Table III.

PID Gene Transfer Studies Currently Open

Study	Center(s)	Sponsor(s)	Vector	Treatment Regimen	Publications
X-SCID
Activation Date: 2011; recruiting Registration: ClinicalTrials.gov NCT01129544 (London & Paris); ClinicalTrials.gov NCT01175239 (Boston MA, Cincinnati OH & Los Angeles CA)	Parallel European and North American studies. Europe: Great Ormond Street Hospital, London, UK; Hôpital Necker-Enfants Malades, Paris, FR USA: Children’s Hospital, Boston MA; Children’s Hospital Medical Center, Cincinnati, OH; University of California, Los Angeles, CA	UK: Great Ormond Street Hospital, NHS Foundation Trust (PI: A. Thrasher) FR: Assistance Publique-Hôpitaux Paris (PI: A. Fischer) USA: NIAID, NIH (PI: D. A. Williams)	Virus: Gamma retrovirus Insert: IL2R gamma chain Modifications: WPRE post-translational regulatory element to enhance expression Safety modifications: EFS (EF1α short) cellular internal promoter; U3 deletion in LTR (SIN configuration) Vector development: C. Baum, Hannover Medical School, Germany Vector manufacture: University of Cincinnati, OH, USA Target: BM CD34+ cells	Conditioning: None	Zychlinski (2008);50 Pai S-Y (2011);51 Hacein-Bey-Abina (2010) (report of follow-up for earlier studies using a gamma retrovirus vector);52 Fischer (2010) (review).53
Activation Date: 2012, recruiting Registration: ClinicalTrials.gov NCT01512888	St. Jude Children’s Research Hospital, Memphis, TN	NHLBI, NIH (PI: B. Sorrentino)	Virus: Lentivirus Insert: IL2R gamma chain Safety modifications: EFS (EF1α short) cellular internal promoter; U3 deletion in LTR (SIN configuration); enhancer blocking insulator sequence(s) Vector development: B. Sorrentino, St. Jude, Memphis, TN, USA Target: BM CD34+ cells	Conditioning: None	NA
X-SCID in Older Children
Activation Date: 2010; recruiting Registration: Clinical Trials.gov NCT01306019	NIAID, NIH Clinical Center, Bethesda, MD	NIAID, NIH (PI: S. S. DeRaven, H. L. Malech)	Virus: Lentivirus Insert: IL2R gamma chain Safety modifications: EFS (EF1α short) cellular internal promoter; U3 deletion in LTR (SIN configuration);enhancer blocking insulator sequence(s) Vector development: B. Sorrentino, St. Jude, Memphis, TN Target: PBSC CD34+ cells	Conditioning: Busulfan 6mg/kg	NA
ADA SCID
Activation Date: May 2013; recruiting Registration: ClinicalTrials.gov NCT01852071	University of California, Los Angeles, CA & NHGRI, NIH Clinical Center, Bethesda, MD	NIAID, NIH (PI: D.B. Kohn)	Virus: Lentivirus Modifications: codon optimized human ADA cDNA, WPRE post-translational regulatory element to enhance expression Safety modifications: EFS (EF1α short) cellular internal promoter; U3 enhancer deletion in LTR (SIN configuration) Vector manufacture: IUVPF Target: BM CD34+ cells	PEG-ADA: Discontinue Conditioning: Myeloreductive Busulfan (4 mg/kg)	Candotti (2012)54 (previous work of this group in ADA SCID using a gamma retrovirus vector); Gaspar (2012) 55(editorial).
Activation Date: November 2011; recruiting Registration: ClinicalTrials.gov NCT01380990	Great Ormond Street Hospital, London, UK	Great Ormond Street Hospital, NHS Foundation Trust (PI: H. B. Gaspar, A. Thrasher)	Virus: Lentivirus Modifications: codon optimized human ADA cDNA, WPRE post-translational regulatory element to enhance expression Safety modifications: EFS (EF1α short) cellular internal promoter; U3 enhancer deletion in LTR (SIN configuration) Vector manufacture: IUVPF Target: BM CD34+ cells	PEG-ADA: Discontinue Conditioning: Myeloreductive Busulfan (4 mg/kg)
X-CGD
Activation Date: 2006 Registration: ClinicalTrials.gov NCT00394316	NIAID, NIH Clinical Center, Bethesda, MD	NIAID, NIH (PI: E. Kang, H. L. Malech)	Virus: Gamma retrovirus MFGS Insert: gp91phox Target: PBSC CD34+ cells	Conditioning: Busulfan (10 mg/kg) Graft: CD34+ dose target 5 × 10e6/kg	Kang (2010);56 Kang (2012).57
