Large-Scale Whole-Genome Analysis of HTLV-1-Associated Myelopathy Identified Hereditary Spastic Paraplegias.

Objectives: Distinguishing human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy from hereditary spastic paraplegia in patients infected with HTLV-1 is challenging due to overlapping clinical symptoms. The aim of this study was to explore the possibility that hereditary spastic paraplegia is inherently present in patients diagnosed with HTLV-1-associated myelopathy. Methods: We performed whole-genome sequencing on 315 unrelated patients registered in the HTLV-1-Associated Myelopathy patient registry "HAM-net," from 2013 to 2022 in Japan. CSF inflammatory biomarkers, including CXCL10, were measured. Results: We identified 5 patients with pathogenic variants in the genes RTN2, SPAST, VCP, and UBAP1, which are the known causes of hereditary spastic paraplegia. These patients had no family history of hereditary spastic paraplegia. The levels of CSF inflammatory biomarkers were lower than expected in these patients, compared with disease severity. Discussion: Genetic analysis is useful for the differentiation of hereditary spastic paraplegia patients from HTLV-1-associated myelopathy patients, especially for the patients with low levels of CSF inflammatory markers. Here we report the presence of hereditary spinal cord diseases in patients diagnosed with HTLV-1-associated myelopathy and provides evidence that genetic analysis would be helpful in the diagnostic workflow.

[National Questionnaire Survey on the Actual Use and Content Evaluation of the human T-cell leukemia virus type I (HTLV-1) -associated Myelopathy (HAM) Practice Guidelines 2019].

It is not enough to just create medical practice guidelines; they are also required to be implemented into practice. Therefore, we surveyed specialists to determine the extent of the dissemination of the "HAM Practice Guidelines 2019," to quantify gaps, identify challenges, and understand needs in daily practice. The survey also revealed that the 25% of the specialists were unaware of the tests required for confirming human T-cell leukemia virus type I (HTLV-1) infection. Additionally, they had insufficient knowledge of the HTLV-1 infection. About 90.7% of the specialists agreed with the policy of determining treatment intensity based on disease activity. However, the implementation rate of cerebrospinal fluid marker measurement, which is useful for this assessment, was as low as 27%. Hence, it is important to use the findings of this study to further promote awareness about this issue.

EZH1/2 dual inhibitors suppress HTLV-1-infected cell proliferation and hyperimmune response in HTLV-1-associated myelopathy.

Background: Human T-cell leukemia virus type 1 (HTLV-1) causes HTLV-1-associated myelopathy (HAM), adult T-cell leukemia/lymphoma (ATL), HTLV-1-associated uveitis, and pulmonary diseases. Although both HAM and ATL show proliferation of infected cells, their pathogeneses are quite different. In particular, the pathogenesis of HAM is characterized by hyperimmune responses to HTLV-1-infected cells. Recently, we demonstrated the overexpression of histone methyltransferase EZH2 in ATL cells and the cytotoxic effects of EZH2 inhibitors and EZH1/2 dual inhibitors on these cells. However, these phenomena have never been studied in HAM. Furthermore, what effect these agents have on the hyperimmune response seen in HAM is completely unknown. Methods: In this study, we investigated histone methyltransferase expression levels in infected cell populations (CD4+ and CD4+CCR4+ cells) from patients with HAM using microarray and RT-qPCR analyses. Next, using an assay system that utilizes the spontaneous proliferation characteristic of peripheral blood mononuclear cells derived from patients with HAM (HAM-PBMCs), we investigated the effects of EZH2 selective inhibitors (GSK126 and tazemetostat) and EZH1/2 dual inhibitors (OR-S1 and valemetostat, also known as DS-3201), particularly on cell proliferation rate, cytokine production, and HTLV-1 proviral load. We also examined the effect of EZH1/2 inhibitors on the proliferation of HTLV-1-infected cell lines (HCT-4 and HCT-5) derived from patients with HAM. Results: We found elevated expression of EZH2 in CD4+ and CD4+CCR4+ cells from patients with HAM. EZH2 selective inhibitors and EZH1/2 inhibitors significantly inhibited spontaneous proliferation of HAM-PBMC in a concentration-dependent manner. The effect was greater with EZH1/2 inhibitors. EZH1/2 inhibitors also reduced the frequencies of Ki67+ CD4+ T cells and Ki67+ CD8+ T cells. Furthermore, they reduced HTLV-1 proviral loads and increased IL-10 levels in culture supernatants but did not alter IFN-γ and TNF-α levels. These agents also caused a concentration-dependent inhibition of the proliferation of HTLV-1-infected cell lines derived from patients with HAM and increased annexin-V(+)7-aminoactinomycin D(-) early apoptotic cells. Conclusion: This study showed that EZH1/2 inhibitors suppress HTLV-1-infected cell proliferation through apoptosis and the hyperimmune response in HAM. This indicates that EZH1/2 inhibitors may be effective in treating HAM.

