Pyruvate Kinase Deficiency
Conditions
Interventions
1:Busulfan Pretreated + autologous gene edited CD34+ cells (DNGT-101 cell injection) (> 2e6CD34+ cells/kg)
Sponsors
Shanghai Children's Medical Center
Eligibility
Sex/Gender
All
Age
6 Years to 17 Years
Inclusion criteria
Inclusion criteria: Main criteria for inclusion: 1. Aged >= 12 years and 18 and <= 50 for the Adult Cohort and 12-17 for the Pediatric Cohort); 2. Previous diagnosis for PKD confirmed by genetic testing (presence of Piruvate Kinase Liver and red blood cells gene -PKLR- mutation); 3. History of severe, transfusion-dependent anemia, defined as: (1) At least 6 red blood cell (RBC) transfusion episodes over a prior 12-month period; (2) Hemoglobulin (Hb) levels < 9.5 g/dl in the previous 12 months despite prior splenectomy; 4. Adequate cardiac, pulmonary, renal and hepatic function, as detailed in relevant exclusion criteria; 5. Availability of detailed medical records, including transfusion requirements, for at least the past 2 years; 6. Willing and able to read and correctly understand theICF and give their consent (or informed assent for minors) to participate in the study by correctly signing and dating the informed consent/assent form document; 7. Negative serum pregnancy test for female patients of childbearing potential*. *According to the clinical trial facilitation group recommendations, a woman is considered of childbearing potential (WOCBP), i.e., fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.
Exclusion criteria
Exclusion criteria: Main Criteria for exclusion 1. Presence of other known causes of hemolysis (in addition to PKD); 2. Sibling HLA-matched donor; 3. Left ventricular ejection fraction (LVEF) = 60 mL/min/1.73m2 according to Modification of Diet in Renal Disease (MDRD) formula; 6. Hepatic dysfunction defined as Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST) > 3 x upper limit of normality (ULN), International Normalized Ratio (INR) >1.5 or direct bilirubin >1.5 x ULN; 7. Known history or evidence of extensive bridging fibrosis or cirrhosis or active hepatitis, as documented on liver biopsy. Liver biopsy is not required to enable study entry, but it is requiredwhen liver iron concentration (LIC) >= 15 mg/g on T2* magnetic resonance imaging (MRI) of liver. If a liver biopsy has been performed less than 6 months prior to enrollment, it does not need to be repeated; 8. Evidence of significant pulmonary hypertension requiring medical intervention; 9. Any evidence of severe iron overload that, per investigator discretion, warrants exclusion; 10. Uncorrected bleeding disorder; 11. Uncontrolled seizure disorder; 12. Significant medical conditions including documented HIV infection, active viral hepatitis; poorly-controlled diabetes, hypertension, cardiac arrhythmia, or congestive heart failure; or arterial thromboembolic events (including stroke, TIA, unstable angina or myocardial infarction); 13. Poor functional status, evidenced by a Karnofsky Index < 70 in adults or Lansky < 70 in children; 14. Any prior or current malignancy or myeloproliferative or immunodeficiency disorder; 15. History of primary malignancy with the exception of curatively treated nonmelanomatous skin cancer, cervical cancer or breast cancer in situ, with no evidence of active malignancy in the last 3 years; 16. Any medical or other contraindication for leukapheresis or bone marrow harvest procedure, as determined by the treating investigator; 17. Any other medical unstable, uncontrolled, or severe condition or any other relevant laboratory test finding which, according to investigator criteria could interfere with a patient's ability to participate in the study; 18. Previous treatment with another gene therapy investigational medicinal product; 19. Participation in another clinical trial with an investigational drug within 30 days before the informed consent signature. Participation in observational studies is allowed; 20. 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*; *Females of childbearing age potential and male patients with partners of childbearing potential must use highly effective contraceptive measures (according to CTFG recommendations). Such methods include: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal) progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| DNGT-101 safety and toxicity evaluation; | — |
Secondary
| Measure | Time frame |
|---|---|
| Gene correction after DNGT-101 treatment;Less than or equal to one time blood transfusion;blood transfusion needs decrease;Clinically significant Anemia decrease;hemolysis decrease; | — |
Countries
China
Contacts
Public ContactJing Chen
Shanghai Children's Medical Center
Outcome results
None listed