape through Core Voucher utilization

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