Clinical trial NCT03538899: Autologous Gene Therapy for Artemis-Deficient SCID
Official title: A Phase I/II Safety and Efficacy Study of AProArt-CD34 in Artemis-Deficient Severe Combined Immunodeficiency in Newly Diagnosed Patients Using a Self-Inactivating Lentiviral Vector (AProArt) to Transduce Autologous CD34 Hematopoietic Cells
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Severe Combined Immunodeficiency
Keywords: Artemis-deficient Severe Combined Immunodeficiency
gene therapy
autologous stem cell transplant
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
First posted: 2018-05-29
Enrollment: 25
Sex: ALL
Minimum age (years): 2
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Longitudinal study of autologous stem cell transplant of cells transduced with corrected DCLRE1C gene using a self-inactivating lentiviral vector (AProArt). The CliniMACS® CD34 Reagent System cell sorter device will be used to select CD 34 cells. Sub-ablative busulfan will be used for pre-transplant conditioning.
Primary purpose: TREATMENT

Brief summary: This study aims to determine if a new method can be used to treat Artemis-deficient Severe Combined Immunodeficiency (ART-SCID), a severe form of primary immunodeficiency caused by mutations in the DCLRE1C gene. This method involves transferring a normal copy of the DCLRE1C gene into stem cells of an affected patient. Participants will receive an infusion of stem cells transduced with a self-inactivating lentiviral vector that contains a normal copy of the DCLRE1C gene. Prior to the infusion they will receive sub-ablative, dose-targeted busulfan conditioning. The study will investigate if the procedure is safe, whether it can be done according to the methods described in the protocol, and whether the procedure will provide a normal immune system for the patient. A total of 24 newly diagnosed patients will be enrolled at the University of California San Francisco in this single-site trial and will be followed for 15 years post-infusion. It is hoped that this type of gene transfer may offer improved outcomes for ART-SCID patients who lack a brother or sister who can be used as a donor for stem cell transplantation or who have failed to develop a functioning immune system after a previous stem cell transplant.

Detailed description: Children with SCID generally do not survive beyond the first year of life without definitive treatment. The most effective current cure is hematopoietic stem cell transplant (HCT) with a human leukocyte antigen (HLA) matched sibling. While a matched sibling HCT can successfully treat ART-SCID, fewer than 20% of affected children have such a donor, and even when a matched sibling donor is available there is often incomplete T and B cell immune reconstitution. ART-SCID is the most difficult type of SCID to cure by hematopoietic stem cell transplant using alternative donors. Engraftment typically requires intensive conditioning with high dose alkylating agents to prevent rejection and to open marrow niches. These patients also have a high risk of developing graft versus host disease (GVHD) when alternative donors are used. The great majority of patients have absent B cell reconstitution and require lifelong administration of immunoglobulin infusions. Patients with ART-SCID who do receive high doses of alkylators, especially when 2 agents are used, have poorer survival, abnormal dental development, endocrinopathies, and short stature in comparison with children exposed to no or limited alkylators or children with SCID types that are not associated with a DNA repair defect. For these reasons, a safer, more effective approach to curing ART-SCID is needed. Autologous gene-corrected hematopoeitic stem cell transplant may eliminate both the risk of GVHD and the need for alkylators to prevent rejection.

The study design is a single-cohort, longitudinal experiment using non-randomized patients treated once with a lentiviral vector for gene-correction of Artemis-deficient SCID after conditioning with low-dose busulfan. No formal control group is planned for gauging safety; rather, intensive monitoring of the initial 6 enrollees will preclude continued accrual in the presence of safety signals, and long-term safety will be monitored for 15 years. Bone marrow stem cells will be harvested from participants who weigh ≤7.5 kilograms or have failed cytokine mobilization previously, and cytokine-mobilized peripheral blood stem cells will be harvested from participants weighing \>7.5 kilograms. CD34 cells will be isolated using the CliniMACS® CD34 Reagent System cell sorter device. The cells will be transduced with the AProArt lentiviral vector. Transduction enhancers will be used to increase the transduction efficiency in peripheral blood CD34+ cells from patients who undergo a peripheral blood stem cell collection. These transduced cells will then be cryopreserved, and aliquots of the cells will undergo safety testing and be reserved for potency evaluation. All patients will receive busulfan conditioning targeted over 2 days to achieve a cumulative area under the curve (AUC) of 20 mg\*hr/L (an ablative cumulative AUC is 60-90mg\*hr/L). Following the infusion of AProArt-transduced cells, patients will be evaluated at 4, 6, 8, 16, and 24 weeks for evidence of gene transduced peripheral blood mononuclear cells and when possible cell lineages including T, B, NK and granulocyte/myeloid cells. If there is no evidence of gene transduced cells at 6 weeks (42 days) post infusion, a decision will be made regarding further therapy.

