Gene therapy of Fanconi anemia: preclinical efficacy using lentiviral vectors

Blood ◽  
2002 ◽  
Vol 100 (8) ◽  
pp. 2732-2736 ◽  
Author(s):  
Francesco Galimi ◽  
Meenakshi Noll ◽  
Yoshiyuki Kanazawa ◽  
Timothy Lax ◽  
Cindy Chen ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Bone Marrow ◽  
Fanconi Anemia ◽  
Bone Marrow Failure ◽  
Allogeneic Bone Marrow Transplantation ◽  
Lentiviral Vectors ◽  
Myelogenous Leukemia ◽  
Great Promise ◽  
Allogeneic Bone ◽  
Hematopoietic Progenitors

Fanconi anemia (FA) is an inherited cancer susceptibility syndrome caused by mutations in a DNA repair pathway including at least 6 genes(FANCA, FANCC, FANCD2, FANCE, FANCF, and FANCG). The clinical course of the disease is dominated by progressive, life-threatening bone marrow failure and high incidence of acute myelogenous leukemia and solid tumors. Allogeneic bone marrow transplantation (BMT) is a therapeutic option but requires HLA-matched donors. Gene therapy holds great promise for FA, but previous attempts to use retroviral vectors in humans have proven ineffective given the impaired proliferation potential of human FA hematopoietic progenitors (HPCs). In this work, we show that using lentiviral vectors efficient genetic correction can be achieved in quiescent hematopoietic progenitors from Fanca−/− andFancc−/−mice. Long-term repopulating HPCs were transduced by a single exposure of unfractionated bone marrow mononuclear cells to lentivectors carrying the normal gene. Notably, no cell purification or cytokine prestimulation was necessary. Resistance to DNA- damaging agents was fully restored by lentiviral transduction, allowing for in vivo selection of the corrected cells with nonablative doses of cyclophosphamide. This study strongly supports the use of lentiviral vectors for FA gene therapy in humans.

Marrow Failure

Hematology ◽  
2004 ◽  
Vol 2004 (1) ◽  
pp. 318-336 ◽  
Author(s):  
Grover C. Bagby ◽  
Jeffrey M. Lipton ◽  
Elaine M. Sloand ◽  
Charles A. Schiffer
Keyword(s):  
Bone Marrow ◽  
Immunosuppressive Therapy ◽  
Fanconi Anemia ◽  
Bone Marrow Failure ◽  
Allogeneic Bone Marrow Transplantation ◽  
Dyskeratosis Congenita ◽  
Allogeneic Bone ◽  
Diagnosis And Management ◽  
Bone Marrow Failure Syndromes ◽  
Made In

Abstract New discoveries in cell biology, molecular biology and genetics have unveiled some of the pathophysiological mysteries of some of the bone marrow failure syndromes. Many of these discoveries have revealed why these syndromes show so much clinical overlap and some hold the potential for influencing the development of new therapies. In children and adults with pancytopenia and hypoplastic bone marrows proper differential diagnosis requires that some attention be directed toward defining molecular and cellular pathogenetic mechanisms because, once identified, some of these mechanisms will clearly suggest rational therapeutic approaches, treatment options that should be avoided, or both. In Section I, Drs. Jeffrey Lipton and Grover Bagby review the approach to diagnosis and management of patients with the inherited bone marrow failure syndromes, Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, and the Shwachman-Diamond syndrome. Extraordinary progress has been made in identifying the genes bearing pathogenetically relevant mutations in these disorders, but slower progress has been made in defining the precise functions of the proteins these genes encode in normal cells, in part because it is increasingly obvious that the proteins are multifunctional. In practice, it is clear that in patients with dyskeratosis congenita and Fanconi anemia, the diagnosis must be considered not only in children but in adults as well. In Section II, Dr. Elaine Sloand outlines a very practical and evidence-based approach to diagnosis and management of acquired hypoplastic states emphasizing overlap between non-clonal and clonal hematopoiesis is such conditions. The pathogenesis of T lymphocyte–mediated marrow failure is presented as a clear-cut rationale for use of immunosuppressive therapy and stem cell transplantation. Practical management of patients with refractory disease with and without evidence of clonal evolution (either paroxysmal nocturnal hemoglobinuria [PNH] or myelodysplasia [MDS]) is presented. In Section III, the challenge of hypoplastic MDS is reviewed by Dr. Charles Schiffer. After reviewing the most up-to-date classification scheme, therapeutic options are reviewed, focusing largely on agents that have most recently shown some promising activity, including DNA demethylating agents, thalidomide and CC5013, arsenic trioxide, and immunosuppressive therapy. Here are also outlined the rationale and the indications for choosing allogeneic bone marrow transplantation, the only therapy with known curative potential.

