Insights into the clinical development of regenerative medical products through a comparison of three cell-based products recently approved for limbal stem cell deficiency.

Three regenerative medical products for limbal stem cell deficiency (LSCD), a rare and intractable ocular surface disease, have recently been approved in Japan. To our knowledge, this is the first time multiple stem-cell-based medical products have been approved for the same ocular disease. Development plans and study designs for each product differ, resulting in differences in indications. Since cell-based products have a heterogeneous formulation and often target rare diseases, they require a flexible approach to development. This review article describes the status and prospects of the clinical development of regenerative medical products by summarizing the issues of the three products from the Pharmaceuticals and Medical Devices Agency (PMDA) standpoint. Implementing stem cell-based products is challenging, requiring scientific and flexible review by regulatory authorities. To overcome these issues in the development process, developers and regulatory authorities need to communicate and fully discuss study protocols from the early stage of development.

Regulatory Issues: PMDA - Review of Sakigake Designation Products: Oncolytic Virus Therapy with Delytact Injection (Teserpaturev) for Malignant Glioma.

In June 2021, the Ministry of Health, Labor and Welfare approved Delytact Injection as a regenerative medical product for oncolytic virus therapy. The active substance of Delytact Injection is teserpaturev, a genetically engineered herpes simplex virus type 1 (strain F) in which the α47 gene and both copies of the γ34.5 gene have been deleted and the infected cell protein 6 (ICP6) gene has been inactivated by the insertion of the lacZ gene from Escherichia coli. Delytact Injection, when intratumorally administered to patients with malignant glioma, is expected to exert the following effects: (1) the mutant virus selectively replicates in tumor cells and destroys the infected cells through the replication process, exerting a cytocidal effect, and (2) the administration leads to induction of tumor-responsive T cells, which activates antitumor immunity and thus prolongs the survival of patients with malignant glioma. A Japanese phase II study (Study GD01) was conducted in patients with glioblastoma who had residual or recurrent tumors after radiotherapy with concomitant temozolomide. In Study GD01, however, stable disease continued for an extended period in some patients with glioblastoma. Hence, Delytact Injection is expected to be effective to a certain level. In line with this, Delytact Injection has been approved as an option for the treatment of malignant glioma, with one of the 3 approval conditions including conducting a use-results comparison survey and resubmission of the marketing authorization application within the granted time period of 7 years, under the conditional and time-limited approval scheme described in Article 23-26 of Act on Securing Quality, Efficacy and Safety of Products Including Pharmaceuticals and Medical Devices.

Medical Record Survey after Comprehensive Health Checkup Referral and Its Contribution to the Early Detection of Cancer.

Comprehensive health checkups in Japan are a preventive method to detect cancer and metabolic diseases. Unlike group medical examinations, individual examinations in health checkups are possible, with additional tests possible for disease detection. However, it is difficult to accurately ascertain the results from only the report after referral to a medical institution in individuals suspected of having cancer who need to be examined. We aimed to conduct a medical record survey of patients referred to the Hospital after undergoing a comprehensive health checkup and investigate the contribution of comprehensive health checkups to the detection of cancer more accurately. The subjects were 1763 examinees who were referred to various departments of our hospital because of doubtful cancer from 23,128 examinees who underwent comprehensive health checkups in our center from January 2018 to December 2022 for 5 years. The medical record survey demonstrated that cancer was detected in more than twice as many individuals as reported and other sources. Early-stage cancers require a significantly longer time to establish a definitive diagnosis. In conclusion, short-term reports from the referring hospital are insufficient for a final diagnosis, and long-term follow-up is extremely important to increase the diagnosis rates of cancer for comprehensive health checkups.

Investigation of arterial-cardiac-pulmonary interaction.

Pulmonary function and arterial stiffness correlate significantly, attributing to the chronic inflammation of atherosclerosis. However, through the pulmonary or systemic circulation, pulmonary and vascular functions associate hemodynamically with cardiac morphology and function. In the present study, we investigated arterial-cardiac-pulmonary interaction by examining how the pulmonary and vascular functions correlate with the heart. This study investigated 55 consecutive subjects not suffering from pulmonary, vascular and cardiac disease who underwent health screening test at our medical center. First, the presence of atherosclerotic disease (hypertension, dyslipidemia and diabetes) and smoking status of the patients were determined. Next, pulmonary function test, vascular function test including cardio-ankle vascular index, and echocardiography were performed. Then, we examined the correlation among the pulmonary, vascular and the heart. Our results revealed many correlations among these three factors. Especially left atrial dimension (LAD) and E/A ratio (E/A) were important cardiac factors associated with both pulmonary and vascular functions independently. Conventionally, inflammatory responses are known to involve in the correlation between pulmonary and vascular functions. Our study demonstrated that cardiac function and morphology were also involved in this correlation, signifying that LAD and E/A plays important roles in the arterial-cardiac-pulmonary interaction.

Echocardiographic Changes in Eosinophilic Endocarditis Induced by Churg-Strauss Syndrome.

Eosinophilic myocarditis may be accompanied by Churg-Strauss syndrome (CSS). We report a case of CSS that was accompanied by myocardial changes in the early stage. A 71-year-old woman complained of mild chest pain at rest, but routine echocardiography did not reveal any endocardial abnormalities. Four months later, the patient was hospitalized due to congestive heart failure with neuropathy of both upper extremities. A diagnosis of eosinophilic myocarditis was made based on the patient's laboratory results and the presence of mural thrombus. This case illustrates that, although early eosinophilic myocarditis is an important differential diagnosis in patients with chest pain, it may be difficult to identify in without an apparent mural thrombus.