After day 42 post-transplant, recipients will be followed for toxicity and durable reconstitution of T and B cell immunity. Immune reconstitution of T cells will be monitored on a regular basis. If the absolute neutrophil count is \< 200/µl or platelets \< 20,000/µl on 3 independent determinations after day 42 post infusion of transduced cells, the patient may receive infusion of the back-up cells or an allogeneic hematopoeitic stem cell transplant. Patients who were neutropenic prior to conditioning (SCID-related neutropenia) but responsive to granulocyte-colony stimulating factor (GCSF) will not be considered to have failed, provided the absolute neutrophil count can be maintained above \>500/µl with GCSF.

After day 42, patients will be assessed weekly through 12 weeks post-transplant and at week 16, monthly through month 6 post-transplant, and then 3 monthly through month 24. They will then be assessed at 6 monthly intervals during years 2-5 and annually through year 15. Study follow-up will include completion of Quality of Life questionnaires and administration of neurodevelopmental testing.

Patients with evidence of clinically inadequate reconstitution, low VCN, or any other features suggesting clinically inadequate response to the initial gene therapy procedure will be offered a repeat infusion of gene-transduced cells. Conditioning regimens given prior to a repeat gene therapy procedure may include low-dose busulfan, other conditioning, or no conditioning.

An independent Data Safety Monitoring Board (DSMB) will be appointed for safety monitoring of this trial. The DSMB will review all data for safety on a regular schedule, based on numbers of enrolled subjects and will also conduct special urgent review of any protocol related Serious Adverse Events (SAE). As the trial is initiated, the DSMB will review results of each of the first 3 cases prior to proceeding with subsequent patients.

The investigational product (IND1711) for the ART-SCID gene transfer study is not available for expanded access use. As per 21 CFR Part 312.305(3), the study management team has determined that providing the investigational product for expanded access use at this time would interfere with the conduct and completion of the clinical trial and potential development of future expanded access use. The investigational product is available to eligible patients through participation in this clinical trial.

Eligibility criteria: Inclusion Criteria:

* ≥2.0 months of age at initiation of busulfan conditioning
* Diagnosis of typical or leaky ART-SCID:

Newly diagnosed ART-SCID patients must have:

* Artemis deficiency; AND
* CD3 count \< 300 autologous cells/µL (typical ART-SCID) OR spontaneous maternal chimerism, OR CD3 count \>300/µL but with restricted T cell receptor Vb diversity, defined as 18/24 or fewer polyclonal families.

AND - CD45 cell response to mitogens (PHA) \< 50% of the lower limit of normal range for the lab (leaky ART-SCID).

Patients diagnosed with ART-SCID per the criteria above who have failed an allogeneic transplant (including an HLA matched sibling transplant) may participate if they meet the criteria below:

- Are at least 3 months post allogeneic hematopoeitic stem cell transplant without evidence of engraftment of allogeneic donor cells (excluding maternal cells)

OR are engrafted but have at least 2 of the following 4 conditions:

* Declining CD3 donor chimerism with at least 3 evaluations separated by at least 1 month prior to time of enrollment OR \< 5% overall donor chimerism in blood and marrow at ≥3 months post transplant.
* Incompletely reconstituted T cell immunity at ≥6 months (1 of the following 2):

  * CD4 \< 200/μL AND CD45 cell PHA \< 50% of the lower limit of normal for lab;
  * CD4 CD45RA \< 20% of total CD4 cells OR T cell receptor Vb diversity is restricted, defined as 18/24 or fewer polyclonal families.
  * No donor B cells OR lack of B cell function (immunoglobulin M isohemagglutinins \< 1:8 (not blood type AB) AND immunoglobulin A (IgA) or IgM values below reference range for age AND if not receiving intravenous immunoglobulin (IVIG), no protective level of antibody to tetanus immunization x2).
  * Clinical manifestations consistent with persistent T and B cell immunodeficiency e.g., chronic infection including norovirus, cytomegalovirus, human herpes virus 6; OR acute or recurrent infection (e.g., PJP), bronchiectasis, chronic sinusitis.

AND

* Have no prior exposure to high dose busulfan (≥10 mg/kg total dose or average cumulative exposure of ≥40 mg\*hr/L). If the total cumulative AUC including previous busulfan exposure plus the dose to be administered in this protocol is predicted to be ≤60 mg\*hr/L, then patient would be eligible providing other criteria are satisfied.
* No medically eligible HLA-identical sibling with a normal immune system who could serve as an allogeneic bone marrow donor (applies to newly diagnosed patients only).

Written informed consent according to guidelines of the Institutional Review Board (IRB).

