anemia red blood cell disease
Conditions
Interventions
None listed
Sponsors
Agios Pharmaceuticals Inc.
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: 1. Adult patients with biochemically and genetically diagnosed PK deficiency, i.e. patients should be compound heterozygous or homozygous for mutations in PKLR, the gene that encodes red blood cell PK. 2. The participant is willing and able to give written informed consent.
Exclusion criteria
Exclusion criteria: Patients who have been recently transfused with packed red blood cells (*Recently* is defined as less than 3 months before blood collection).
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Stage 1. The primary endpoints will be: PK activity, PK protein stability, ATP levels, and measures of cell deformability. To determine whether AG-348 treatment results in objective differences compared to vehicle control samples will be split, and part of the sample will be incubated with AG-348, whereas the other part will not be exposed to treatment. In doing so, each patient sample will serve as its own control to determine whether AG-348 treatment results in objective differences compared to vehicle control, and compared to a measured baseline value for each endpoint. Stage 2. Erythroid differentiation will be monitored by the examination of erythroid cell morphology, and the measurement of erythroid differentiation markers, e.g. glycophorin A and transferrin receptor, in cells from PKD patients and wild type controls in the presence or absence of AG-348. Quantitation will be assessed by FACS. At specific time points PK activity and stability will be measured. We will also monitor the PK isozyme switch that takes place during normal red blood cell development. This isozyme switch concerns the gradual replacement of the PK-M2 isozyme (transcribed from the PKM2 gene) to the PK-R isozyme (transcribed from the PKLR gene) during red cell development. Both isozymes are highly homologous on the amino acid level, and PK-M2 could therefore represent an (additional) target of AG-348 during PKD erythropoiesis. | — |
Secondary
| Measure | Time frame |
|---|---|
| A major secondary study goal is to define broadly differences in cellular metabolite profiles, red cell deformability, and erythroid differentiation in PKD red cells compared to wild type controls (PKD baseline values). For instance, it is well known that PKD red cells are characterized by changes in metabolism associated with defective glycolysis, including a build-up of the PK-R substrate phosphenolpyruvate (PEP) and deficiency in the PK-R product adenosine triphosphate (ATP). We would like to identify further biomarkers that might shed more light on the mechanism of disease and could inform future treatment. | — |
Countries
Netherlands
Outcome results
None listed