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CRISPR-CAS9 modified CD34+ human hematopoietic stem and progenitor cells and uses thereof

A technology of stem cells and progenitor cells, applied in the field of CRISPR-CAS9 modified CD34+ human hemoglobin stem cells and progenitor cells and their applications, can solve problems such as shortened lifespan

Pending Publication Date: 2020-09-04
VERTEX PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] About 90 percent of children born with SCD in the United States or Europe will survive to adulthood, but their lives are shortened by twenty to thirty years compared to the general population, who die at an average age of about forty to fifty years year

Method used

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  • CRISPR-CAS9 modified CD34+ human hematopoietic stem and progenitor cells and uses thereof
  • CRISPR-CAS9 modified CD34+ human hematopoietic stem and progenitor cells and uses thereof
  • CRISPR-CAS9 modified CD34+ human hematopoietic stem and progenitor cells and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0452] Example 1. Non-clinical research

[0453] The following nonclinical efficacy and toxicology studies were performed.

[0454] Briefly, in a preclinical study of the investigational product (CTX001), CD34 + CRISPR-Cas9 gene editing at the erythroid enhancer of the BCL11A gene of cells resulted in γ-globin mRNA (mean γ / α-globin ratio of 0.30 (standard deviation [SD] ± 0.20) and γ / (γ+β)-globin Protein ratio was 0.41 (SD±0.15)) and HbF (mean percentage of HbF / (HbF+HbA) protein level was 32% (SD±9%)) increased. The mean allelic editing frequency was 80% (SD ± 4%), and across CD34 including long-term hematopoietic stem cells (LT-HSCs) + Cell subpopulations are consistent. Most editors are biallelic.

[0455] In a mouse xenograft study, at 16 weeks after transplantation, CD34 edited with drug or control (EGFP) + There was no difference in implantation chimerism between hHSPC-infused NOD SCIDγ(NSG) mice ( figure 1 ). The mean frequency of the edited allele present in bone...

Embodiment 2

[0462] Example 2. A study evaluating the safety and efficacy of a single dose of autologous CRISPR-Cas9-modified CD34+ human hematopoietic stem and progenitor cells in subjects with transfusion-dependent β-thalassemia

[0463] A Phase 1 / 2 Safety and Efficacy Study to Evaluate Single Dose of Autologous CRISPR-Cas9 Modified CD34+ Human Hematopoietic Stem and Progenitor Cells (hHSPC) (Drug Product) in Subjects with Transfusion-Dependent β-Thalassemia Safety and efficacy (primary purpose). To assess the effect of drug infusion on disease-specific events and clinical status, and to quantify gene editing efficiency (secondary objectives). In addition, the biomarkers were assessed for their ability to characterize drug effects and predict treatment outcomes (exploratory purposes). Such studies will initially include up to 12 subjects participating in the study and may be expanded to 30 or more subjects. Subjects participating in the study were 18 to 35 years old (including at the t...

Embodiment 3

[0611] Example 3. A study evaluating the safety and efficacy of a single dose of autologous CRISPR-Cas9-modified CD34+ human hematopoietic stem and progenitor cells in subjects with severe sickle cell disease

[0612] A Phase 1 / 2 Safety and Efficacy Study to Evaluate Single Dose of Autologous CRISPR-Cas9 Modified CD34+ Human Hematopoietic Stem and Progenitor Cells (hHSPC) (Drug Products) in Subjects with Transfused Severe Sickle Cell Disease (SCD) Safety and Efficacy (Primary Purpose) in . To assess the effect of drug infusion on disease-specific events and clinical status, and to quantify gene editing efficiency (secondary objectives). In addition, the biomarkers were assessed for their ability to characterize drug effects and predict treatment outcomes (exploratory purposes). Such a study will initially include up to 12 subjects participating in the study, with potential expansion to 45 or more subjects. Subjects enrolled in the study were 18 to 35 years old (inclusive at ...

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Abstract

Provided herein, in some embodiments, are methods and compositions for treatment of subjects with [beta]-thalassemia and subjects with severe sickle cell disease using autologous CRISPR-Cas9 modifiedCD34+ human hematopoietic stem and progenitor cells.

Description

[0001] related application [0002] This application claims U.S. Provisional Application Serial No. 62 / 594,689 filed December 5, 2017, U.S. Provisional Application Serial No. 62 / 664,023 filed April 27, 2018, U.S. Provisional Application Serial No. 62 / 664,023 filed May 15, 2018 62 / 671,770, U.S. Provisional Application Serial No. 62 / 734,431, filed September 21, 2018, and U.S. Provisional Application Serial No. 62 / 734,543, filed September 21, 2018, benefit under 35 U.S.C. § 119(e), which The respective contents are incorporated herein by reference in their entirety. Background technique [0003] Hemoglobin (Hb) is a tetramer formed by four globin peptides, each tightly bound to a heme group containing an iron atom. During pregnancy, the predominant form of hemoglobin is fetal hemoglobin (HbF), which consists of two α-globin chains and two γ-globin chains. Shortly before birth, there is a switch from HbF to adult hemoglobin, which contains two α-globin polypeptide chains and two...

Claims

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Application Information

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IPC IPC(8): A61K38/46C12N9/22C12N15/10C12N15/113
CPCA61K35/28C12N15/113C12N2310/20A61K38/193A61K35/18A61K31/4535A61K2300/00C12N5/0647C12N15/102C12N9/22A61K31/255A61P7/00A61K31/395C12N15/11C12N2310/315C12N2310/321
Inventor E.莫拉瓦T.查克拉博蒂A.S.伦德伯格T.霍L.桑德勒B.尤斯塔斯J.罗瑟特R.考夫曼
Owner VERTEX PHARMA INC