Exclusion Criteria:

* Liver function tests (aspartate aminotransferase, alanine transaminase, gamma-glutamyl transferase) \> three times the upper limit of normal for lab and/or total bilirubin \>1.50 mg/dl at the time of planned initiation of busulfan conditioning.
* Prior history of veno-occlusive disease (Sinusoidal obstruction syndrome) of the liver.
* Medically eligible HLA-matched sibling (applies to newly diagnosed patients only).
* Evidence of HIV infection by polymerase chain reaction or p24 antigen testing.
* Unable to tolerate general anesthesia and/or marrow harvest or peripheral blood stem cell collection (apheresis) or insertion of central venous catheter.
* Presence of a medical condition indicating that survival is predicted to be less than 4 months, such as the requirement for mechanical ventilation, severe failure of a major organ system, or evidence of a serious, progressive infection that is refractory to medical therapy.
* Pregnancy
* A social situation indicating that the family may not be able to comply with protocol procedures and recommended medical care and follow-up.
* Other conditions which in the opinion of the Principal Investigator and/or co-investigators, contra-indicate the infusion of transduced cells or study participation.

Primary outcomes:
measure: Survival of patients with ART-SCID who receive self-inactivating (SIN) lentiviral vector transduced CD34 cells (AProArt-CD34) through autologous stem cell transplant
timeFrame: 24 months
Secondary outcomes:
measure: Number of participants with B cell immune reconstitution
timeFrame: 24 months
measure: Number of participants with T cell immune reconstitution
timeFrame: 24 months
measure: Event Free Survival
timeFrame: 24 months
Other outcomes:
measure: Adverse event (AE) profile associated with the study intervention from treatment through 15 years after the gene transfer procedure
timeFrame: 15 years
measure: Number of participants with B cell reconstitution beyond 24 months, including B cell numbers and function
timeFrame: 15 years
measure: Efficacy of targeting low exposure busulfan in infants and children, calculated by percentage of participants whose treatment meets study parameters using a validated population pharmacokinetic model to calculate individualized busulfan clearance.
timeFrame: 42 days
measure: Repertoire diversity of T and B cells, as assessed by analyzing T cell receptor gene variable beta sequence (TCR-Vb) and immunoglobulin heavy chain (IGH) rearranged receptors and calculating diversity Shannon Index.
timeFrame: 24 months
measure: Determine if B cell receptor diversity at 6 months is predictive of B cell reconstitution over 15 years by analyzing B cell receptor gene variable beta sequence and immunoglobulin heavy chain rearranged receptors and calculating diversity Shannon Index.
timeFrame: 15 years
measure: Determine if at 6 months T cell receptor (TCR) diversity and/or absolute CD3, CD4, naïve CD4 counts predict T cell reconstitution at 24 months or need for 2nd treatment throughout the 15 year follow-up period.
timeFrame: 15 years
measure: Stability of mean vector copy number (VCN) and the location of vector integration sites in sorted T, B, and natural killer (NK) cells, granulocytes and monocytes in peripheral blood over time after infusion of transduced HSC.
timeFrame: 24 months
measure: Characterization of insertion sites in multiple cell lineages as an indicator of diversity, multilineage engraftment, and tabulation of any clonal expansion that might indicate development of a malignancy.
timeFrame: 24 months
measure: Potential benefit of prophylactic sirolimus in reducing the incidence of transient autoimmune hemolytic anemia (AIHA) post infusion of AProArt-CD34, as assessed by number of participants with clinical diagnosis of AIHA.
timeFrame: 24 months
measure: Measurement of radiation sensitivity in peripheral blood NK cells for development and validation of a rapid functional assay for radiation-sensitive SCID.
