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Mobilized bone marrow-derived stem cells (BMSC) have been discussed as an alternative strategy for endogenous repair. Thereby, different approaches for BMSC mobilization have been pursued. Herein, the role of a newly discovered oligonucleotide for retinal homing and regeneration capability of BMSCs was investigated in the sodium iodate (NaIO3) model of retinal degeneration. Mobilization was achieved in GFP-chimera with NOX-A12, a CXC-motif chemokine ligand 12 (CXCL12)/stromal cell-derived factor 1 (SDF-1)-neutralizing L-aptamer. BMSC homing was directed by intravitreal SDF-1 injection. Visual acuity was measured using the optokinetic reflex. Paraffin cross sections were stained with hematoxylin and eosin for retinal thickness measurements. Immunohistochemistry was performed to investigate the expression of cell-specific markers after mobilization. A single dose of NOX-A12 induced significant mobilization of GFP(+) cells which were found in all layers within the degenerating retina. An additional intravitreal injection of SDF-1 increased migration towards the site of injury. Thereby, the number of BMSCs (Sca-1(+)) found in the damaged retina increased whereas a decrease of activated microglia (Iba-1(+)) was found. The mobilization led to significantly increased visual acuity. However, no significant changes in retinal thickness or differentiation towards retinal cell types were detected. Systemic mobilization by a single dose of NOX-A12 showed increased homing of BMSCs into the degenerated retina, which was associated with improved visual function when injection of SDF-1 was additionally performed. The redistribution of the cells to the site of injury combined with their observed beneficial effects support the endogenous therapeutic strategy for retinal repair.

Olaptesed pegol (olaptesed, NOX-A12) is a pegylated l-oligoribonucleotide that binds and neutralizes CXCL12, a chemokine which signals through CXCR4 and CXCR7 regulating a variety of processes during multiple myeloma (MM) development.1 CXCL12 inhibition reduces the myeloma-supportive activity of the bone marrow microenvironment and mobilizes myeloma cells to the circulation.2 In addition, CXCL12α levels were reported to correlate with osteolytic bone lesions and with increased bone marrow angiogenesis.3 Targeting CXCL12, therefore, is a promising strategy for disrupting myeloma-stroma interactions and inhibiting myeloma growth and survival. Here, we report pharmacokinetic, pharmacodynamic, safety and efficacy data of olaptesed in patients with relapsed/refractory MM and present data on baseline CXCL12α levels in this patient cohort. This first-in-patient Phase IIa study aims to translate the novel concept of combining proteasome and CXCL12 inhibition into the clinic and builds on a preclinical proof-of-concept regarding the significance of CXCL12 blockade in MM2 and on Phase I data in healthy subjects.4 Combining CXCL12 inhibition with bortezomib and dexamethasone (VD) was investigated in 28 patients with relapsed/refractory MM, who were either bortezomib-naive or considered not refractory to bortezomib. The median number of prior lines of therapy was 2 (range: 1–5), 39 and 14% of the patients presented with 3 or 4 prior lines, respectively. Cytogenetics were tested in 21 patients and high risk features were found in 36% of them. 54% of patients had prior treatment with bortezomib, 39% had a prior stem cell transplant and 57% were refractory to prior treatment. Further details on patient characteristics (Supplementary Table S1) and inclusion and exclusion criteria are available in the Supplementary Information. In the pilot phase, three cohorts of three patients each (four patients in the 1 mg/kg cohort due to patient replacement) were administered single doses of 1, 2 or 4 mg/kg of olaptesed alone by slow intravenous bolus injection 2 weeks prior to starting the combination treatment. Combination treatment was administered for eight cycles of 21 days. An intra-patient escalation was applied for safety reasons as olaptesed was combined for the first time with VD in cancer patients. Olaptesed was given 1–2 h prior to bortezomib at doses of 1 mg/kg in cycle 1, 2 mg/kg in cycle 2 and 4 mg/kg in cycles 3–8. Bortezomib was given on days 1, 4, 8 and 11 of each 21-day treatment cycle as intravenous injection of 1.3 mg/m2. Oral dexamethasone (20 mg) was added on the day of and the day after bortezomib administration. An outline of the study and details of patients’ flow are given in Supplementary Figures S1 and S2.