Long-term safety and efficacy of mogamulizumab (anti-CCR4) for treating virus-associated myelopathy.

Some carriers of human T-cell leukaemia virus type 1 (HTLV-1), a retrovirus that primarily infects CD4+ T cells and causes lifelong infection, develop HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Current treatments for HAM/TSP are insufficient with problematic long-term side effects. This study evaluated the long-term safety and efficacy of the anti-CCR4 antibody mogamulizumab in patients with HAM/TSP over a 4-year period. We conducted an open-label, extended long-term study (UMIN trial number: UMIN000019942) of a phase 1-2a trial with mogamulizumab for HAM/TSP (UMIN000012655). The study participants were patients with corticosteroid-resistant HAM/TSP who could walk 10 m with or without assistive tools. Mogamulizumab was administered at 0.01, 0.03, 0.1 or 0.3 mg/kg at intervals of ≥8 weeks (0.01 and 0.03 mg/kg) or ≥12 weeks (0.1 and 0.3 mg/kg). HTLV-1 proviral load, CSF inflammatory markers and clinical symptoms were summarized by descriptive statistics. Missing observations were imputed using the last-observation-carried-forward method. As a post hoc analysis, we evaluated the therapeutic effect of mogamulizumab on gait function by comparing it with contemporary control data from a HAM/TSP patient registry. Of the 21 participants in the phase 1-2a, 18 (86%) enrolled in the long-term study and 15 (71%) continued repeated doses of mogamulizumab for 4 years. The median dose was 0.1 mg/kg after 4 years. Seventeen of 21 participants (81%) experienced grade 1-2 skin-related adverse events. Observed grade 3 drug-related adverse effects included three cases of lymphopenia and one case each of microscopic polyangiitis, elevated levels of aspartate aminotransferase, and neutropenia. Four of 21 participants (19%) developed neutralizing antibodies. After 4 years, the peripheral blood proviral load and the number of infected cells in CSF decreased by 60.7% and 66.3%, respectively. Neopterin and CXCL10 CSF concentrations decreased by 37.0% and 31.0%, respectively. Among the 18 participants, spasticity and Osame Motor Disability Score (OMDS) improved in 17 (94%) and four (22%), respectively. However, 10 m walking time worsened by 7.3% on average. Comparison with the contemporary control group demonstrated that mogamulizumab inhibited OMDS progression (P = 0.02). The results of the study suggest that mogamulizumab has long-term safety and inhibitory effects on lower limb motor disability progression in corticosteroid-treated patients with HAM/TSP. This will provide a basis for the application of mogamulizumab in HAM/TSP treatment.

Potential role of HTLV-1 Tax-specific cytotoxic t lymphocytes expressing a unique t-cell receptor to promote inflammation of the central nervous system in myelopathy associated with HTLV-1.