Activation Date: In development Registration: Pending	NIAID, NIH Clinical Center, Bethesda, MD	NIAID, NIH (PI: E. Kang, H. L. Malech)	Virus: Lentivirus Insert: gp91phox Safety modifications: EFS (EF1α short) cellular internal promoter; U3 deletion in LTR (SIN configuration); enhancer blocking insulator sequence(s) Target: PBSC CD34+ cells	Conditioning: TBA
Activation Date: In development Registration: Pending	Great Ormond Street Hospital, London, UK; Hôpital Necker-Enfant Malades, Paris, FR; University Hospital Frankfurt and Institute for Biomedical Research, Georg-Speyer-Haus, Frankfurt, Germany; University Children’s Hospital Zürich, Switzerland	Great Ormond Street Hospital, NHS Foundation Trust (PI: A. Thrasher)	Virus: Lentivirus Insert: gp91phox Modifications: Regulated promoter (chimeric CatG/cFes promoter with mutated TATA box contains binding sites for transcription factors needed for commitment & differentiation myeloid cells to granulocyte lineage) Vector manufacture: Genethon, Paris, FR Target: PBSC CD34+ cells	Conditioning: TBA	Santilli (2011).58
WAS
Activation Date: 2006–2009; recruitment complete, follow-up continuing. Registration: German Clinical Trials Register Number DRKS00000330	Hannover Medical School Children’s Hospital, Germany	Deutsche Forschungsgemeinscha ft and Bundesministerium fur Bildung und Forschung (PI: C. Klein)	Virus: GALV pseudotyped CMMP, a novel derivative of MFG, which is a type of MLV gamma retrovirus Insert: WASp Modifications: MLV LTRs are replaced with the corresponding myeloproliferative sarcoma virus (MPSV) LTRs (this is a strong viral promoter) and the normal MLV tRNA primer binding site is replaced by a glutamine tRNA primer binding site. Vector manufacture: Hannover Medical School, Germany Target: PBSC CD34+ cells	Conditioning: Partially myeloablative Busulfan 8 mg/kg	Boztug (2010);59 Paruzynski (2012)60 (report of insertional mutagenesis resulting in leukemia).
Activation Date: 2011; recruiting Registration: ClinicalTrials.gov NCT01347242 (London); ClinicalTrials.gov NCT01515462 (Milan); ClinicalTrials.gov NCT01347346 (Paris); ClinicalTrials.gov NCT01410825 (Boston)	Europe: Great Ormond Street Hospital, London, UK; San Raffale Telethon Institute of Gene Therapy, Milan, IT; Hôpital Necker-Enfants Malades, Paris, FR USA: Children’s Hospital, Boston MA	UK: Great Ormond Street Hospital, NHS Foundation Trust (PI: A. Thrasher) IT: IRCCS San Raffaele and Fondazione Telethon (PI: A. Aiuti, M. G. Roncarolo) FR: Assistance Publique- Hôpitaux Paris (PI: A. Fischer) USA: GTRP, NHLBI, Bethesda, MD (PI: D. A. Williams, S.-Y. Pai, L. Notarangelo)	Virus: Lentivirus Insert: WASp Modifications: WPRE post-translational regulatory element to enhance expression Safety modifications: hWAS endogenous promoter Vector manufacture: Genethon, Paris, FR; Target: PBSC CD34+ cells	Pre-Conditioning: Anti-CD20 monoclonal Ab Conditioning: Reduced intensity Busulfan (4 mg/kg), Fludarabine (120 mg/m2); ATG if autoimmune manifestations	Science (a manuscript is in press; not yet available); Scaramuzza ( 2012);61 Biasco L (2012).62

Gamma-retrovirus and lentivirus vectors have been/are used in PID; adeno-associated virus is not persistent in proliferating bone marrow stem cells and lymphocytes (so cannot be used for GT for PID). The necessity to transfect CD34 ex vivo or lymphocytes ex vivo is cumbersome, but relatively effective. WPRE = Woodchuck hepatitis virus post-transcriptional regulatory element; LTR = long terminal repeat; SIN= self-inactivating; MLV = Moloney murine leukemia virus; MPSV = Myeloproliferative sarcoma virus. IUVPF = Indiana University, Indianapolis, IN, Vector Production Facility. GTRP = Gene Therapy Resource Program, NHLBI, NIH.