timeFrame: 24 months
measure: Potency of AProArt-CD34 as indicated by capacity for in vitro differentiation of participant specimens into T cells and assessment of average VCN as a surrogate marker for potency.
timeFrame: 5 years
measure: Hematopoietic recovery in patients with ART-SCID who receive self-inactivating (SIN) lentiviral vector (AProArt)-transduced CD34 cells through a repeat infusion autologous stem cell transplant.
timeFrame: 5 years
measure: Specific antibody titers to measure establishment of immune function in patients who have received a repeat infusion AProArt lentiviral vector-transduced autologous CD34 hematopoietic stem cell transplant
timeFrame: 5 years
measure: Incidence of Adverse Events related to a repeat infusion autologous stem cell transplant of self-inactivating (SIN) lentiviral vector (AProArt)-transduced CD34 cells
timeFrame: 5 years
measure: Repertoire diversity in ART-SCID recipients gene therapy post-repeat infusion of gene-corrected cells.
timeFrame: 5 years
measure: Incidence of long-term Adverse Events related to a repeat autologous stem cell transplant of self-inactivating (SIN) lentiviral vector (AProArt)-transduced CD34 cells.
timeFrame: 15 years
measure: Vector copy number sustained over time after a repeat infusion of transduced hematopoeitic stem cell transplant.
timeFrame: 5 years
measure: Patient reported outcome of undergoing treatment with gene-corrected cells as assessed by the PedsQL questionnaires.
timeFrame: 15 years
measure: Family impact of undergoing treatment with gene-corrected cells.
timeFrame: 15 years
Locations:
city: San Francisco
country: United States
facility: University of California, San Francisco (UCSF) Children's Hospital
state: California
Study officials:
affiliation: University of California, San Francisco
name: Morton Cowan, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Buckley RH. The multiple causes of human SCID. J Clin Invest. 2004 Nov;114(10):1409-11. doi: 10.1172/JCI23571.
citation: Gatti RA, Meuwissen HJ, Allen HD, Hong R, Good RA. Immunological reconstitution of sex-linked lymphopenic immunological deficiency. Lancet. 1968 Dec 28;2(7583):1366-9. doi: 10.1016/s0140-6736(68)92673-1. No abstract available.
citation: Chan A, Scalchunes C, Boyle M, Puck JM. Early vs. delayed diagnosis of severe combined immunodeficiency: a family perspective survey. Clin Immunol. 2011 Jan;138(1):3-8. doi: 10.1016/j.clim.2010.09.010. Epub 2010 Oct 28.
citation: Chan K, Puck JM. Development of population-based newborn screening for severe combined immunodeficiency. J Allergy Clin Immunol. 2005 Feb;115(2):391-8. doi: 10.1016/j.jaci.2004.10.012.
citation: Kwan A, Puck JM. History and current status of newborn screening for severe combined immunodeficiency. Semin Perinatol. 2015 Apr;39(3):194-205. doi: 10.1053/j.semperi.2015.03.004. Epub 2015 Apr 30.
citation: Pai SY, Logan BR, Griffith LM, Buckley RH, Parrott RE, Dvorak CC, Kapoor N, Hanson IC, Filipovich AH, Jyonouchi S, Sullivan KE, Small TN, Burroughs L, Skoda-Smith S, Haight AE, Grizzle A, Pulsipher MA, Chan KW, Fuleihan RL, Haddad E, Loechelt B, Aquino VM, Gillio A, Davis J, Knutsen A, Smith AR, Moore TB, Schroeder ML, Goldman FD, Connelly JA, Porteus MH, Xiang Q, Shearer WT, Fleisher TA, Kohn DB, Puck JM, Notarangelo LD, Cowan MJ, O'Reilly RJ. Transplantation outcomes for severe combined immunodeficiency, 2000-2009. N Engl J Med. 2014 Jul 31;371(5):434-46. doi: 10.1056/NEJMoa1401177.
citation: Dorsey MJ, Dvorak CC, Cowan MJ, Puck JM. Treatment of infants identified as having severe combined immunodeficiency by means of newborn screening. J Allergy Clin Immunol. 2017 Mar;139(3):733-742. doi: 10.1016/j.jaci.2017.01.005.
