Lentiviral Mediated Gene Therapy for Pyruvate Kinase Deficiency: Interim Results of a Global Phase 1 Study for Adult and Pediatric Patients

Shah, Ami J.; Lorenzo, José Luis López; Navarro, Susana; Sevilla, Julián; Llanos, Lucía; Gaisse, Begoña Pérez de Camino; Sánchez, Silvia Barrientos; Glader, Bert; Chien, May; Quintana-Bustamante, Óscar; Beard, Brian C.; Law, Kenneth; Zeini, Miriam; Choi, Grace; Nicoletti, Eileen; Rao, Gayatri R; Roncarolo, Maria Grazia; Bueren, Juan A.; Schwartz, Jonathan D.; Segovia, José C.

doi:10.1182/blood-2021-148161

Cited by 5 publications

(5 citation statements)

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“…A phase I lentiviral gene therapy clinical trial is ongoing to assess its safety and efficacy (NCT04105166). Preliminary data from the first two PKD patients transplanted with lentiviral-corrected autologous HSPCs have shown a fast hematologic recovery after transplant (13 days) and a complete recovery of erythroid parameters more than 18 months post-transplant ( Shah et al, 2021 ), thus demonstrating the feasibility of this strategy to treat hemolytic anemias as well ( Figure 1 ).…”

Section: Additional Gene Therapy: Current Successesmentioning

confidence: 99%

Gene Editing for Inherited Red Blood Cell Diseases

et al. 2022

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Today gene therapy is a real therapeutic option to address inherited hematological diseases that could be beneficial for thousands of patients worldwide. Currently, gene therapy is used to treat different monogenic hematological pathologies, including several red blood cell diseases such as β-thalassemia, sickle cell disease and pyruvate kinase deficiency. This approach is based on addition gene therapy, which consists of the correction of hematopoietic stem cells (HSCs) using lentiviral vectors, which integrate a corrected version of the altered gene. Lentivirally-corrected HSCs generate healthy cells that compensate for the deficiency caused by genetic mutations. Despite its successful results, this approach lacks both control of the integration of the transgene into the genome and endogenous regulation of the therapeutic gene, both of which are important aspects that might be a cause for concern. To overcome these limitations, gene editing is able to correct the altered gene through more precise and safer approaches. Cheap and easy-to-design gene editing tools, such as the CRISPR/Cas9 system, allow the specific correction of the altered gene without affecting the rest of the genome. Inherited erythroid diseases, such as thalassemia, sickle cell disease and Pyruvate Kinase Deficiency, have been the test bed for these gene editing strategies, and promising results are currently being seen. CRISPR/Cas9 system has been successfully used to manipulate globin regulation to re-activate fetal globin chains in adult red blood cells and to compensate for hemoglobin defects. Knock-in at the mutated locus to express the therapeutic gene under the endogenous gene regulatory region has also been accomplished successfully. Thanks to the lessons learned from previous lentiviral gene therapy research and trials, gene editing for red blood cell diseases is rapidly moving from its proof-of-concept to its first exciting results in the clinic. Indeed, patients suffering from β-thalassemia and sickle cell disease have already been successfully treated with gene editing, which will hopefully inspire the use of gene editing to cure erythroid disorders and many other inherited diseases in the near future.

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Section: Additional Gene Therapy: Current Successesmentioning

confidence: 99%

Gene Editing for Inherited Red Blood Cell Diseases

et al. 2022

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“…Given the promising results in preclinical studies, gene therapy by lentiviral transduction of autologous stem cells and progenitor cells is currently under investigation in an open-label Phase I trial (NCT04105166). 50 At the last update, two adult splenectomized patients had been enrolled, with a substantial Hb increase from the baseline in both subjects (from 7.4 to 13.3 g/dL and from 7 to 14.8 g/dL at 12 months, respectively), associated with an improvement in hemolytic markers. Notably, no severe adverse events were reported.…”

Section: Future Prospectsmentioning

confidence: 99%

“…• Transfusion-free status maintained in all 6 patients during LTE [45] Gene therapy NCT04105166, phase 1 Estimated enrollment: 6 pts • Ongoing (two adult splenectomized patients enrolled: Hb increase from the baseline respectively from 7.4 to 13.3 g/dL and from 7 to 14.8 g/dL at 12 months; improvement in hemolysis markers) [50] Journal of Blood Medicine 2022:13 https://doi.org/10.2147/JBM.S353907…”

Section: Activate-t Long Term Extensionmentioning

confidence: 99%

Pyruvate Kinase Deficiency: Current Challenges and Future Prospects

Fattizzo¹,

Cavallaro²,

Marcello³

et al. 2022

JBM

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Pyruvate kinase deficiency (PKD) is a rare autosomal recessive disease marked by chronic hemolytic anemia of various severity and frequent complications including gallstones, splenomegaly, iron overload, and others. Disease phenotype is highly heterogeneous and changes over time with children, adolescents and adult patients displaying different transfusion requirement and rates of complications. The diagnosis relies on the initial clinical suspicion in a patient with chronic hemolysis and exclusion of other more common congenital forms of hemolytic anemias; it is supported by the demonstration of reduced PK enzyme activity, and further confirmed by the detection of (homozygous or compound heterozygous) mutations of PKLR gene. Therapy is mainly supportive, with vitamin supplementation and transfusions (based on symptoms and patient growth rather than on fixed Hb thresholds). Splenectomy is widely performed, although it is less effective than in membrane defects and carries thrombotic and infectious risk. In the last decade, the allosteric PK enzyme activator mitapivat showed dramatic clinical benefit in clinical trials and gene therapy is also being studied to substitute the defective enzyme. In this review, we provide an insight in the current challenges of PKD diagnosis and management and discuss the future application of novel drugs and gene therapy, including a focus on quality of life.

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“…Allogeneic hematopoietic stem‐cell transplant has been curative in some cases, although toxicity precludes its consideration as a standard‐of‐care (see S8 in supplementary material). Gene therapy utilizing lentiviral transduction of autologous hematopoietic stem and progenitor cells (HSPCs) has yielded results in two initial adult patients suggesting potential for extensive correction of anemia and hemolysis 3 (see S9 in supplementary material). As gene therapy is evaluated in additional adult and pediatric patients, there is a need to more extensively categorize severe PKD.…”

Section: Tablementioning

confidence: 99%

“…No severe adverse events related to the investigational infusion were reported as of November 2021. 3 Pediatric evaluation is underway.…”

Section: Tablementioning

confidence: 99%