Publications by authors named "Colleen Dansereau"

4 Publications

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Post-Transcriptional Genetic Silencing of to Treat Sickle Cell Disease.

N Engl J Med 2021 01 5;384(3):205-215. Epub 2020 Dec 5.

From the Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School (E.B.E., L.E.L., A.B., C.B., M.F.C., B.M., K.B., S.-Y.P., W.B.L., C.D., M.M.H., D.A.W.), the Harvard Stem Cell Institute, Harvard Medical School (A.B., C.B.), the Gene Therapy Program, Dana-Farber/Boston Children's Cancer and Blood Disorders Center (A.B., M.F.C., B.M., E.M., A.F., S.-Y.P., C.D., D.A.W.), the Division of Hematology, Brigham and Women's Hospital, Harvard Medical School (M. Achebe), the Connell and O'Reilly Families Cell Manipulation Core Facility, Dana-Farber Cancer Institute (H.D., R.K., K.S., H.N., S.N., J.R.), the TransLab, Boston Children's Hospital (D.A., M. Armant), and the Department of Laboratory Medicine, Boston Children's Hospital, Harvard Medical School (J.P.M.) - all in Boston; and Bluebird Bio, Cambridge, MA (O.N.).

Background: Sickle cell disease is characterized by hemolytic anemia, pain, and progressive organ damage. A high level of erythrocyte fetal hemoglobin (HbF) comprising α- and γ-globins may ameliorate these manifestations by mitigating sickle hemoglobin polymerization and erythrocyte sickling. is a repressor of γ-globin expression and HbF production in adult erythrocytes. Its down-regulation is a promising therapeutic strategy for induction of HbF.

Methods: We enrolled patients with sickle cell disease in a single-center, open-label pilot study. The investigational therapy involved infusion of autologous CD34+ cells transduced with the BCH-BB694 lentiviral vector, which encodes a short hairpin RNA (shRNA) targeting mRNA embedded in a microRNA (shmiR), allowing erythroid lineage-specific knockdown. Patients were assessed for primary end points of engraftment and safety and for hematologic and clinical responses to treatment.

Results: As of October 2020, six patients had been followed for at least 6 months after receiving BCH-BB694 gene therapy; median follow-up was 18 months (range, 7 to 29). All patients had engraftment, and adverse events were consistent with effects of the preparative chemotherapy. All the patients who could be fully evaluated achieved robust and stable HbF induction (percentage HbF/(F+S) at most recent follow-up, 20.4 to 41.3%), with HbF broadly distributed in red cells (F-cells 58.9 to 93.6% of untransfused red cells) and HbF per F-cell of 9.0 to 18.6 pg per cell. Clinical manifestations of sickle cell disease were reduced or absent during the follow-up period.

Conclusions: This study validates BCL11A inhibition as an effective target for HbF induction and provides preliminary evidence that shmiR-based gene knockdown offers a favorable risk-benefit profile in sickle cell disease. (Funded by the National Institutes of Health; number, NCT03282656).
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January 2021

A Genetics Learning Program for Nurses Caring for Children Treated With Ex Vivo Autologous Gene Therapy.

J Contin Educ Nurs 2019 May;50(5):218-227

As our growing knowledge of genetics and genomics continues to inform, change, and customize health care, an understanding of genetics and genomics is now central to up-to-date and proficient nursing practice. There is a growing need for relevant nursing educational programs that aid practicing nurses in securing genetics/genomics knowledge and an understanding of gene therapy. This article describes a day-long, evidence-based, hands-on genetics learning program developed specifically for practicing nurses caring for children enrolled in ex vivo gene therapy clinical trials. [J Contin Educ Nurs. 2019;50(5):218-227.].
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May 2019

CAR T-Cell Therapy: Update on the State of the Science.

Clin J Oncol Nurs 2019 04;23(2):6-12

Dana-Farber/Boston Children's Cancer and Blood Disorders Center.

Background: Chimeric antigen receptor (CAR) T-cell therapy leverages the power of the patient's own immune system by serving as a bridge to connect genetically modified T cells to the surface antigens of tumor cells based on targeted ligands. Clinical trials have demonstrated compelling overall response and survival rates in individuals with B-cell malignancies. The current approved agents target CD19, an antigen commonly overexpressed in B-cell hematologic and other malignancies.