citation: Dvorak CC, Hassan A, Slatter MA, Honig M, Lankester AC, Buckley RH, Pulsipher MA, Davis JH, Gungor T, Gabriel M, Bleesing JH, Bunin N, Sedlacek P, Connelly JA, Crawford DF, Notarangelo LD, Pai SY, Hassid J, Veys P, Gennery AR, Cowan MJ. Comparison of outcomes of hematopoietic stem cell transplantation without chemotherapy conditioning by using matched sibling and unrelated donors for treatment of severe combined immunodeficiency. J Allergy Clin Immunol. 2014 Oct;134(4):935-943.e15. doi: 10.1016/j.jaci.2014.06.021. Epub 2014 Aug 7.
citation: Neven B, Leroy S, Decaluwe H, Le Deist F, Picard C, Moshous D, Mahlaoui N, Debre M, Casanova JL, Dal Cortivo L, Madec Y, Hacein-Bey-Abina S, de Saint Basile G, de Villartay JP, Blanche S, Cavazzana-Calvo M, Fischer A. Long-term outcome after hematopoietic stem cell transplantation of a single-center cohort of 90 patients with severe combined immunodeficiency. Blood. 2009 Apr 23;113(17):4114-24. doi: 10.1182/blood-2008-09-177923. Epub 2009 Jan 23.
citation: Schuetz C, Neven B, Dvorak CC, Leroy S, Ege MJ, Pannicke U, Schwarz K, Schulz AS, Hoenig M, Sparber-Sauer M, Gatz SA, Denzer C, Blanche S, Moshous D, Picard C, Horn BN, de Villartay JP, Cavazzana M, Debatin KM, Friedrich W, Fischer A, Cowan MJ. SCID patients with ARTEMIS vs RAG deficiencies following HCT: increased risk of late toxicity in ARTEMIS-deficient SCID. Blood. 2014 Jan 9;123(2):281-9. doi: 10.1182/blood-2013-01-476432. Epub 2013 Oct 21.
citation: Wahlstrom JT, Dvorak CC, Cowan MJ. Hematopoietic Stem Cell Transplantation for Severe Combined Immunodeficiency. Curr Pediatr Rep. 2015 Mar 1;3(1):1-10. doi: 10.1007/s40124-014-0071-7.
citation: Horn B, Cowan MJ. Unresolved issues in hematopoietic stem cell transplantation for severe combined immunodeficiency: need for safer conditioning and reduced late effects. J Allergy Clin Immunol. 2013 May;131(5):1306-11. doi: 10.1016/j.jaci.2013.03.014.
citation: Cowan MJ, Gennery AR. Radiation-sensitive severe combined immunodeficiency: The arguments for and against conditioning before hematopoietic cell transplantation--what to do? J Allergy Clin Immunol. 2015 Nov;136(5):1178-85. doi: 10.1016/j.jaci.2015.04.027. Epub 2015 Jun 6.
citation: Cicalese MP, Aiuti A. Clinical applications of gene therapy for primary immunodeficiencies. Hum Gene Ther. 2015 Apr;26(4):210-9. doi: 10.1089/hum.2015.047.
citation: Cavazzana-Calvo M, Fischer A. Gene therapy for severe combined immunodeficiency: are we there yet? J Clin Invest. 2007 Jun;117(6):1456-65. doi: 10.1172/JCI30953.
citation: Hacein-Bey-Abina S, Pai SY, Gaspar HB, Armant M, Berry CC, Blanche S, Bleesing J, Blondeau J, de Boer H, Buckland KF, Caccavelli L, Cros G, De Oliveira S, Fernandez KS, Guo D, Harris CE, Hopkins G, Lehmann LE, Lim A, London WB, van der Loo JC, Malani N, Male F, Malik P, Marinovic MA, McNicol AM, Moshous D, Neven B, Oleastro M, Picard C, Ritz J, Rivat C, Schambach A, Shaw KL, Sherman EA, Silberstein LE, Six E, Touzot F, Tsytsykova A, Xu-Bayford J, Baum C, Bushman FD, Fischer A, Kohn DB, Filipovich AH, Notarangelo LD, Cavazzana M, Williams DA, Thrasher AJ. A modified gamma-retrovirus vector for X-linked severe combined immunodeficiency. N Engl J Med. 2014 Oct 9;371(15):1407-17. doi: 10.1056/NEJMoa1404588.
citation: Greene MR, Lockey T, Mehta PK, Kim YS, Eldridge PW, Gray JT, Sorrentino BP. Transduction of human CD34+ repopulating cells with a self-inactivating lentiviral vector for SCID-X1 produced at clinical scale by a stable cell line. Hum Gene Ther Methods. 2012 Oct;23(5):297-308. doi: 10.1089/hgtb.2012.150. Epub 2012 Nov 7.
citation: De Ravin SS, Wu X, Moir S, Anaya-O'Brien S, Kwatemaa N, Littel P, Theobald N, Choi U, Su L, Marquesen M, Hilligoss D, Lee J, Buckner CM, Zarember KA, O'Connor G, McVicar D, Kuhns D, Throm RE, Zhou S, Notarangelo LD, Hanson IC, Cowan MJ, Kang E, Hadigan C, Meagher M, Gray JT, Sorrentino BP, Malech HL, Kardava L. Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency. Sci Transl Med. 2016 Apr 20;8(335):335ra57. doi: 10.1126/scitranslmed.aad8856.
