X'e Bağlı Kronik Granülomatöz Hastalık İçin Hematopoietik Kök ve Öncü Hücrelerde Mutasyon Onarımına Yönelik Baz Düzenleme

Sade dilde özet

Bu çalışma, kan yapıcı kök hücrelerdeki CYBB c.676 C>T mutasyonunu onaran bir baz düzenleme (base editing) gen terapisini incelemektedir. Çalışmaya, X'e bağlı kronik granülomatöz hastalık (X-linked chronic granulomatous disease) tanısı bulunan, 18 yaş ve üzeri erkek hastalar alınmaktadır. Çalışma Faz 1/Faz 2 aşamasında yürütülmekte ve halen katılımcı almaktadır.

Yukarıdaki özet, resmî kaydın sade dile aktarılmış halidir. Orijinal İngilizce başlık referans için gösterilir.

Deney bilgileri

Faz

PHASE1/PHASE2

Durum

Katılımcı alıyor

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)

Müdahale

Plerixafor, Filgrastim, Palifermin, Busulfan, Base-edited hematopoietic stem and progenitor cells, Sirolimus

Başlangıç

17.04.2024

Tahmini bitiş

31.12.2032

Ülkeler

United States

İlgili genler

Merkezler

• Bethesda, United States

Uygunluk kriterleri

Kriterler ClinicalTrials.gov kaydından orijinal İngilizce haliyle alınmıştır. Uygunluk kararını yalnızca deneyi yürüten ekip verebilir.

* INCLUSION CRITERIA:

  -\>= 18 years of age.
* Confirmed CYBB c.676 C\>T mutation.
* Male patients.
* Clinically stable and eligible to undergo apheresis and conditioning chemotherapy.

  -\>=5 x 10\^6 cryopreserved cells/kg body weight available for study product manufacturing.
* History of at least one prior serious infection or inflammatory complication requiring hospitalization despite conventional therapy.
* In the experience of a qualified clinical investigator, the patient has a poor prognosis.
* Able and willing to use a highly effective method of contraception, AND partner has communicated her willingness through subject to do same, if engaging in potentially reproductive sex from the signing of the informed consent and for 6 months after IMP infusion. Acceptable methods of contraception include the following:

  * Hormonal contraception in continuously effective use by female partner.
  * Male or female condom with spermicide as indicated.
  * Diaphragm or cervical cap in consistent and effective pattern of use with a spermicide by female partner.
  * Intrauterine device in-situ throughout above period by female partner.

EXCLUSION CRITERIA:

Individuals meeting any of the following criteria will be excluded from study participation:

* Untreated, acute infection.
* Elevated anti-gp91 specific autoantibodies \>2 x ULN
* Elevated anti-gp91 specific T cells (\>10 fold)
* Anti-platelet antibody screening with \>1 anti-platelet antibody positive in the presence of an ongoing brain infection; OR \>1 anti-platelet antibody positive and considered unsafe for study participation after consultation with hematology specialist.
* Known hypersensitivity to busulfan or any component of the product.
* Contraindications for administration of busulfan.
* Any current or pre-existing hematologic malignancy.
* Chronic infections that are considered unsafe for participation in the study by Infectious Disease Consultant.
* Cardiac abnormalities and neurological abnormalities that are deemed unsafe to participate in the study.
* Childhood malignancy (occurring before 18 years of age) in the patient or a first degree relative, or previously diagnosed known genotype of the participant conferring a predisposition to cancer (no DNA or other testing for cancer predisposition genes will be performed as part of the screen for this protocol).
* Hematological parameters unsafe for apheresis or above Grade 2 Common Terminology Criteria for Adverse Events (CTCAE) criteria until improved.
* Hepatic dysfunction- alanine aminotransferase (ALT \>3.0 - 5.0 x upper limit of normal \[ULN\]), aspartate aminotransferase (AST \>3.0 - 5.0 x ULN), bilirubin (\>1.5 - 3.0 x ULN).
* Renal dysfunction-serum creatinine \>1.5 - 3.0 x ULN or creatinine clearance 59-30 mL/min/1.73 m\^2.
* Coagulation dysfunction- Prothrombin INR or Partial thromboplastin time \>2 x ULN (patients on controlled anticoagulation agents will not be excluded for therapeutic levels).
* Uncontrolled hypertension- Systolic BP 140-159 mm Hg or diastolic BP 90-99 mm Hg.
* Abnormal blood chemistries- Hyperkalemia (K \>5.5 - 6.0 mmol/L), Hypokalemia (\<LLN - 3.0 mmol/L and requiring intervention); OR Hypercalcemia (corrected serum calcium \>11.5 - 12.5 mg/dL), Hypocalcemia (corrected serum calcium \<8.0 -7.0 mg/dL)

These values exclude false abnormalities secondary to hemolysis.

* Cytogenetic abnormalities evidenced on bone marrow aspirate.
* Pulmonary dysfunction FEV1\<25% predicted.
* Previous treatment with gene therapy or gene editing products.
* Previous receipt of non-HLA matched donor granulocyte transfusions.
* Any other condition that, in the opinion of the investigator, may unduly compromise the safety or compliance of the patient, or would make successful study completion highly unlikely.