Gene Therapy for Pyruvate Kinase Deficiency (PKD)

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.
• •Uncontrolled seizure disorder.
• •Cardiac T2\*\<10 ms by magnetic resonance imaging (MRI) or left ventricular ejection fraction (LVEF) \<45% by echocardiogram or multiple gated acquisition (MUGA) scanning.
• •Hepatic dysfunction as defined by: alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>2.5× the upper limit of normal.(ULN).
• •Renal dysfunction as defined as serum creatinine \> ULN. Patients with creatinine above ULN may be eligible pending documentation of a GFR ≥60 mL/min/1.73m2 as calculated by the Modification of Diet in Renal Disease equation (Stevens 2006), the revised Schwartz formula (for patients under 18 years old) (Schwartz 2009), or 24-hour urine collection.
• •Pulmonary dysfunction as defined by either:
• •* Need for supplemental oxygen during the prior 2 weeks (in absence of acute infection) or
• •* Oxygen saturation (by pulse oximetry) \<90%.
• •Any medical or other contraindication for both leukapheresis and BM harvest procedure as determined by the treating Investigator.
• •Any medical or psychiatric condition that in the opinion of the Investigator renders the subject unfit for trial participation or at higher than acceptable risk for participation.
• •Poor functional status, evidenced by Karnofsky Index \<70 in adults or Lansky \<70 in children.
• •Participation in another clinical trial with an investigational drug within 14 days before the informed consent signature. Participation in observational studies is allowed.
• •Pregnant women or women with a positive serum pregnancy test at screening or breast feeding or planning to become pregnant within the next 24 months. Women not willing to use highly effective contraceptive methods during the complete study period.