Constitutive elevation of serum alpha-fetoprotein in Fanconi anemia

Blood ◽  
2000 ◽  
Vol 96 (3) ◽  
pp. 859-863 ◽  
Author(s):  
Bruno Cassinat ◽  
Philippe Guardiola ◽  
Sylvie Chevret ◽  
Marie-Hélène Schlageter ◽  
Marie-Elisabeth Toubert ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Fanconi Anemia ◽  
Bone Marrow Failure ◽  
Allogeneic Bone Marrow Transplantation ◽  
Cost Effective ◽  
Alpha Fetoprotein ◽  
Allogeneic Bone ◽  
Bone Marrow Failure Syndromes ◽  
Chromosomal Breaks ◽  
Serum Alpha Fetoprotein

The diagnosis of Fanconi anemia (FA) is based on the association of congenital malformations, bone marrow failure syndrome, and hypersensitivity to chromosomal breaks induced by cross-linking agents. In the absence of typical features, the diagnosis is not easy to establish because there is no simple and cost-effective test; thus, investigators must rely on specialized analyses of chromosomal breaks. Because we observed elevated serum alpha-fetoprotein (sAFP) levels in FA patients, we investigated this parameter as a possible diagnostic tool. Serum AFP levels from 61 FA patients and 27 controls with acquired aplastic anemia or other inherited bone marrow failure syndromes were analyzed using a fluoroimmunoassay based on the TRACE technology. Serum AFP levels were significantly more elevated (P < .0001) in FA than in non-FA aplastic patients. In the detection of FA patients among patients with bone marrow failure syndromes, this assay had a sensitivity of 93% and a specificity of 100%. This elevation was not explained by liver abnormalities. Levels of sAFP were unchanged during at least 4 years of follow-up, and allogeneic bone marrow transplantation did not modify sAFP levels. Three of 4 FA patients with mosaicism as well as 5 of 6 FA patients with myelodysplastic syndrome were detected by this test. Heterozygous parents of FA patients had normal sAFP levels. Measurement of sAFP levels with this automated, cost-effective, and reproducible fluoroimmunoassay could be proposed for the preliminary diagnosis of FA whenever this disorder is suspected.

Constitutive elevation of serum alpha-fetoprotein in Fanconi anemia

Blood ◽  
2000 ◽  
Vol 96 (3) ◽  
pp. 859-863 ◽  
Author(s):  
Bruno Cassinat ◽  
Philippe Guardiola ◽  
Sylvie Chevret ◽  
Marie-Hélène Schlageter ◽  
Marie-Elisabeth Toubert ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Fanconi Anemia ◽  
Bone Marrow Failure ◽  
Allogeneic Bone Marrow Transplantation ◽  
Cost Effective ◽  
Alpha Fetoprotein ◽  
Allogeneic Bone ◽  
Bone Marrow Failure Syndromes ◽  
Chromosomal Breaks ◽  
Serum Alpha Fetoprotein