Human T-lymphotropic virus 1 (HTLV-1) infection causes two serious diseases: adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy (HAM). Immunological studies have revealed that HTLV-1 Tax-specific CD8+ cytotoxic T-cells (Tax-CTLs) in asymptomatic carriers (ACs) and ATL patients play an important role in the elimination of HTLV-1-infected host cells, whereas Tax-CTLs in HAM patients trigger an excessive immune response against HTLV-1-infected host cells infiltrating the central nervous system (CNS), leading to local inflammation. Our previous evaluation of HTLV-1 Tax301-309 (SFHSLHLLF)-specific Tax-CTLs (Tax301-309-CTLs) revealed that a unique T-cell receptor (TCR) containing amino acid (AA)-sequence motif PDR, was shared among HLA-A*24:02+ ACs and ATL patients and behaved as an eliminator by strong activity against HTLV-1. However, it remains unclear whether PDR+Tax301-309-CTLs also exist in HLA-A*24:02+ HAM patients and are involved in the pathogenesis of HAM. In the present study, by high-throughput TCR repertoire analysis technology, we revealed TCR repertoires of Tax301-309-CTLs in peripheral blood (PB) of HLA-A*24:02+ HAM patients were skewed, and a unique TCR-motif PDR was conserved in HAM patients (10 of 11 cases). The remaining case dominantly expressed (-DR, P-R, and PD-), which differed by one AA from PDR. Overall, TCRs with unique AA-sequence motifs PDR, or (-DR, P-R, and PD-) accounted for a total of 0.3-98.1% of Tax301-309-CTLs repertoires of HLA-A*24:02+ HAM patients. Moreover, TCR repertoire analysis of T-cells in the cerebrospinal fluid (CSF) from four HAM patients demonstrated the possibility that PDR+Tax301-309-CTLs and (-DR, P-R, and PD-)+Tax301-309-CTLs efficiently migrated and accumulated in the CSF of HAM patients fostering increased inflammation, although we observed no clear significant correlation between the frequencies of them in PB and the levels of CSF neopterin, a known disease activity biomarker of HAM. Furthermore, to better understand the potential function of PDR+Tax301-309-CTLs, we performed immune profiling by single-cell RNA-sequencing of Tax301-309-CTLs, and the result showed that PDR+Tax301-309-CTLs up-regulated the gene expression of natural killer cell marker KLRB1 (CD161), which may be associated with T-cell activation and highly cytotoxic potential of memory T-cells. These findings indicated that unique and shared PDR+Tax301-309-CTLs have a potential role in promoting local inflammation within the CNS of HAM patients.

RAISING is a high-performance method for identifying random transgene integration sites.

Both natural viral infections and therapeutic interventions using viral vectors pose significant risks of malignant transformation. Monitoring for clonal expansion of infected cells is important for detecting cancer. Here we developed a novel method of tracking clonality via the detection of transgene integration sites. RAISING (Rapid Amplification of Integration Sites without Interference by Genomic DNA contamination) is a sensitive, inexpensive alternative to established methods. Its compatibility with Sanger sequencing combined with our CLOVA (Clonality Value) software is critical for those without access to expensive high throughput sequencing. We analyzed samples from 688 individuals infected with the retrovirus HTLV-1, which causes adult T-cell leukemia/lymphoma (ATL) to model our method. We defined a clonality value identifying ATL patients with 100% sensitivity and 94.8% specificity, and our longitudinal analysis also demonstrates the usefulness of ATL risk assessment. Future studies will confirm the broad applicability of our technology, especially in the emerging gene therapy sector.

Health-Related Quality of Life Evaluation Using the Short Form-36 in Patients With Human T-Lymphotropic Virus Type 1-Associated Myelopathy.

