Tolerance induction in hemophilia: innovation and accomplishments

Sherman, Alexandra; Biswas, Moanaro; Herzog, Roland W.

doi:10.1097/moh.0000000000000446

Cited by 12 publications

(9 citation statements)

References 97 publications

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“…It has been suggested that liver-directed transgene expression is able to induce tolerance toward the transgene product and prevent the emergence of immune responses, including ADAs 26, 27, 28, 29, 30, 31, 32, 33, 34. We thus designed a 4L6 IgG1 expression cassette with a liver-specific promoter to investigate whether liver-directed AAV-antibody delivery could avoid unwanted ADAs.…”

Section: Resultsmentioning

confidence: 99%

“…We have identified in our pilot monkey studies two strategies that may help to overcome the problems of ADA and inconsistency of delivery: liver targeting and use of prime and boost. Liver-targeted expression has been previously shown to have a tolerogenic effect toward the AAV-delivered transgene product 26, 27, 28, 29, 30, 31, 32, 33, 34. Furthermore, AAV8 has been shown to transduce APCs poorly, as compared to AAV1, 46 and to express well in liver 35, 36, 37, 38.…”

Section: Discussionmentioning

confidence: 99%

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Liver-Directed but Not Muscle-Directed AAV-Antibody Gene Transfer Limits Humoral Immune Responses in Rhesus Monkeys

Fuchs

Martinez-Navío

Rakasz

et al. 2020

Molecular Therapy - Methods & Clinical Development

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A number of publications have described the use of adenoassociated virus (AAV) for the delivery of anti-HIV and antisimian immunodeficiency virus (SIV) monoclonal antibodies (mAbs) to rhesus monkeys. Anti-drug antibodies (ADAs) have been frequently observed, and long-term AAV-mediated delivery has been inconsistent. Here, we investigated different AAV vector strategies and delivery schemes to rhesus monkeys using the rhesus monkey mAb 4L6. We compared 4L6 immunoglobulin G1 (IgG1) delivery using the AAV1 versus the AAV8 serotype with a cytomegalovirus (CMV) promoter and the use of a muscle-specific versus a liver-specific promoter. Long-term expression levels of 4L6 IgG1 following AAV8mediated gene transfer were comparable to those following AAV1-mediated gene transfer. AAV1-mediated gene transfer, using a muscle-specific promoter, showed robust ADAs and transiently low 4L6 IgG1 levels that ultimately declined to below detectable levels. Intravenous AAV8-mediated gene transfer, using a liver-specific promoter, also resulted in low levels of delivered 4L6 IgG1, but those low levels were maintained in the absence of any detectable ADAs. Booster injections using AAV1-CMV allowed for increased 4L6 IgG1 serum levels in animals that were primed with AAV8 but not with AAV1. Our results suggest that liver-directed expression may help to limit ADAs and that re-administration of AAV of a different serotype can result in successful long-term delivery of an immunogenic antibody.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Liver-Directed but Not Muscle-Directed AAV-Antibody Gene Transfer Limits Humoral Immune Responses in Rhesus Monkeys

Fuchs

Martinez-Navío

Rakasz

et al. 2020

Molecular Therapy - Methods & Clinical Development

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“…The first approach, ITI, has been studied extensively in hemophilia. Most ITI protocols require long term, frequent (>3 times a week) administration of the recombinant protein and are still only successful in 60-70% of cases for hemophilia A and only 30% of cases for hemophilia B [19,30]. In Pompe disease, ITI has been tried with intensive immune-modulatory protocols (including rituximab, methotrexate, bortezomib and intraveneus immunoglobulines) resulting in a steady decrease in iADAs and improvement of therapeutic effectiveness, but full tolerization was not achieved [17,18].…”

Section: Discussionmentioning

confidence: 99%

Predicting the Development of Anti-Drug Antibodies against Recombinant alpha-Galactosidase A in Male Patients with Classical Fabry Disease