Objectives: This article provides information on the current state of the science related to commercially available CAR T-cell products and examines how CAR T-cell science is evolving.

Methods: An overview of pathophysiology, indications, and nursing implications of the currently approved CAR T-cell agents is presented. Future directions for CAR T-cell development and treatment indications are discussed.

Findings: Tisagenlecleucel (Kymriah®) and axicabtagene ciloleucel (Yescarta®) received approval in 2017 for the treatment of B-cell precursor acute lymphoblastic leukemia in pediatric and young adult patients, and relapsed or refractory diffuse large B-cell lymphoma after two or more lines of systemic therapy in adult patients, respectively. Additional indications have since been approved, and new agents are in development.
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April 2019

Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy.

N Engl J Med 2017 10 4;377(17):1630-1638. Epub 2017 Oct 4.

From Massachusetts General Hospital and Harvard Medical School (F.E., P.L.M.), Dana-Farber and Boston Children's Cancer and Blood Disorders Center (C. Duncan, M.A., C. Dansereau, D.A.W.), and Boston Children's Hospital, Harvard Medical School, and Harvard Stem-Cell Institute (D.A.W.), Boston, and Bluebird Bio, Cambridge (A.M.P., E.S., T.O., D.D.) - all in Massachusetts; University of Minnesota Children's Hospital, Minneapolis (P.J.O., T.C.L., W.P.M., G.V.R.); University of California, Los Angeles, Los Angeles (S.D.O., R.S., A.J.S.); University College London Great Ormond Street Hospital Institute of Child Health and Great Ormond Street Hospital NHS Trust, London (A.J.T., H.B.G., P.G.); Pediatric Neurology Department, Hôpital Bicêtre-Hôpitaux Universitaires Paris Sud, Le Kremlin Bicêtre, France (C.S., P.A.); Fundacion Investigar, Buenos Aires (H.A.); and Women's and Children's Hospital, North Adelaide, SA, Australia (D.B., N.J.C.S.).

Background: In X-linked adrenoleukodystrophy, mutations in ABCD1 lead to loss of function of the ALD protein. Cerebral adrenoleukodystrophy is characterized by demyelination and neurodegeneration. Disease progression, which leads to loss of neurologic function and death, can be halted only with allogeneic hematopoietic stem-cell transplantation.

Methods: We enrolled boys with cerebral adrenoleukodystrophy in a single-group, open-label, phase 2-3 safety and efficacy study. Patients were required to have early-stage disease and gadolinium enhancement on magnetic resonance imaging (MRI) at screening. The investigational therapy involved infusion of autologous CD34+ cells transduced with the elivaldogene tavalentivec (Lenti-D) lentiviral vector. In this interim analysis, patients were assessed for the occurrence of graft-versus-host disease, death, and major functional disabilities, as well as changes in neurologic function and in the extent of lesions on MRI. The primary end point was being alive and having no major functional disability at 24 months after infusion.

Results: A total of 17 boys received Lenti-D gene therapy. At the time of the interim analysis, the median follow-up was 29.4 months (range, 21.6 to 42.0). All the patients had gene-marked cells after engraftment, with no evidence of preferential integration near known oncogenes or clonal outgrowth. Measurable ALD protein was observed in all the patients. No treatment-related death or graft-versus-host disease had been reported; 15 of the 17 patients (88%) were alive and free of major functional disability, with minimal clinical symptoms. One patient, who had had rapid neurologic deterioration, had died from disease progression. Another patient, who had had evidence of disease progression on MRI, had withdrawn from the study to undergo allogeneic stem-cell transplantation and later died from transplantation-related complications.

Conclusions: Early results of this study suggest that Lenti-D gene therapy may be a safe and effective alternative to allogeneic stem-cell transplantation in boys with early-stage cerebral adrenoleukodystrophy. Additional follow-up is needed to fully assess the duration of response and long-term safety. (Funded by Bluebird Bio and others; STARBEAM number, NCT01896102 ; number, 2011-001953-10 .).
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October 2017