Background: Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy (HAM) is a neuroinflammatory disease, causing various neurological symptoms, including motor, sensory, and bladder and bowel dysfunctions. This study was designed to reveal the impact of HAM and related symptoms on health-related quality of life (HRQoL). Methods: We analyzed the Short Form-36 (SF-36) and clinical data of 538 patients with HAM registered in the HAM-net, a nationwide patient registry for HAM in Japan. HRQoL was evaluated using the SF-6D (a health state utility value calculated from the SF-36) and eight SF-36 subscales. A general liner model was used to estimate the impact of major HAM-related symptoms, including gait dysfunction, sensory disturbance in the legs (pain and numbness), urinary dysfunction, and constipation, on the SF-6D and SF-36 subscale scores. Results: The mean age and disease duration were 62.0 and 16.5 years, respectively. Of the patients, 73.2% needed walking aid; 42.7 and 67.1% had leg pain and numbness, respectively; 92.1% had urinary dysfunction; and 77.9% had constipation. The mean SF-6D score was 0.565, which was significantly lower than the national average (0.674 in the 60-69 years age group; p < 0.001), exceeding the minimal important difference (0.05-0.1). All the major symptoms were significantly associated with a decrease in the SF-6D score. The SF-36 subscale scores were significantly lower than the national standard of 50 (p ≤ 0.001), except for mental health (MH). Gait dysfunction was associated with lower scores in physical functioning (PF), limitations on role functioning because of physical health, bodily pain, general health perception (GH), vitality (VT), and social functioning; however, no association was observed between gait dysfunction and limitations on role functioning because of emotional problems and MH. Meanwhile, sensory disturbance in the legs was associated with a decrease in scores in all subscales. Urinary dysfunction was associated with worse PF, GH, VT, and MH. Constipation was associated only with PF. Conclusion: HRQoL of patients with HAM was worse than that of the general population and was associated with all major symptoms. Thus, patients should be comprehensively managed to achieve better HRQoL.

Efficacy of Corticosteroid Therapy for HTLV-1-Associated Myelopathy: A Randomized Controlled Trial (HAMLET-P).

Corticosteroids are most commonly used to treat HTLV-1-associated myelopathy (HAM); however, their clinical efficacy has not been tested in randomized clinical trials. This randomized controlled trial included 8 and 30 HAM patients with rapidly and slowly progressing walking disabilities, respectively. Rapid progressors were assigned (1:1) to receive or not receive a 3-day course of intravenous methylprednisolone in addition to oral prednisolone therapy. Meanwhile, slow progressors were assigned (1:1) to receive oral prednisolone or placebo. The primary outcomes were a composite of ≥1-grade improvement in the Osame Motor Disability Score or ≥30% improvement in the 10 m walking time (10 mWT) at week 2 for rapid progressors and changes from baseline in 10 mWT at week 24 for slow progressors. In the rapid progressor trial, all four patients with but only one of four without intravenous methylprednisolone achieved the primary outcome (p = 0.14). In the slow progressor trial, the median changes in 10 mWT were -13.8% (95% CI: -20.1--7.1; p < 0.001) and -6.0% (95% CI: -12.8-1.3; p = 0.10) with prednisolone and placebo, respectively (p for between-group difference = 0.12). Whereas statistical significance was not reached for the primary endpoints, the overall data indicated the benefit of corticosteroid therapy. (Registration number: UMIN000023798, UMIN000024085).

Clinical course of neurogenic bladder dysfunction in human T-cell leukemia virus type-1-associated myelopathy/tropical spastic paraparesis: a nationwide registry study in Japan.

