Milestones

MS1

Achievement of efficient (>20%) and specific (>90%) targeted IL2RG gene-correction in HSPC.
Final selection of the best performing nucleases for functional correction of the IL2RG.
ZFNs targeting exon 5 of IL2RG gene restore expression and function of gamma chain coupled receptors in the lymphoid progeny of edited HSPCs.

MS2

Proof of IL2RG gene correction in SCID-repopulating HSC at the established target level.
Validation of the HSC gene targeting protocol in xenotransplant repopulation studies.
Edited HSPC reach clinically relevant level of human graft in NSG mice (5% for IDLV edited cells and 10% for AAV edited cells).

MS3

Selection of the 3 TCRs most frequently detected in responding patients for further development.
Final selection of the 3 TCRs showing highest level of activity/covering the largest patient population.
Melanoma-reactive TCR melanoma and patient-derived tumor xenograft mouse model.

MS4

Proof of ability to edit T cell specificity in a single-step of manipulation.
Outcome of task 3 of WP2.
Mastaglio et al, manuscript under revision

MS5

In vivo validation of safety and efficacy of TCR gene edited T-lymphocytes for the treatment of leukemias.
Preclinical validation of TCR gene edited cells.
Mastaglio et al, manuscript under revision

MS6

Characterization of the TCR Repertoire and constitution of the Database.
Outcome of task 5 of WP2.
Oliveira et al., Sci Transl Med. 2015

MS7

Scale up and optimization of gene targeting protocols in HSPC for the SCID-X1 application.
Outcome of task 2 of WP3.
Scale-up and optimization of gene targeting in HSPC for X-SCID.

MS8

Scale up and optimization of gene targeting protocols in T-cells for the Leukemia application.
Outcome of task 2 of WP3.

MS9

Likelihood to launch a clinical trial of the developed gene correction strategy.
Outcome of task 4 of WP3.

MS10

Follow-up of the regulatory changes by the project and IP management.
Annual consortium meetings, session on IP and regulations.