Abstract The diagnosis of Fanconi anemia (FA) is based on the association of congenital malformations, bone marrow failure syndrome, and hypersensitivity to chromosomal breaks induced by cross-linking agents. In the absence of typical features, the diagnosis is not easy to establish because there is no simple and cost-effective test; thus, investigators must rely on specialized analyses of chromosomal breaks. Because we observed elevated serum alpha-fetoprotein (sAFP) levels in FA patients, we investigated this parameter as a possible diagnostic tool. Serum AFP levels from 61 FA patients and 27 controls with acquired aplastic anemia or other inherited bone marrow failure syndromes were analyzed using a fluoroimmunoassay based on the TRACE technology. Serum AFP levels were significantly more elevated (P &lt; .0001) in FA than in non-FA aplastic patients. In the detection of FA patients among patients with bone marrow failure syndromes, this assay had a sensitivity of 93% and a specificity of 100%. This elevation was not explained by liver abnormalities. Levels of sAFP were unchanged during at least 4 years of follow-up, and allogeneic bone marrow transplantation did not modify sAFP levels. Three of 4 FA patients with mosaicism as well as 5 of 6 FA patients with myelodysplastic syndrome were detected by this test. Heterozygous parents of FA patients had normal sAFP levels. Measurement of sAFP levels with this automated, cost-effective, and reproducible fluoroimmunoassay could be proposed for the preliminary diagnosis of FA whenever this disorder is suspected.

Philadelphia chromosome and terminal transferase-positive acute leukemia: similarity of terminal phase of chronic myelogenous leukemia and de novo acute presentation.

1983 ◽  
Vol 1 (11) ◽  
pp. 669-676 ◽  
Author(s):  
K Jain ◽  
Z Arlin ◽  
R Mertelsmann ◽  
T Gee ◽  
S Kempin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
Chronic Myelogenous Leukemia ◽  
Lymphoblastic Leukemia ◽  
Allogeneic Bone Marrow Transplantation ◽  
Philadelphia Chromosome ◽  
Myelogenous Leukemia ◽  
Allogeneic Bone ◽  
Leukocyte Antigen ◽  
Terminal Transferase

Twenty-eight patients with Philadelphia chromosome (Ph1)--positive and terminal transferase (TdT)--positive acute leukemia (AL) were treated with intensive chemotherapy used for adult acute lymphoblastic leukemia (L-10 and L-10M protocols). Fifteen patients had a documented chronic phase of Ph1-positive chronic myelogenous leukemia preceding the acute transformation (TdT + BLCML) while the remaining 13 patients did not (TdT + Ph1 + AL). An overall complete remission (CR) rate of 71% was obtained with a median survival of 13 months in the responders. Clinical presentation, laboratory data, cytogenetics, response to treatment, and survivals of the two groups of patients are compared. These results appear to be similar, suggesting a common or closely related origin. Since the overall survival of those receiving chemotherapy maintenance is poor, three patients underwent allogeneic bone marrow transplantation (BMT) from histocompatibility leukocyte antigen--matched siblings after they achieved CR. One of them is a long-term survivor (35 + months) with a Ph1-negative bone marrow. New techniques such as BMT should be considered in young patients with a histocompatibility leukocyte antigen--compatible sibling once a CR has been achieved.

scholarly journals Use of alpha interferon for the treatment of relapse of chronic myelogenous leukemia in chronic phase after allogeneic bone marrow transplantation

Blood ◽  
1992 ◽  
Vol 80 (6) ◽  
pp. 1437-1442 ◽  
Author(s):  
CS Higano ◽  
WH Raskind ◽  
JW Singer
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Chronic Myelogenous Leukemia ◽  
Marrow Transplantation ◽  
Allogeneic Bone Marrow Transplantation ◽  
Chronic Phase ◽  
Allogeneic Bone Marrow ◽  
Myelogenous Leukemia ◽  
Allogeneic Bone ◽  
Sex Marker