BACKGROUND: Most patients with human T-cell leukemia virus type 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) develop neurogenic bladder dysfunction. However, longitudinal changes and treatment effects remain poorly understood. This study aimed to characterize the clinical course of urinary dysfunction in this population. METHODS: This prospective observational study included 547 patients enrolled in HAM-net, a nationwide registry for HAM/TSP in Japan. Urinary dysfunction severity was evaluated using the HAM/TSP-bladder dysfunction symptom score (HAM-BDSS) and the HAM/TSP-bladder dysfunction severity grade (HAM-BDSG). These specific measures were recently developed for assessing urinary dysfunction in HAM/TSP. We analyzed longitudinal changes over a 6-year follow-up period, associations between urinary and gait dysfunction, and treatment efficacy of urinary catheterization and mirabegron (a ß3-adrenergic agonist for overactive bladder symptoms). RESULTS: The mean (standard deviation [SD]) age and disease duration at enrollment were 61.9 (10.7) years and 16.6 (11.6) years, respectively, and 74.6% of patients were women. Only 8.0% were free from urinary symptoms (HAM-BDSG 0), 65.4% had urinary symptoms or were on medication (HAM-BDSG I), and 23.2% and 3.3% used intermittent and indwelling catheters (HAM-BDSG II and III), respectively. HAM-BDSG and BDSS were worse in patients with greater gait dysfunction (p < 0.001 for both). During the 6-year follow-up, 66.7% of patients with HAM-BDSG 0 developed new urinary symptoms. Of those with HAM-BDSG I at enrollment, 10.8% started using urinary catheters. Importantly, HAM-BDSS significantly improved after initiating catheterization (mean [SD] change, - 8.93 [10.78], p < 0.001). The number of patients receiving mirabegron increased in the fourth year. Multivariable linear regression analysis significantly associated mirabegron with improvement in HAM-BDSS (- 5.82, 95% confidence interval - 9.13 to - 2.51, p = 0.001). CONCLUSIONS: Urinary dysfunction affected 92% of patients and progressed over the 6-year follow-up. Urinary symptoms were more severe in patients with poorer gait function. Urinary catheterization and mirabegron were effective in relieving symptoms. Effective utilization of real-world data is key to establishing evidence for rare diseases, such as HAM/TSP.

An update on human T-cell leukemia virus type I (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) focusing on clinical and laboratory biomarkers.

Human T-cell leukemia virus type I (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a rare inflammatory disease causing unremitting and progressive neurological disorders, such as spastic paraparesis, neurogenic bladder, and sensory disturbance of the lower extremities. Although there is no cure, immune-modulating agents such as corticosteroids are most widely used to slow disease progression. Biomarkers for the clinical assessment of HAM/TSP should be identified because the prediction of functional prognosis and the assessment of treatment efficacy are challenging due to the slowly progressive nature of the disease. The lack of surrogate biomarkers also hampers clinical trials of new drugs. This review summarizes biomarker candidates for the clinical assessment of patients with HAM/TSP. Most of the reported biomarker candidates are associated with viral components or inflammatory mediators because immune dysregulation provoked by HTLV-1 infection is thought to cause chronic inflammation and damage the spinal cord of patients with HAM/TSP. Although information on the diagnostic accuracy of most of the reported biomarkers is insufficient, several molecules, including inflammatory mediators such as CXCL10 and neopterin in the cerebrospinal fluid, have been suggested as potential biomarkers of functional prognosis and treatment response. Several clinical trials for HAM/TSP are currently underway, and we expect that these studies will provide not only evidence pertaining to treatment, but also novel findings regarding the utility of biomarkers in this disease. The establishment of clinical biomarkers will improve patient care and promote the development of therapies for HAM/TSP.

Enhanced expression of synoviolin in peripheral blood from obese/overweight donors.

Obesity is currently a major medical and societal issue. Synoviolin (SYVN1) is an E3 ubiquitin ligase involved in endoplasmic reticulum (ER) stress. Overexpression of Syvn1 has been found in genetically obese mice (ob/ob and db/db), and treatment with a Syvn1 inhibitor suppresses weight gain in some mouse models (C57BL/6J and db/db). However, SYVN1 expression in humans has not yet been elucidated. In the present study, 35 human volunteers were analyzed, and the expression level of SYVN1 mRNA in peripheral blood mononuclear cells (PBMCs) was detected using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis. Expression of SYVN1 mRNA was significantly increased in PBMCs from volunteers with a BMI ≥25.0, compared with volunteers with a BMI <25.0. In addition, PCR array and RT-qPCR of ER stress-responsive genes revealed that the expression of activating transcription factor 6 (ATF6), which plays an important role in the transcriptional activation of SYVN1, was increased in PBMCs from volunteers with a BMI ≥25.0. These results suggest that the ATF6-SYVN1 axis might be an important pathway in the progression of obesity.