Report of the International Regulatory Forum on Human Cell Therapy and Gene Therapy Products.

The development of human cell therapy and gene therapy products has progressed internationally. Efforts have been made to address regulatory challenges in the evaluation of quality, efficacy, and safety of the products. In this forum, updates on the specific challenges in quality, efficacy, and safety of products in the view of international development were shared through the exchange of information and opinions among experts from regulatory authorities, academic institutions, and industry practitioners. Sessions identified specific/critical points to consider for the evaluation of human cell therapy and gene therapy products that are different from conventional biological products; common approaches and practices among regulatory regions were also shared. Certain elements of current international guidelines might not be appropriate to be applied to these products. Further, international discussion on the concept of potency and in vivo tumorigenicity studies, among others, is needed. This forum concluded that the continued collective actions are expected to promote international convergence of regulatory approaches of the products. The Pharmaceuticals and Medical Devices Agency and Japanese Society for Regenerative Medicine jointly convened the forum with support from the National Institutes of Biomedical Innovation, Health and Nutrition. Participants at the forum include 300 experts in and outside of Japan.

Effect of angiotensin converting enzyme inhibitors and beta-blockers on left ventricular remodeling after coronary artery bypass graft surgery.

Preventing left ventricular (LV) remodeling after coronary artery bypass graft surgery (CABG) is important to avoid long-term congestive heart failure. The present study evaluated the effects of angiotensin converting enzyme inhibitors (ACEIs) and beta-blockers on LV remodeling. Twenty-three patients with angina pectoris and 36 with old myocardial infarction underwent CABG. We assessed end diastolic volume index (EDVI), end systolic volume index (ESVI), and ejection fraction (EF) using left ventriculography before and after CABG. Changes in EDVI, ESVI, and EF were studied in the ACEI, beta-blocker, and control groups. Although EDVI was reduced in the ACEI group, ESVI and EF improved only slightly, whereas in the group given beta-blockers, ESVI was reduced, EF improved, and EDVI was minimally reduced. These results indicate that ACEIs and beta-blockers both protect against LV remodeling, although through different mechanisms.

Transient receptor potential channel 6-mediated, localized cytosolic [Na+] transients drive Na+/Ca2+ exchanger-mediated Ca2+ entry in purinergically stimulated aorta smooth muscle cells.

The Na+/Ca2+ exchanger (NCX) is increasingly recognized as a physiological mediator of Ca2+ influx and significantly contributes to salt-sensitive hypertension. We recently reported that Ca2+ influx by the NCX (1) is the primary mechanism of Ca2+ entry in purinergically stimulated rat aorta smooth muscle cells and (2) requires functional coupling with transient receptor potential channel 6 nonselective cation channels. Using the Na+ indicator CoroNa Green, we now directly observed and characterized the localized cytosolic [Na+] ([Na+]i) elevations that have long been hypothesized to underlie physiological NCX reversal but that have never been directly shown. Stimulation of rat aorta smooth muscle cells caused both global and monotonic [Na+]i elevations and localized [Na+]i transients (LNats) at the cell periphery. Inhibition of nonselective cation channels with SKF-96365 (50 micromol/L) and 2-amino-4-phosphonobutyrate (75 micromol/L) reduced both global and localized [Na+]i elevations in response to ATP (1 mmol/L). This effect was mimicked by expression of a dominant negative construct of transient receptor potential channel 6. Selective inhibition of NCX-mediated Ca2+ entry with KB-R7943 (10 micromol/L) enhanced the LNats, whereas the global cytosolic [Na+] signal was unaffected. Inhibition of mitochondrial Na+ uptake with CGP-37157 (10 micromol/L) increased both LNats and global cytosolic [Na+] elevations. These findings directly demonstrate NCX regulation by LNats, which are restricted to subsarcolemmal, cytoplasmic microdomains. Analysis of the LNats, which facilitate Ca2+ entry via NCX, suggests that mitochondria limit the cytosolic diffusion of LNats generated by agonist-mediated activation of transient receptor potential channel 6-containing channels.

A traditional herbal medicine, rikkunshi-to (TJ-43), prevents intracellular signaling disorders in gastric smooth muscle of diabetic rats.

Prevention of diabetic gastrointestinal dysfunction is of utmost importance. The present study demonstrated that diacylglycerol kinase (DGK) activity in diabetic gastric smooth muscle in the resting state was approximately 3.5-fold greater than that in controls. However, oral administration of TJ-43 (1% of food intake) or subcutaneous insulin injection (12 units/kg/day) in streptozotocin-induced diabetic rats (DM) for 2 weeks prevented DGK abnormalities based on the control level. Increased DGK activity in the resting state of DM was inhibited significantly by R59022, neomycin or staurosporine; in contrast, these drugs did not affect DGK activity in controls, insulin-treated DM or TJ-43-treated DM. In controls, the endogenous phosphatidic acid (PA) level was inhibited significantly by R59022 or neomycin but not affected by staurosporine. On the other hand, these three drugs significantly inhibited endogenous PA levels in DM, and neomycin significantly inhibited endogenous PA levels in insulin-treated and TJ-43-treated DM. This suggests that TJ-43 could prevent alteration of DGK activity and PA formation without reduction of blood glucose levels. Moreover, these effects were greater than those of insulin treatment. Results suggested that TJ-43 treatment influenced the hyperreactivity of DGK and DAG formation via phospholipase C activity. In conclusion, TJ-43 can be recommended with respect to enhancement of the quality of life in patients displaying diabetic gastrointestinal complications.