Physician‐initiated first‐in‐human clinical study using a novel angiogenic peptide, AG30/5C, for patients with severe limb ulcers

Nakagami, Hironori; Yamaoka, Toshifumi; Hayashi, Misa; Tanemura, Atsushi; Takeya, Yasushi; Kurinami, Hitomi; Sugimoto, Ken; Nakamura, Ayumi; Tomono, Kazunori; Tamai, Katsuto; Katayama, Ichiro; Rakugi, Hiromi; Kaneda, Yasufumi

doi:10.1111/ggi.13051

Cited by 7 publications

(3 citation statements)

References 20 publications

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“…WS patients frequently experience chronic skin ulcers, which are difficult to heal. In addition, the recurrence rate is considerably higher in WS patients than in nonsyndromic patients (Nakagami et al, ). Skin atrophy and type‐2 diabetes are the common phenotypes of WS, further challenging wound healing and tissue regeneration.…”

Section: Resultsmentioning

confidence: 99%

Genetic correction of Werner syndrome gene reveals impaired pro‐angiogenic function and HGF insufficiency in mesenchymal stem cells

Wan

Zhang

et al. 2020

Aging Cell

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WRN mutation causes a premature aging disease called Werner syndrome (WS). However, the mechanism by which WRN loss leads to progeroid features evident with impaired tissue repair and regeneration remains unclear. To determine this mechanism, we performed gene editing in reprogrammed induced pluripotent stem cells (iPSCs) derived from WS fibroblasts. Gene correction restored the expression of WRN. WRN+/+ mesenchymal stem cells (MSCs) exhibited improved pro‐angiogenesis. An analysis of paracrine factors revealed that hepatocyte growth factor (HGF) was downregulated in WRN−/− MSCs. HGF insufficiency resulted in poor angiogenesis and cutaneous wound healing. Furthermore, HGF was partially regulated by PI3K/AKT signaling, which was desensitized in WRN−/− MSCs. Consistently, the inhibition of the PI3K/AKT pathway in WRN+/+ MSC resulted in reduced angiogenesis and poor wound healing. Our findings indicate that the impairment in the pro‐angiogenic function of WS‐MSCs is due to HGF insufficiency and PI3K/AKT dysregulation, suggesting trophic disruption between stromal and epithelial cells as a mechanism for WS pathogenesis.

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Section: Resultsmentioning

confidence: 99%

Genetic correction of Werner syndrome gene reveals impaired pro‐angiogenic function and HGF insufficiency in mesenchymal stem cells

Wan

Zhang

et al. 2020

Aging Cell

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“…Furthermore, Nakagami and colleagues (2012) identified and tested the efficacy of AG30 peptide to treat diabetic mice tail wounds. They observed antibacterial and angiogenic effects in mice and later in humans [86][87][88]. Together, these results demonstrate the importance of mice to discover new drugs and therapies, even when the animal model does not perfect mirror the human disease.…”

Section: Genetically Modified Modelsmentioning

confidence: 91%

Skin wound healing in humans and mice: Challenges in translational research

Zomer

Trentin

2018

Journal of Dermatological Science

353

263

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Despite the great progress in translational research concerning skin wound healing in the last few decades, no animal model fully predicts all clinical outcomes. The mouse is the most commonly used model, as it is easy to maintain and standardize, and is economically accessible. However, differences between murine and human skin repair, such as the contraction promoted by panniculus carnosus and the role of specific niches of skin stem cells, make it difficult to bridge the gap between preclinical and clinical studies. Therefore, this review highlights the particularities of each species concerning skin morphophysiology, immunology, and genetics, which is essential to properly interpret findings and translate them to medicine.

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“…We have developed a number of novel peptide drugs to treat skin ulcers over the past 10 years, beginning with a discovery in basic science experiments and extending to clinical trials to evaluate the safety and efficacy for the treatment of severe limb ulcers. 8,13,[15][16][17] In the present study, we evaluated the effect of SR-0379 on limb ulcers in Werner syndrome patients.…”

Section: Discussionmentioning

confidence: 99%

Investigator‐initiated clinical study of a functional peptide, SR‐0379, for limb ulcers of patients with Werner syndrome as a pilot study

Nakagami

Sugimoto

Ishikawa

et al. 2019

Geriatrics Gerontology Int

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Aim An investigator‐initiated clinical study was carried out to evaluate the therapeutic potency of SR‐0379 for the treatment of leg ulcers in patients with Werner syndrome. Methods A multicenter, open‐label study was carried out from September 2017 to February 2018. The inclusion criteria for leg ulcers were: (i) leg ulcers in patients with Werner syndrome, diabetes or critical limb ischemia/venous stasis; and (ii) a wound size of >1 cm and <6 cm in diameter. Four individuals with Werner syndrome and diabetic ulcers, respectively, were enrolled. SR‐0379 (0.1%) was sprayed on skin ulcers once per day for 4 weeks. Efficacy was evaluated by determining the rate of wound size reduction as a primary end‐point at 4 weeks after the first treatment compared with the pretreatment wound size. As secondary end‐points, the DESIGN‐R score index, the 50% wound size reduction ratio, time to wound closure and quantification of wound bacteria were also evaluated. The safety of SR‐0379 was evaluated during the study period. Results The reduction rate of ulcer size treated with 0.1% SR‐0379 was 22.90% (mean) in the Werner syndrome ulcers group (n = 4) and 35.70% (mean) in the diabetic ulcers group (n = 4), respectively. The DESIGN‐R score decreased by 4.0 points in the Werner syndrome ulcers group and 4.3 points in the diabetic ulcers group. Two mild adverse events were reported in two patients, and causal relationships were denied in any events. Conclusion Treatment with SR‐0379 was safe, well‐tolerated, and effective for leg ulcers of both Werner syndrome and diabetes patients. Geriatr Gerontol Int 2019; 19: 1118–1123.

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Physician‐initiated first‐in‐human clinical study using a novel angiogenic peptide, AG30/5C, for patients with severe limb ulcers

Abstract: Topical treatment with AG30/5C for severe leg ulcers was safe, well tolerated and effective. Geriatr Gerontol Int 2017; 17: 2150-2156.

Cited by 7 publications

References 20 publications

Genetic correction of Werner syndrome gene reveals impaired pro‐angiogenic function and HGF insufficiency in mesenchymal stem cells

Genetic correction of Werner syndrome gene reveals impaired pro‐angiogenic function and HGF insufficiency in mesenchymal stem cells

Skin wound healing in humans and mice: Challenges in translational research

Investigator‐initiated clinical study of a functional peptide, SR‐0379, for limb ulcers of patients with Werner syndrome as a pilot study

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