Creation and validation of a bladder dysfunction symptom score for HTLV-1-associated myelopathy/tropical spastic paraparesis.

BACKGROUND: Urinary dysfunction is one of the main features of human T-cell leukemia virus type 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). However, a comprehensive assessment of the severity is difficult because a standardized assessment measure is unavailable. Therefore, this study aimed to develop a novel symptom score for the assessment of urinary dysfunction in HAM/TSP. We interviewed 449 patients with HAM/TSP using four internationally validated questionnaires for assessment of urinary symptoms (27 question items in total): the International Prostate Symptom Score; the International Consultation on Incontinence Questionnaire-Short Form; the Overactive Bladder Symptom Score; and the Nocturia Quality-of-Life questionnaire. We developed a symptom score based on the data of 322 patients who did not use urinary catheters by selecting question items from questionnaires focused on descriptive statistics, correlation analysis, and exploratory factor analysis. The score distribution, reliability, and validity of the developed score were evaluated. RESULTS: First, 16 questions related to quality of life, situations, or subjective assessment were omitted from the 27 questions. Exploratory factor analysis revealed that the remaining 11 questions pertained to three factors: frequent urination, urinary incontinence, and voiding symptoms. Three questions, which had similar questions with larger factor loading, were deleted. Finally, we selected eight question items for inclusion in the novel score. The score distribution exhibited no ceiling or floor effect. The Cronbach's alpha (0.737) demonstrated reliable internal consistency. The new score comprised two subscales with acceptable factorial validity (inter-factor correlation coefficient, 0.322): storage symptoms (frequent urination plus urinary incontinence) and voiding symptoms. The correlation between each item and the subscales suggested acceptable construct validity. CONCLUSIONS: We developed a novel score, the HAM/TSP-Bladder Dysfunction Symptom Score, and demonstrated its reliability and validity. The applicability of this score to patients using catheters should be examined in future research.

Mortality and risk of progression to adult T cell leukemia/lymphoma in HTLV-1-associated myelopathy/tropical spastic paraparesis.

Human T cell leukemia virus 1 (HTLV-1) causes the functionally debilitating disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) as well as adult T cell leukemia lymphoma (ATLL). Although there were concerns that the mortality of HAM/TSP could be affected by the development of ATLL, prospective evidence was lacking in this area. In this 5-y prospective cohort study, we determined the mortality, prevalence, and incidence of ATLL in 527 HAM/TSP patients. The standard mortality ratio of HAM/TSP patients was 2.25, and ATLL was one of the major causes of death (5/33 deaths). ATLL prevalence and incidence in these patients were 3.0% and 3.81 per 1,000 person-y, respectively. To identify patients at a high risk of developing ATLL, flow cytometry, Southern blotting, and targeted sequencing data were analyzed in a separate cohort of 218 HAM/TSP patients. In 17% of the HAM/TSP patients, we identified an increase in T cells positive for cell adhesion molecule 1 (CADM1), a marker for ATLL and HTLV-1-infected cells. Genomic analysis revealed that somatic mutations of HTLV-1-infected cells were seen in 90% of these cases and 11% of them had dominant clone and developed ATLL in the longitudinal observation. In this study, we were able to demonstrate the increased mortality in patients with HAM/TSP and a significant effect of ATLL on their prognosis. Having dominant clonal expansion of HTLV-1-infected cells with ATLL-associated somatic mutations may be important characteristics of patients with HAM/TSP who are at an increased risk of developing ATLL.

Real-world clinical course of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in Japan.

