Mar 15, 2019 Meeting to fast track progress on rare disease research

AMED meeting shares the latest knowledge of tools, trials and therapies for Japan’s rare and intractable diseases

Atsuhiko Kawamoto, divisional director of the Division of Medical Innovation at TRI, addressing clinicians and researchers
at the Overcoming Disease event held in Tokyo in 7-8 February 2019

@2019 Timothy Hornyak

Physicians in Japan are working with international colleagues to build knowledge of some of the world’s most rare and complex illnesses. To share progress made during 2018, the Overcoming Disease event was held at Tokyo International Forum on 7-8 February 2019, with the participation of clinicians from institutes across Japan as well as rare disease patients and their families.

Getting to the roots of disease

A wide spectrum of disorders, from relatively common diseases to extremely rare ones, were discussed at the conference. One of the more prevalent diseases — it affects 10-20 million people worldwide — is HTLV-1 Associated Myelopathy (HAM), also known as tropical spastic paraparesis (TSP) or chronic progressive myelopathy. HAM is a progressive spinal cord disease that can lead to paralysis, with most patients becoming wheelchair-bound within 20 years of onset. The causative HTLV-1 virus is endemic in parts of Africa, the Caribbean and Japan, which is home to about 3,000 HAM patients.

A major goal of HAM research, explained Yoshihisa Yamano of St. Marianna University School of Medicine, is to establish surrogate biomarkers to predict the disease’s progression. One current line of enquiry is to analyse patient data gathered through HAM-net, a national patient registry. Another is to study the protein C-X-C motif chemokine 10 (CXCL10), which is overproduced amid HTLV-1 infection. CXCL10 is a promising biomarker and researchers are trying to develop a kit that would enable its measurement outside labs.

“HAM is a disease with slow progression, so it will also require a long time to conduct clinical trials and to prove the effectiveness of an agent,” Yamano said. “By developing a biomarker that could substitute for a clinical index, we would like to shorten the period it takes to develop an agent.”

By developing a biomarker that could substitute for a clinical index, we would like to shorten the period it takes to develop an agent

One of the rare diseases discussed at the conference was fibrodysplasia ossificans progressiva (FOP). There are fewer than 1,000 FOP cases around the world, and roughly 80 in Japan. FOP is a slow, progressive disorder in which normal tissue gradually becomes ossified, leaving patients paralysed. Most patients, as many as 95 per cent, have a defect in ACVR1, a type-1 bone morphogenic protein receptor.

FOP still lacks an approved treatment, said Junya Toguchida of the Institute for Frontier Life and Medical Sciences, Kyoto University. With the protein activin A identified as a trigger for tissue hardening, researchers are evaluating the efficacy of the compound sirolimus to block its function. The Institute for Advancement of Clinical and Translational Science (iACT) at the Kyoto University Hospital and other centres have run a trial with 24 patients administered sirolimus for 24 weeks. The results are still being evaluated, however sirolimus is already approved for treatment of a lung disease lymphangioleiomyomatosis (LAM), and it may also prove effective against FOP, said Toguchida.

“To understand the natural course of the disease in Japan, we’d like to create a FOP registry covering all 80 patients so that we can follow them,” Toguchida said. “With data from this continuous agent administration, we could apply for the approval of this agent so that eventually patients can benefit from an effective cure.”

Another difficult disease discussed at the conference is primary immunodeficiency disorder (PID), a group of more than 100 illnesses resulting from defects in immune function or development. They include combined immune deficiency: the severe form of this illness was made famous by the case of David Vetter, an American child known as the ‘boy in a bubble’, who lived in a sterile room for 12 years until he died in 1984.

In Japan, the prevalence of PID is about 2.3 in 100,000. While researchers have identified more than 300 genes that play a role, a causal agent remains unknown for more than half of all patients, explained Satoshi Okada of the Department of Pediatrics at Hiroshima University Graduate School of Biomedical & Health Sciences.