citation: Kwan A, Hu D, Song M, Gomes H, Brown DR, Bourque T, Gonzalez-Espinosa D, Lin Z, Cowan MJ, Puck JM. Successful newborn screening for SCID in the Navajo Nation. Clin Immunol. 2015 May;158(1):29-34. doi: 10.1016/j.clim.2015.02.015. Epub 2015 Mar 8.
citation: Li L, Drayna D, Hu D, Hayward A, Gahagan S, Pabst H, Cowan MJ. The gene for severe combined immunodeficiency disease in Athabascan-speaking Native Americans is located on chromosome 10p. Am J Hum Genet. 1998 Jan;62(1):136-44. doi: 10.1086/301688.
citation: Li L, Moshous D, Zhou Y, Wang J, Xie G, Salido E, Hu D, de Villartay JP, Cowan MJ. A founder mutation in Artemis, an SNM1-like protein, causes SCID in Athabascan-speaking Native Americans. J Immunol. 2002 Jun 15;168(12):6323-9. doi: 10.4049/jimmunol.168.12.6323.
citation: Li L, Salido E, Zhou Y, Bhattacharyya S, Yannone SM, Dunn E, Meneses J, Feeney AJ, Cowan MJ. Targeted disruption of the Artemis murine counterpart results in SCID and defective V(D)J recombination that is partially corrected with bone marrow transplantation. J Immunol. 2005 Feb 15;174(4):2420-8. doi: 10.4049/jimmunol.174.4.2420.
citation: Xiao Z, Dunn E, Singh K, Khan IS, Yannone SM, Cowan MJ. A non-leaky Artemis-deficient mouse that accurately models the human severe combined immune deficiency phenotype, including resistance to hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2009 Jan;15(1):1-11. doi: 10.1016/j.bbmt.2008.10.026.
citation: Multhaup M, Karlen AD, Swanson DL, Wilber A, Somia NV, Cowan MJ, McIvor RS. Cytotoxicity associated with artemis overexpression after lentiviral vector-mediated gene transfer. Hum Gene Ther. 2010 Jul;21(7):865-75. doi: 10.1089/hum.2009.162.
citation: Multhaup MM, Podetz-Pedersen KM, Karlen AD, Olson ER, Gunther R, Somia NV, Blazar BR, Cowan MJ, McIvor RS. Role of transgene regulation in ex vivo lentiviral correction of artemis deficiency. Hum Gene Ther. 2015 Apr;26(4):232-43. doi: 10.1089/hum.2014.062. Epub 2015 Apr 13.
citation: Punwani D, Kawahara M, Yu J, Sanford U, Roy S, Patel K, Carbonaro DA, Karlen AD, Khan S, Cornetta K, Rothe M, Schambach A, Kohn DB, Malech HL, McIvor RS, Puck JM, Cowan MJ. Lentivirus Mediated Correction of Artemis-Deficient Severe Combined Immunodeficiency. Hum Gene Ther. 2017 Jan;28(1):112-124. doi: 10.1089/hum.2016.064. Epub 2016 Sep 7.
citation: Yeager AM, Shinn C, Shinohara M, Pardoll DM. Hematopoietic cell transplantation in the twitcher mouse. The effects of pretransplant conditioning with graded doses of busulfan. Transplantation. 1993 Jul;56(1):185-90. doi: 10.1097/00007890-199307000-00034.
citation: Modlich U, Navarro S, Zychlinski D, Maetzig T, Knoess S, Brugman MH, Schambach A, Charrier S, Galy A, Thrasher AJ, Bueren J, Baum C. Insertional transformation of hematopoietic cells by self-inactivating lentiviral and gammaretroviral vectors. Mol Ther. 2009 Nov;17(11):1919-28. doi: 10.1038/mt.2009.179. Epub 2009 Aug 11.
citation: O'Marcaigh AS, DeSantes K, Hu D, Pabst H, Horn B, Li L, Cowan MJ. Bone marrow transplantation for T-B- severe combined immunodeficiency disease in Athabascan-speaking native Americans. Bone Marrow Transplant. 2001 Apr;27(7):703-9. doi: 10.1038/sj.bmt.1702831.
citation: Grunebaum E, Roifman CM. Bone marrow transplantation using HLA-matched unrelated donors for patients suffering from severe combined immunodeficiency. Immunol Allergy Clin North Am. 2010 Feb;30(1):63-73. doi: 10.1016/j.iac.2009.11.001.
citation: Griffith LM, Cowan MJ, Notarangelo LD, Kohn DB, Puck JM, Pai SY, Ballard B, Bauer SC, Bleesing JJ, Boyle M, Brower A, Buckley RH, van der Burg M, Burroughs LM, Candotti F, Cant AJ, Chatila T, Cunningham-Rundles C, Dinauer MC, Dvorak CC, Filipovich AH, Fleisher TA, Bobby Gaspar H, Gungor T, Haddad E, Hovermale E, Huang F, Hurley A, Hurley M, Iyengar S, Kang EM, Logan BR, Long-Boyle JR, Malech HL, McGhee SA, Modell F, Modell V, Ochs HD, O'Reilly RJ, Parkman R, Rawlings DJ, Routes JM, Shearer WT, Small TN, Smith H, Sullivan KE, Szabolcs P, Thrasher A, Torgerson TR, Veys P, Weinberg K, Zuniga-Pflucker JC; workshop participants. Primary Immune Deficiency Treatment Consortium (PIDTC) report. J Allergy Clin Immunol. 2014 Feb;133(2):335-47. doi: 10.1016/j.jaci.2013.07.052. Epub 2013 Oct 15.
