From mouse to sheep: Generating a sheep model and developing a gene therapy for sialidosis

Context: In CML, BCR-ABL1 oncoprotein induces overexpression of STAT5 and its target genes for example CITED2 gene. This gene is involved in regulating the proliferation and quiescence states of leukemic stem cells (LSCs). Recently, studies reported that adding pioglitazone (PPARγ agonist approved for T2DM treatment) to imatinib may decrease the transcription of both STAT5 and CITED2 gene, eliminate the quiescent LSCs (resist TKIs), and ameliorate the patients' response. Objectives: The primary objective is to clarify the value of combining pioglitazone with imatinib to downregulate the CITED2 gene aiming to eradicate the LSCs in CML treatment. Design: In the context of a clinical trial (approved by the Ethical Committee of the Faculty of Medicine Mansoura University), the study group patients (N=26) were treated with combination therapy after having their consent. The planned follow-up time is 2 years. Setting: Hematology unit, Oncology Center, Mansoura University. Patients or Other Participants: The eligibility criteria for study group patients were de novo, Philadelphia+ve CML (chronic phase) aged 18-60 years old. Interventions: Those patients were treated with imatinib 400 mg and pioglitazone 15 mg once daily for 6 months. Pre- and post-treatment samples (after 6 months) were collected to assess the expression levels of the CITED2 gene. Responders continued on the same TKI and their sequential BCR/ABL Q-PCR was monitored. Main Outcome Measures: The study proposed that this combination therapy can put more patients into deeper and faster molecular response via eliminating the LSCs. Results: The study group included 15 males (57.7%) and 11 females (42.3%) with a mean age of 43.2 years. The BCR-ABL and CITED2 genes' pretreatment expression levels decreased significantly after 6 months of combined treatment (p<0.001 and p=0.005, respectively). Moreover, at 6 months 65.4% and 23% of the patients had response ≥ CCyR and ≥ MMR respectively. The most frequent complaints among patients were increased body weight and edema (p<0.001). Conclusions: Adding pioglitazone to imatinib improved the patients' response and downregulate the overexpressed CITED2 gene. A longer follow-up is planned and needed to confirm the safety and efficacy of the combination.