Okada and colleagues in Australia are focusing on potential causes. They have conducted PID exome sequencing and analysis followed by induced pluripotent stem (iPS) cell and mouse experiments that found a V2031 mutation was causative for PID. The team has shown that a gain-of-function mutation in the IKBKB gene causes combined immune deficiency. They have also focused on a mutation in NF-kB Essential Modulator (NEMO), a protein encoded by IKBKB that is associated with PID.

“We’ve discovered three genetic defects that are totally new,” Okada said. “Even with all the exome sequencing, the cause cannot be clarified for nearly two-thirds of patients, so we definitely want to solve this issue. We’ll continue our research to find mutations that cannot be detected through genomic analysis.”

Teaming up to win

Pooling knowledge and collaborating were discussed at the conference as effective weapons against rare diseases. About 36,000 people in Japan are suffering from undiagnosed illnesses. To help these patients obtain diagnoses and treatment, in 2015 AMED established the Initiative on Rare and Undiagnosed Diseases (IRUD), a nationwide network aimed at finding genetic culprits through exhaustive genomic analysis and other techniques. Hidehiro Mizusawa of the National Center of Neurology and Psychiatry explained that through IRUD, 9,524 samples from 3,356 families had been registered by late July 2018. Diagnoses were made for 1,027 out of 2,756 families analysed, a rate of 37 per cent, with 18 new diseases identified.

Pooling knowledge and collaborating were discussed at the conference as effective weapons against rare diseases

The program’s latest initiative is IRUD Beyond. Mutations discovered through IRUD research will be targeted with new drug candidates, new technologies will be applied to unsolved diseases, and data will be made available to international colleagues through data-sharing programs.

“One future challenge is working on the 63 per cent of patients who remain undiagnosed,” said Mizusawa. “We’d like to pursue more collaboration with groups including the Japanese Society of Medical Networking for Intractable Diseases (JSMNID), as well as to outsource genetic screening. One of our goals is to develop treatment methods for diseases caused by unknown genes that are identified through our initiative.”

Important for developing new treatments for some rare diseases is having a disease model in other organisms. The Japanese Rare Disease Models & Mechanisms Network (J-RDMM) is an IRUD Beyond initiative inspired by a Canadian group that brings together the model organism and clinical research communities. Ituro Inoue of the National Institute of Genetics described the use of flies and fish animal models to study rare diseases. He explained that some species have about 70 per cent of human genes in homologous form, including TAK1, a gene often implicated in human disease. “Animal model research can be effective in cases where there is only one patient with a disease,” Inoue said. “Researchers throughout Japan are passionately working on 104 genes, and in some cases there have been findings from analyses on killifish or zebrafish that were not found in mouse experiments.”

Looking to the future

New collaborations are ensuring Japan’s research efforts are world class.  Atsuhiko Kawamoto, divisional director of the Division of Medical Innovation at TRI, described how in 2017 Japan became the first Asian country to join Orphanet, a multilingual medical database established in France in 1997. Covering more than 6,000 rare diseases and some 40 countries, Orphanet is helping doctors make diagnoses when patients present with mysterious ailments; around 110 of the disease descriptions will be translated into Japanese.

Illustrating the importance of such online resources, Kawamoto described a recent case of a bedridden 12-year-old Russian girl with a history of seizures. Following internet searches for doctors that could help, the patient’s mother sought help from epilepsy experts at Nishi-Niigata Chuo National Hospital. Subsequently, clinicians with an interest in rare diseases at Yokohama City University, were able to diagnose the child with a hereditary folic acid metabolism disorder, an illness that had only been reported twice in Japan. The girl’s condition has since improved with treatment.

“For Orphanet Japan, we’d like to enhance intractable disease information so that Japanese specialised knowledge and expertise is more available to foreign patients and can provide opportunities for more international collaborative research,” Kawamoto said.

Raising awareness through Nan-byo Research

It is also important to spread the news of this research and collaborations so that patients and their families, clinicians and researchers can learn more about these rare conditions. Kawamoto said that the Nan-byo Research website is helping to promote research in Japan and to sow the seeds of cross-border teamwork. “The goal for Nan-byo Research is to raise awareness about Japanese initiatives in intractable diseases so it can also introduce more Japanese pharmaceutical agents and medical equipment into foreign markets,” he explained.

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