citation: Ferrua F, Brigida I, Aiuti A. Update on gene therapy for adenosine deaminase-deficient severe combined immunodeficiency. Curr Opin Allergy Clin Immunol. 2010 Dec;10(6):551-6. doi: 10.1097/ACI.0b013e32833fea85.
citation: Candotti F, Shaw KL, Muul L, Carbonaro D, Sokolic R, Choi C, Schurman SH, Garabedian E, Kesserwan C, Jagadeesh GJ, Fu PY, Gschweng E, Cooper A, Tisdale JF, Weinberg KI, Crooks GM, Kapoor N, Shah A, Abdel-Azim H, Yu XJ, Smogorzewska M, Wayne AS, Rosenblatt HM, Davis CM, Hanson C, Rishi RG, Wang X, Gjertson D, Yang OO, Balamurugan A, Bauer G, Ireland JA, Engel BC, Podsakoff GM, Hershfield MS, Blaese RM, Parkman R, Kohn DB. Gene therapy for adenosine deaminase-deficient severe combined immune deficiency: clinical comparison of retroviral vectors and treatment plans. Blood. 2012 Nov 1;120(18):3635-46. doi: 10.1182/blood-2012-02-400937. Epub 2012 Sep 11.
citation: Multhaup MM, Gurram S, Podetz-Pedersen KM, Karlen AD, Swanson DL, Somia NV, Hackett PB, Cowan MJ, McIvor RS. Characterization of the human artemis promoter by heterologous gene expression in vitro and in vivo. DNA Cell Biol. 2011 Oct;30(10):751-61. doi: 10.1089/dna.2011.1244. Epub 2011 Jun 10.
citation: Heimall J, Puck J, Buckley R, Fleisher TA, Gennery AR, Neven B, Slatter M, Haddad E, Notarangelo LD, Baker KS, Dietz AC, Duncan C, Pulsipher MA, Cowan MJ. Current Knowledge and Priorities for Future Research in Late Effects after Hematopoietic Stem Cell Transplantation (HCT) for Severe Combined Immunodeficiency Patients: A Consensus Statement from the Second Pediatric Blood and Marrow Transplant Consortium International Conference on Late Effects after Pediatric HCT. Biol Blood Marrow Transplant. 2017 Mar;23(3):379-387. doi: 10.1016/j.bbmt.2016.12.619. Epub 2017 Jan 6.
citation: Pai SY, Cowan MJ. Stem cell transplantation for primary immunodeficiency diseases: the North American experience. Curr Opin Allergy Clin Immunol. 2014 Dec;14(6):521-6. doi: 10.1097/ACI.0000000000000115.
citation: Hacein-Bey-Abina S, Hauer J, Lim A, Picard C, Wang GP, Berry CC, Martinache C, Rieux-Laucat F, Latour S, Belohradsky BH, Leiva L, Sorensen R, Debre M, Casanova JL, Blanche S, Durandy A, Bushman FD, Fischer A, Cavazzana-Calvo M. Efficacy of gene therapy for X-linked severe combined immunodeficiency. N Engl J Med. 2010 Jul 22;363(4):355-64. doi: 10.1056/NEJMoa1000164.
citation: Hacein-Bey Abina S, Gaspar HB, Blondeau J, Caccavelli L, Charrier S, Buckland K, Picard C, Six E, Himoudi N, Gilmour K, McNicol AM, Hara H, Xu-Bayford J, Rivat C, Touzot F, Mavilio F, Lim A, Treluyer JM, Heritier S, Lefrere F, Magalon J, Pengue-Koyi I, Honnet G, Blanche S, Sherman EA, Male F, Berry C, Malani N, Bushman FD, Fischer A, Thrasher AJ, Galy A, Cavazzana M. Outcomes following gene therapy in patients with severe Wiskott-Aldrich syndrome. JAMA. 2015 Apr 21;313(15):1550-63. doi: 10.1001/jama.2015.3253.
citation: Howe SJ, Mansour MR, Schwarzwaelder K, Bartholomae C, Hubank M, Kempski H, Brugman MH, Pike-Overzet K, Chatters SJ, de Ridder D, Gilmour KC, Adams S, Thornhill SI, Parsley KL, Staal FJ, Gale RE, Linch DC, Bayford J, Brown L, Quaye M, Kinnon C, Ancliff P, Webb DK, Schmidt M, von Kalle C, Gaspar HB, Thrasher AJ. Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients. J Clin Invest. 2008 Sep;118(9):3143-50. doi: 10.1172/JCI35798.
citation: Braun CJ, Boztug K, Paruzynski A, Witzel M, Schwarzer A, Rothe M, Modlich U, Beier R, Gohring G, Steinemann D, Fronza R, Ball CR, Haemmerle R, Naundorf S, Kuhlcke K, Rose M, Fraser C, Mathias L, Ferrari R, Abboud MR, Al-Herz W, Kondratenko I, Marodi L, Glimm H, Schlegelberger B, Schambach A, Albert MH, Schmidt M, von Kalle C, Klein C. Gene therapy for Wiskott-Aldrich syndrome--long-term efficacy and genotoxicity. Sci Transl Med. 2014 Mar 12;6(227):227ra33. doi: 10.1126/scitranslmed.3007280.