BACKGROUND: As human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a rare chronic neurological disease, large scale studies to collect continuous clinical data have been difficult to conduct. Therefore, the incidence of comorbidities and drug utilization data remain unknown. When conducting trials to develop new drugs in rare disease such as HAM/TSP, historical control data obtained from registry studies would be useful, as cohorts in rare disease tend to be small. Long-term follow-up of patients with a chronic disease can also be challenging. In this study, we addressed the following two goals using registry data on patients (n = 486) enrolled in the Japanese HAM/TSP patient registry "HAM-net" from 2012 to 2016: 1) to clarify the epidemiological information of HAM/TSP such as the incidence of comorbidities and drug utilization and 2) to provide the real-world data on changes in lower limb motor dysfunction. RESULTS: In HAM-net-registered patients, common comorbidities were fractures, herpes zoster, and uveitis, with incidences of 55.5, 10.4, and 6.5, respectively, per 1000 person-years. Every year, oral steroid treatment was administered in 48.2-50.7% of the HAM-net-registered patients and interferon-α treatment was used in 2.6-3.5% of patients. The median dose of oral prednisolone was low at 5.0 mg/day. The incidence of fractures and herpes zoster tended to be higher in the steroid-treated group than in the untreated group (fractures: 61.0 vs. 48.3, herpes zoster: 12.7 vs. 8.8, per 1000 person-years). The analysis of chronological change in Osame motor disability score (OMDS) indicated that the mean change in OMDS was + 0.20 [95% confidence intervals (CI): 0.14-0.25] per year in the one-year observation group (n = 346) and + 0.57 (95% CI: 0.42-0.73) over four years in the four-year observation group (n = 148). Significant deterioration of OMDS was noted in all subgroups with varying steroid use status. CONCLUSIONS: This study revealed the incidence of comorbidities and drug utilization data in patients with HAM/TSP using registry data. Furthermore, this study provided real-world data on chronological changes in lower limb motor dysfunction in patients with HAM/TSP, indicating the utility of these data as historical controls.

The Nature of the HTLV-1 Provirus in Naturally Infected Individuals Analyzed by the Viral DNA-Capture-Seq Approach.

The retrovirus human T-cell leukemia virus type 1 (HTLV-1) integrates into the host DNA, achieves persistent infection, and induces human diseases. Here, we demonstrate that viral DNA-capture sequencing (DNA-capture-seq) is useful to characterize HTLV-1 proviruses in naturally virus-infected individuals, providing comprehensive information about the proviral structure and the viral integration site. We analyzed peripheral blood from 98 naturally HTLV-1-infected individuals and found that defective proviruses were present not only in patients with leukemia, but also in those with other clinical entities. We further demonstrated that clones with defective-type proviruses exhibited a higher degree of clonal abundance than those with full-length proviruses. The frequency of defective-type proviruses in HTLV-1-infected humanized mice was lower than that in infected individuals, indicating that defective proviruses were rare at the initial phase of infection but preferentially selected during persistent infection. These results demonstrate the robustness of viral DNA-capture-seq for HTLV-1 infection and suggest potential applications for other virus-associated cancers in humans.

Cerebrospinal Fluid CXCL10 as a Candidate Surrogate Marker for HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis.

