DVC1-0101 to treat peripheral arterial disease: a Phase I/IIa open-label dose-escalation clinical trial

Abstract

We here report the results of a Phase I/IIa open-label four dose-escalation clinical study assessing the safety, tolerability, and possible therapeutic efficacy of a single intramuscular administration of DVC1-0101, a new gene transfer vector based on a nontransmissible recombinant Sendai virus (rSeV) expressing the human fibroblast growth factor-2 (FGF-2) gene (rSeV/dF-hFGF2), in patients with peripheral arterial disease (PAD). Gene transfer was done in 12 limbs of 12 patients with rest pain, and three of them had ischemic ulcer(s). No cardiovascular or other serious adverse events (SAEs) caused by gene transfer were detected in the patients over a 6-month follow-up. No infectious viral particles, as assessed by hemagglutination activity, were detected in any patient during the study. No representative elevation of proinflammatory cytokines or plasma FGF-2 was seen. Significant and continuous improvements in Rutherford category, absolute claudication distance (ACD), and rest pain were observed (P < 0.05 to 0.01). To the best of our knowledge, this is the first clinical trial of the use of a gene transfer vector based on rSeV. The single intramuscular administration of DVC1-0101 to PAD patients was safe and well tolerated, and resulted in significant improvements of limb function. Larger pivotal studies are warranted as a next step.

Figures

Figure 1

Time course of walking activity examined by treadmill. (a) Time course of absolute claudication distance (ACD; m, n = 6). (b) Change of ACD (ΔACD; %, n = 5). *P < 0.05, #P < 0.01. The data for the two patients with Buerger's disease were excluded. Mo, month.

Figure 2

The case of a 65-year-old Japanese woman (case no. 201 at Stage 2). Both limbs were affected, with ~200 m of intermittent claudication since 1993 due to PAD. Her symptoms had been stable for 14 years, and then she developed rest pain in the right foot, which was treated by NSAIDs. (a) Her angiogram (left panel) demonstrated complete obstruction of the whole superficial femoral to popliteal arteries and all main arteries at the ankle level in both limbs. Severe calcification was seen throughout the superficial femoral to popliteal arteries on soft X-ray (right panel, white arrows). (b) A thermographic examination. A right limb-specific increase of foot temperature (white arrows) is apparent at 3 months after the gene transfer. (c) A pulse-volume recording (PVR). Right first toe-specific pulsation was seen. (d) Clinical course. Her rest pain completely disappeared within 1 week after the gene transfer, and her treadmill examination demonstrated the linear increase of absolute claudication distance (ACD) and claudication onset distance (COD) at 4 months after the gene transfer. These improvements of clinical symptoms have been maintained at 5 years post-gene transfer. IA-DSA, intraarterial-digital subtraction angiography; Mo, month; NSAID, nonsteroidal anti-inflammatory drug; PAD, peripheral arterial disease.