Veen

Vlietstra²,

Dussen

et al. 2020

IJMS

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Fabry Disease (FD) is a rare, X-linked, lysosomal storage disease that mainly causes renal, cardiac and cerebral complications. Enzyme replacement therapy (ERT) with recombinant alpha-galactosidase A is available, but approximately 50% of male patients with classical FD develop inhibiting anti-drug antibodies (iADAs) that lead to reduced biochemical responses and an accelerated loss of renal function. Once immunization has occurred, iADAs tend to persist and tolerization is hard to achieve. Here we developed a pre-treatment prediction model for iADA development in FD using existing data from 120 classical male FD patients from three European centers, treated with ERT. We found that nonsense and frameshift mutations in the α-galactosidase A gene (p = 0.05), higher plasma lysoGb3 at baseline (p < 0.001) and agalsidase beta as first treatment (p = 0.006) were significantly associated with iADA development. Prediction performance of a Random Forest model, using multiple variables (AUC-ROC: 0.77) was compared to a logistic regression (LR) model using the three significantly associated variables (AUC-ROC: 0.77). The LR model can be used to determine iADA risk in individual FD patients prior to treatment initiation. This helps to determine in which patients adjusted treatment and/or immunomodulatory regimes may be considered to minimize iADA development risk.

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“…Antibody formation directed at the newly-introduced proteins represents a serious complication in protein replacement therapy for the X-linked bleeding disorder hemophilia (1)(2)(3)(4)(5). One partial remedy is ITI ("immune tolerance induction, " consisting of daily high-dose intravenous infusion of FVIII), which however may take months to years and can cost >$1M (1).…”

Section: Introductionmentioning

confidence: 99%

“…Hence, we and others have been developing diverse novel protocols aimed at reversal of inhibitor formation by immune tolerance induction (ITI), which have primarily been tested in hemophilic mice in which either the F8 or F9 gene had been deleted (9)(10)(11)(12)(13)(14). These studies employ a range of strategies, including lymphocyte-based therapies and administration of small molecule/protein/antibody drugs, which modulate distinct immune responses (5). However, methodologies that allow for a prediction of inhibitor formation by individual patients need to be improved and a better understanding of risk factors will be requisite.…”

Section: Introductionmentioning

confidence: 99%

Role of Small Intestine and Gut Microbiome in Plant-Based Oral Tolerance for Hemophilia

et al. 2020

Self Cite

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Fusion proteins, which consist of factor VIII or factor IX and the transmucosal carrier cholera toxin subunit B, expressed in chloroplasts and bioencapsulated within plant cells, initiate tolerogenic immune responses in the intestine when administered orally. This approach induces regulatory T cells (Treg), which suppress inhibitory antibody formation directed at hemophilia proteins induced by intravenous replacement therapy in hemophilia A and B mice. Further analyses of Treg CD4 + lymphocyte sub-populations in hemophilia B mice reveal a marked increase in the frequency of CD4 + CD25 − FoxP3 − LAP + T cells (but not of CD4 + CD25 + FoxP3 + T cells) in the lamina propria of the small but not large intestine. The adoptive transfer of very small numbers of CD4 + CD25 − LAP + Treg isolated from the spleen of tolerized mice was superior in suppression of antibodies directed against FIX when compared to CD4 + CD25 + T cells. Thus, tolerance induction by oral delivery of antigens bioencapsulated in plant cells occurs via the unique immune system of the small intestine, and suppression of antibody formation is primarily carried out by induced latency-associated peptide (LAP) expressing Treg that likely migrate to the spleen. Tolerogenic antigen presentation in the small intestine requires partial enzymatic degradation of plant cell wall by commensal bacteria in order to release the antigen. Microbiome analysis of hemophilia B mice showed marked differences between small and large intestine. Remarkably, bacterial species known to produce a broad spectrum of enzymes involved in degradation of plant cell wall components were found in the small intestine, in particular in the duodenum. These were highly distinct from populations of cell wall degrading bacteria found in the large intestine. Therefore, FIX antigen presentation and Treg induction by the immune system of the small intestine relies on activity of a distinct microbiome that can potentially be augmented to further enhance this approach.

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Tolerance induction in hemophilia: innovation and accomplishments

Abstract: Until now, no clinical prophylactic immune modulatory protocol exists to prevent inhibitor formation to infused clotting factors. Recent innovative technologies provide hope for improved eradication and perhaps even prevention of inhibitors.

Cited by 12 publications

References 97 publications

Liver-Directed but Not Muscle-Directed AAV-Antibody Gene Transfer Limits Humoral Immune Responses in Rhesus Monkeys

Liver-Directed but Not Muscle-Directed AAV-Antibody Gene Transfer Limits Humoral Immune Responses in Rhesus Monkeys

Predicting the Development of Anti-Drug Antibodies against Recombinant alpha-Galactosidase A in Male Patients with Classical Fabry Disease

Role of Small Intestine and Gut Microbiome in Plant-Based Oral Tolerance for Hemophilia

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