Human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a debilitating, progressive disease without effective treatment; therefore, development of disease modifying therapy that improves long-term functional outcomes is an unmet need for patients. However, it is virtually impossible to consider this as a primary endpoint in clinical trials owing to the prolonged disease course. Therefore, development of surrogate markers that help predict the effectiveness of new interventions is essential. Currently, several candidate surrogate markers have been identified for HAM/TSP. Cerebrospinal fluid (CSF) C-X-C motif chemokine 10 (CXCL10) is involved in the pathogenesis of HAM/TSP and was shown to correlate with disease progression. However, it remains unclear whether changes in CSF CXCL10 levels are observed in response to treatment and whether these correlate with prognosis. Here we investigated several markers, including CSF CXCL10, in this respect. Data pertaining to patient characteristics and results of motor function evaluation and CSF examination of 13 HAM/TSP patients who received steroid treatment were retrospectively analyzed. Osame motor disability scores (OMDS), 10 m walking time, and CSF levels of CXCL10, neopterin, total protein, cell counts, and anti-HTLV-1 antibody titer were compared before and after steroid therapy. Levels of all CSF markers, with the exception of cell count, were significantly decreased after treatment. Nine of the 13 patients (69.2%) showed improvement in OMDS and were considered responders. Pre-treatment CSF levels of CXCL10 and anti-HTLV-1 antibody titer in responders were higher than those in non-responders (p = 0.020 and p = 0.045, respectively). Patients who continued low-dose oral prednisolone maintenance therapy after methylprednisolone pulse therapy showed sustained improvement in OMDS and CSF CXCL10 and neopterin levels lasting for 2 years. In contrast, OMDS and the CSF marker levels in patients who discontinued treatment returned to pre-treatment levels. This rebound phenomenon was also observed in patients who discontinued oral prednisolone therapy independently of pulse therapy. Our findings suggest that CSF CXCL10 may serve as a therapy-response and therapy-predictive marker for HAM/TSP. In addition, since decrease in CSF CXCL10 level was associated with good functional prognosis, CSF CXCL10 is a potential surrogate marker for treatment of HAM/TSP.

Establishment of a Comprehensive Information Infrastructure and a Support Organization for Rare Disease Research in Japan (RADDAR-J).

There are more than 300 research groups for rare diseases in Japan. Although various clinical and genomic information of patients are being collected by the groups, the information is managed individually by each research group and the current practices for managing and sharing research data are not very efficient. Since "rare diseases" are literally rare, the understanding of the underlying disease mechanisms are incomplete and collecting a sufficient number of patients for clinical trials is difficult. Therefore, there is a need to collect and integrate the data and construct a data integration platform for rare disease research. Funded by the Japan Agency for Medical Research and Development, a national research and development project to establish a standard platform and supporting organization for rare disease registries in Japan is currently under way. In this article, we report the background, purpose, process, results, current status, and future plans of this project.

National platform for Rare Diseases Data Registry of Japan.

INTRODUCTION: In Japan, there are approximately 300 projects conducting research on rare diseases supported by the Ministry of Health, Labour and Welfare of Japan (MHLW) and the Japan Agency for Medical Research and Development (AMED). Diverse data, including clinical, genomic, and sample-related data, are generated by these projects. However, at present, such data are managed individually by each project. This makes it difficult for third parties to ascertain the data generated by projects. METHODS: Again this background, at the beginning of 2017, the AMED started the National Platform for Rare Diseases Data Registry of Japan (RADDAR-J), whose mission is to construct a cross-sectional data integration platform incorporating projects supported by the AMED and MHLW. RADDAR-J promotes data sharing by the projects in accordance with the data-sharing policy established by the AMED, which classifies data sharing into three categories based on the strategies used to protect the rights of researchers while promoting data sharing. RADDAR-J integrates and analyzes data shared by each project to add value to the resources and promote secondary use by third parties while protecting the rights of the researchers who shared their data. The platform is designed to provide incentives to projects that shared their data by supporting registry construction or genomic analysis to promote data sharing. RADDAR-J also has the function of data identification to securely integrate data originating from the same person. RADDAR-J accelerates clinical research by encouraging each project to utilize a central ethics committee. RESULTS/CONCLUSION: The use of the platform by projects is expected to lead to streamlined data collection, improved quality assurance, improved access to data, and promotion of joint research and the secondary use of shared data. These benefits will accelerate research into diagnosis and treatment technologies and will hopefully lead to improved quality of life for patients with rare diseases.

Publisher Correction: Fgf10 is essential for limb and lung formation.

In the version of the paper initially published, Fig. 5a was inadvertently duplicated and presented as both Fig. 5a and 5f, and the correct image for Fig. 5f was omitted. Images of the original and corrected figure panels are shown in the correction notice.