Eighteen patients with relapse of chronic myelogenous leukemia (CML) after allogeneic bone marrow transplantation (BMT) were treated with recombinant human alpha 2a interferon (IFN). Relapse was defined as greater than 90% metaphases containing the Philadelphia chromosome (Ph) and hematologic abnormalities consistent with chronic-phase (CP) CML. There were 11 males and seven females, with a median age of 38 years (range, 3 to 55). Three patients relapsed after second BMT. Only one patient had received T-cell-depleted marrow initially. The initial IFN dose of 3 x 10(6) U/m2/d was escalated to the maximum tolerated dose or to a maximum of 6 x 10(6) U/m2/d. IFN controlled the white blood cell (WBC) counts in 14 of 16 patients who had abnormal counts, and in all six patients with an elevated platelet count. Six patients (33%) have had a complete disappearance of the Ph and two have had a partial response (less than 35% Ph+ metaphases). One patient has a decrease in Ph+ metaphases after 9 months of IFN. Five patients had no significant cytogenetic response after 9 to 12 months, and four developed clinical accelerated phase or blast crisis after 3 to 6 months on therapy. Of four patients with a sex marker, the Ph- population was of donor origin in three and of host origin in one. Clonal cytogenetic abnormalities other than Ph were present in 13 patients and did not predict for lack of response to IFN. IFN is effective in suppressing the Ph clone in some patients who relapse with CML after allogeneic BMT and controls the blood counts in the majority.

Interferon- Before Allogeneic Bone Marrow Transplantation in Chronic Myelogenous Leukemia Does Not Affect Outcome Adversely, Provided It Is Discontinued at Least 90 Days Before the Procedure

Blood ◽  
1999 ◽  
Vol 94 (11) ◽  
pp. 3668-3677 ◽  
Author(s):  
Rüdiger Hehlmann ◽  
Andreas Hochhaus ◽  
Hans-Jochem Kolb ◽  
Jörg Hasford ◽  
Alois Gratwohl ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Chronic Myelogenous Leukemia ◽  
Marrow Transplantation ◽  
Allogeneic Bone Marrow Transplantation ◽  
Chronic Phase ◽  
Observation Time ◽  
Allogeneic Bone Marrow ◽  
Myelogenous Leukemia ◽  
Allogeneic Bone

Abstract The influence of interferon- (IFN) pretreatment on the outcome after allogeneic bone marrow transplantation (BMT) in chronic myelogenous leukemia (CML) is controversial. One goal of the German randomized CML Studies I and II, which compare IFN ± chemotherapy versus chemotherapy alone, was the analysis of whether treatment with IFN as compared to chemotherapy had an influence on the outcome after BMT. One hundred ninety-seven (23%) of 856 Ph/bcr-abl–positive CML patients were transplanted. One hundred fifty-two patients transplanted in first chronic phase were analyzed: 86 had received IFN, 46 hydroxyurea, and 20 busulfan. Forty-eight patients (32%) had received transplants from unrelated donors. Median observation time after BMT was 4.7 (0.7 to 13.5) years. IFN and chemotherapy cohorts were compared with regard to transplantation risks, duration of treatments, interval from discontinuation of pretransplant treatment to BMT, conditioning therapy, graft-versus-host disease prophylaxis and risk profiles at diagnosis and transplantation, and IFN cohorts also with regard to performance and resistance to IFN. Outcome of patients receiving related or unrelated transplants pretreated with IFN, hydroxyurea, or busulfan was not significantly different. Five-year survival after transplantation was 58% for all patients (57% for IFN, 60% for hydroxyurea and busulfan patients). The outcome within the IFN group was not different by duration of prior IFN therapy more or less than 5 months, 1 year, or 2 years. In contrast, a different impact was observed in IFN-pretreated patients depending on the time of discontinuation of IFN before transplantation. Five-year survival was 46% for the 50 patients who received IFN within the last 90 days before BMT and 71% for the 36 patients who did not (P = .0057). Total IFN dosage had no impact on survival after BMT. We conclude that outcome after BMT is not compromised by pretreatment with IFN if it is discontinued at least 3 months before transplantation. Clear candidates for early transplantation should not be pretreated with IFN.

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