citation: Burroughs LM, Nemecek ER, Torgerson TR, Storer BE, Talano JA, Domm J, Giller RH, Shimamura A, Delaney C, Skoda-Smith S, Thakar MS, Baker KS, Rawlings DJ, Englund JA, Flowers ME, Deeg HJ, Storb R, Woolfrey AE. Treosulfan-based conditioning and hematopoietic cell transplantation for nonmalignant diseases: a prospective multicenter trial. Biol Blood Marrow Transplant. 2014 Dec;20(12):1996-2003. doi: 10.1016/j.bbmt.2014.08.020. Epub 2014 Sep 6.
citation: Danylesko I, Shimoni A, Nagler A. Treosulfan-based conditioning before hematopoietic SCT: more than a BU look-alike. Bone Marrow Transplant. 2012 Jan;47(1):5-14. doi: 10.1038/bmt.2011.88. Epub 2011 Apr 11.
citation: Moshous D, Callebaut I, de Chasseval R, Corneo B, Cavazzana-Calvo M, Le Deist F, Tezcan I, Sanal O, Bertrand Y, Philippe N, Fischer A, de Villartay JP. Artemis, a novel DNA double-strand break repair/V(D)J recombination protein, is mutated in human severe combined immune deficiency. Cell. 2001 Apr 20;105(2):177-86. doi: 10.1016/s0092-8674(01)00309-9.
citation: Rivera-Munoz P, Abramowski V, Jacquot S, Andre P, Charrier S, Lipson-Ruffert K, Fischer A, Galy A, Cavazzana M, de Villartay JP. Lymphopoiesis in transgenic mice over-expressing Artemis. Gene Ther. 2016 Feb;23(2):176-86. doi: 10.1038/gt.2015.95. Epub 2015 Oct 1.
citation: Cavazzana M, Six E, Lagresle-Peyrou C, Andre-Schmutz I, Hacein-Bey-Abina S. Gene Therapy for X-Linked Severe Combined Immunodeficiency: Where Do We Stand? Hum Gene Ther. 2016 Feb;27(2):108-16. doi: 10.1089/hum.2015.137.
citation: Long-Boyle JR, Savic R, Yan S, Bartelink I, Musick L, French D, Law J, Horn B, Cowan MJ, Dvorak CC. Population pharmacokinetics of busulfan in pediatric and young adult patients undergoing hematopoietic cell transplant: a model-based dosing algorithm for personalized therapy and implementation into routine clinical use. Ther Drug Monit. 2015 Apr;37(2):236-45. doi: 10.1097/FTD.0000000000000131.
citation: Romero Z, Campo-Fernandez B, Wherley J, Kaufman ML, Urbinati F, Cooper AR, Hoban MD, Baldwin KM, Lumaquin D, Wang X, Senadheera S, Hollis RP, Kohn DB. The human ankyrin 1 promoter insulator sustains gene expression in a beta-globin lentiviral vector in hematopoietic stem cells. Mol Ther Methods Clin Dev. 2015 Apr 22;2:15012. doi: 10.1038/mtm.2015.12. eCollection 2015.
citation: French D, Sujishi KK, Long-Boyle JR, Ritchie JC. Development and validation of a liquid chromatography-tandem mass spectrometry assay to quantify plasma busulfan. Ther Drug Monit. 2014 Apr;36(2):169-74. doi: 10.1097/01.ftd.0000443060.22620.cd.
citation: Varni JW, Seid M, Kurtin PS. PedsQL 4.0: reliability and validity of the Pediatric Quality of Life Inventory version 4.0 generic core scales in healthy and patient populations. Med Care. 2001 Aug;39(8):800-12. doi: 10.1097/00005650-200108000-00006.
citation: Varni JW, Sherman SA, Burwinkle TM, Dickinson PE, Dixon P. The PedsQL Family Impact Module: preliminary reliability and validity. Health Qual Life Outcomes. 2004 Sep 27;2:55. doi: 10.1186/1477-7525-2-55.
citation: Stoto MA. The accuracy of population projections. J Am Stat Assoc. 1983 Mar;78(381):13-20. doi: 10.1080/01621459.1983.10477916.
citation: Casella G. Refining binomial confidence intervals. Canadian Journal of Statistics 14(2): 113-129, 1986.
citation: Mamcarz E, Zhou S, Lockey T, Abdelsamed H, Cross SJ, Kang G, Ma Z, Condori J, Dowdy J, Triplett B, Li C, Maron G, Aldave Becerra JC, Church JA, Dokmeci E, Love JT, da Matta Ain AC, van der Watt H, Tang X, Janssen W, Ryu BY, De Ravin SS, Weiss MJ, Youngblood B, Long-Boyle JR, Gottschalk S, Meagher MM, Malech HL, Puck JM, Cowan MJ, Sorrentino BP. Lentiviral Gene Therapy Combined with Low-Dose Busulfan in Infants with SCID-X1. N Engl J Med. 2019 Apr 18;380(16):1525-1534. doi: 10.1056/NEJMoa1815408.