Gene Therapy for Pyruvate Kinase Deficiency (PKD)

Conditions

Pyruvate Kinase Deficiency

Keywords

hemolytic anemia, anemia, gene therapy

Brief summary

This is an open-label Phase I trial to evaluate the safety of a hematopoietic cell-based gene therapy for patients with Pyruvate Kinase Deficiency (PKD).

Detailed description

Autologous hematopoietic stem cells from mobilized peripheral blood will be transduced ex vivo (outside the body) with a lentiviral vector carrying a correct copy of the deficient PKD gene. The corrected stem cells will be infused intravenously back to the patient with the goal of correcting the hematological manifestations of the disease.

Rachael F. Grace, Eduard J. van Beers, Joan‐Lluís Vives Corrons, Bertil Glader, Andreas Glenthøj et al. (16 authors)

BMJ Open2023-03-015 citations

10.1136/bmjopen-2022-063605

Lentiviral-mediated Gene Therapy for Adults and Children with Severe Pyruvate Kinase Deficiency: Results from an Ongoing Global Phase 1 Study

Ami J. Shah, José Luis López Lorenzo, Julián Sevilla, Susana Navarro, Lucía Llanos et al. (19 authors)

Blood2022-11-157 citations

10.1182/blood-2022-170948

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

Ami J. Shah, José Luis López Lorenzo, Susana Navarro, Julián Sevilla, Lucía Llanos et al. (20 authors)

Blood2021-11-054 citations

10.1182/blood-2021-148161

Correction of the Energetic Defects in Pyruvate Kinase Deficiency through Genome Editing in Hematopoietic Stem and Progenitor Cells

Sara Fañanas-Baquero, Óscar Quintana-Bustamante, Daniel P. Dever, Omaira Alberquilla, Rebeca Sánchez‐Domínguez et al. (13 authors)

Blood2020-11-05

10.1182/blood-2020-139117

Lentiviral Mediated Gene Therapy for Pyruvate Kinase Deficiency: A Global Phase 1 Study for Adult and Pediatric Patients

José Luis López Lorenzo, Susana Navarro, Ami J. Shah, Maria Grazia Roncarolo, Julián Sevilla et al. (20 authors)

Blood2020-11-049 citations

10.1182/blood-2020-137246

Interventions

BIOLOGICALRP-L301

Autologous genetically modified CD34+ hematopoietic stem cells containing the corrected PKD gene

Study design

Allocation

NA

Intervention model

SEQUENTIAL

Primary purpose

TREATMENT

Masking

NONE

Intervention model description

Initial safety evaluation will occur in an adult cohort (n=2) patients, followed by pediatric patients ages 8-17 (n=2-3).

Eligibility

Sex/Gender

ALL

Age

8 Years to 50 Years

Healthy volunteers

No

Inclusion criteria

* PKD diagnosis with a confirmed PKLR mutation. * Adult Cohort ≥18 years old and \<50 years for the initial 2 patients enrolled; Pediatric Cohort ≥8-17 years for the next 2-3 patients. * History of severe, transfusion-dependent anemia, defined as: 1. At least 6 red blood cell transfusion episodes over a prior 12-month period and Hb levels \<9.5 g/dL in the previous 12 months despite splenectomy OR 2. At least 3 red blood cell transfusion episodes per year over 2 prior years (in the absence of precipitating events such as infection or surgery) and Hb levels \<9.5 g/dL in the previous 12 months despite prior splenectomy. OR 3. Hb levels \<8.0 g/dL despite prior splenectomy in the absence of transfusions (documented during 2 or more assessments during the prior 1-2 years) regardless of transfusion requirements. * Adequate cardiac, pulmonary, renal and hepatic function, as detailed in relevant

Exclusion criteria

. * Availability of detailed medical records, including transfusion requirements, for at least the prior 2 years. * Willing and able to read and correctly understand the patient information sheet and provide consent (or informed assent for minors) regarding study participation. * Negative serum pregnancy test for female patients of childbearing potential.

Design outcomes

Primary

Measure	Time frame	Description
Evaluation of the safety and toxicity of RP-L301: number of participants with treatment-related adverse events	2 years	The number of participants with treatment-related adverse events as assessed by United States (US) National Cancer Institute (NCI) v.5.0.

Secondary

Measure	Time frame	Description
Genetic correction following administration of RP-L301	2 years	Evidence of multi-lineage gene correction in peripheral blood (PB) and bone marrow (BM cells) will be assessed by measuring vector copy number
Transfusion independence	1 year	Transfusion independence (when relevant) at 12 months defined as need for less than or equal to 1 red blood cell transfusion in the previous 6 months
Reduction in transfusion requirements	1 year	50% reduction in transfusion requirements (when relevant) at 12 months (assessed in the previous 6 months for the 12-month assessment) relative to the 1-year period prior to enrollment
Clinically significant reduction in anemia	2 years	Increase in pre-transfusion hemoglobin (Hb) levels of 1.5 g/dL (determined by 2 assessments separated at least three months over the first and second year of follow up) relative to the average of patient's Hb levels before blood transfusions over the year prior to enrollment OR Increase of at least two-fold in the time to pre-transfusion Hb nadir relative to the average transfusion interval over the year prior to enrollment, where pre-transfusion Hb nadir is defined as the average Hb value (during the year prior to enrollment) prior to red blood cell (RBC) transfusions
Reduction of hemolysis	1 year	Reduction of reticulocytosis, defined as the number of patients with a reduction of 50% from the average of a patient's absolute reticulocyte counts (obtained prior to therapeutic blood transfusions) over the year prior to enrollment at 12 months subsequent to investigational therapy

Countries

Spain, United States

Outcome results

None listed