Spring 2019 > Research Excellence

Branching Out for Better Health

Those of us who have lived in Hong Kong long enough know that tuberculosis was once a major killer back in the 1950s, when overcrowded living environments and unsanitary conditions were a common sight.

Tuberculosis (結核病, commonly known as 肺癆, which refers to depletion of the lung), is regarded as one of the oldest contagious diseases in humans. In addition to a low-grade fever and blood in the sputum, persistent cough is also an obvious symptom of tuberculosis. The significant decline in the death rate in developed countries can be attributed to advances in medical technology and improvements in health care and quality of life. Around 5,000 cases are reported annually in Hong Kong, compared with a peak of more than 10,000 cases in the 1950s.1

What an X-ray May Not Tell You

Another disease that has many similarities to tuberculosis is pulmonary sarcoidosis (結節病).

Both tuberculosis and pulmonary sarcoidosis form granulomas, masses of granulation tissue caused by irritation or inflammation. These lung diseases have common symptoms, such as fever, fatigue, and weight loss due to loss of appetite. Their similarities sometimes make diagnosis difficult, and even a chest x-ray can cause confusion, particularly in areas where tuberculosis is endemic.

Distinguishing pulmonary sarcoidosis from tuberculosis is not easy, but they do have some differentiations. Unlike tuberculosis, which is caused by Mycobacterium tuberculosis, pulmonary sarcoidosis is a major form of interstitial lung disease, a group of more than 100 types of immune-mediated disorders that cause progressive fibrosis of lung tissue.

Tuberculosis can be cured with a course of treatment that can last for six months or longer, but pulmonary sarcoidosis has no known cure.

Pulmonary sarcoidosis is the most common form of interstitial lung disease (ILD, 間質性肺病) in the US, occupying 30% of the ILD patients. There are about 200,000 sarcoidosis patients in the US; more than half of them require systemic therapy, and 30% have chronic progressive disease despite currently available treatments, including corticosteroids, cytotoxic agents, and anti-tumor necrosis factor agents. ILD has a worldwide distribution, including China. Idiopathic pulmonary fibrosis, another form of fibrotic lung disease that accounts for 28% of the ILD patients in China, is estimated with around 500,000 patients.2 In China, pulmonary sarcoidosis appears less prevalent than in the US, but there is a trend towards better classification of ILD subtypes and more patients may be diagnosed.3

Source: https://www.thoracic.org

A lung at the end-stage of ILD | Photo: Dean E. Schraufnagel

A New Potential Therapeutic

Thanks to a collaboration between HKUST and Pangu BioPharma, a Hong Kong subsidiary of the US biotherapeutics company aTyr Pharma, Inc., a new investigational therapeutic called ATYR1923 has been developed to treat pulmonary sarcoidosis.

This is certainly good news for patients with pulmonary sarcoidosis.

At a press conference at HKUST this January, Dr. Sanjay SHUKLA, President and Chief Executive Officer of aTyr Pharma, Inc., shared with the public that the company is advancing its lead candidate ATYR1923 through clinical development in patients with pulmonary sarcoidosis.

“ATYR1923 is a selective modulator of Neuropilin-2 that downregulates the innate and adaptive immune response in inflammatory disease states. It is a modified form of a tRNA synthetase that is entering a proof-of-concept Phase 1b/2a clinical trial,” said Shukla.

According to aTyr Pharma, Inc., the Phase 1b/2a study is “a multiple-ascending dose, placebo-controlled, first-in-patient study that has been designed to evaluate the safety, tolerability, steroid sparing effect, immunogenicity, and pharmacokinetic profile of multiple doses of ATYR1923, as well as to evaluate well-established clinical endpoints and certain biomarkers to assess preliminary efficacy.”4

The trial is being conducted in collaboration with the Foundation for Sarcoidosis Research, a leading nonprofit organization in the US that is dedicated to finding a cure for sarcoidosis and improving care for sarcoidosis patients.

ATYR1923 is a fusion protein that comprises the immuno-modulatory domain (iMod), a naturally occurring splice variant of histidyl-tRNA synthetase (HARS) that is enriched in the lung tissue, fused to the FC region of a human antibody.3

Possible further developments of ATYR1923 include Phase 3 clinical trial in pulmonary sarcoidosis, and Phase 2 studies in other types of ILD such as Connective Tissue Disease Associated ILD (CTD-ILD) and Chronic Hypersensitivity Pneumonitis (CHP).

“There is a need for drugs that are better tolerated and have less side effects than steroids, and it is our goal for ATYR1923 to meet that,” said Prof. ZHANG Mingjie, Chair Professor of Life Science, Kerry Holdings Professor of Science, IAS Senior Fellow at HKUST, and project coordinator of the Pangu collaboration.

Looking Forward

The discovery of ATYR1923 and the extracellular signaling functions of tRNA synthetases would not have been possible without the pioneering work of HKUST researchers and Pangu BioPharma. “We are grateful to HKUST researchers for the essential collaborative efforts that made this important milestone possible,” said Shukla.

Prof. Zhang believes that the important discoveries “serve as an excellent example of the potential role that Hong Kong’s translational science and early discovery capabilities can play in the development of potentially life-changing therapies for patients worldwide.”

Prof. Paul SCHIMMEL, Co-founder and Director of aTyr Pharma and IAS Senior Visiting Fellow, said, “Our understanding of tRNA synthetase biology was greatly enhanced by the joint efforts of the research teams at aTyr and Pangu/HKUST. We see the potential to replicate this model with many of the novel forms of tRNA synthetases covered in our expansive and largely untapped intellectual property portfolio that includes more than 300 issued or pending patents covering both biologically active variants and engineered forms of human tRNA synthetases. Each of these protein compositions offers opportunities for potential development of therapeutics to treat a wide array of conditions.”

The journey to transform translational research into new treatment is not always easy, and a treatment for patients with diseases like pulmonary sarcoidosis may be still a few years away, but the future of human health is promising.

1. The Center for Health Protection, Department of Health, HKSAR, Notification & death rate of tuberculosis (all forms), 1947-2018. Retreved from  https://www.chp.gov.hk/en/statistics/data/10/26/43/88.html
2. Wen Wei Po, Feburary 13, 2017
3. Chengjun Ban et al. (2018) Spectrum of interstitial lung disease in China from 2000 to 2012. European Respiratory Journal 52 (3) 1701554
4. aTyr Pharma, ATYR1923 (IMOD.FC), Retrieved from https://www.atyrpharma.com/programs/atyr1923/

Prof. Paul Schimmel and IAS-Scripps R&D Laboratory

Prof. Paul Schimmel received his PhD in Biophysical Chemistry from the Massachusetts Institute of Technology (MIT) in 1966. Before he joined the Scripps Research Institute in 1997, he was a John D. and Catherine T. MacArthur Professor of Biochemistry and Biophysics at MIT. His major research activities concern the decoding of genetic information, with emphasis on the rules of the universal genetic code that are established via aminoacylation reactions catalyzed by a group of enzymes known as aminoacyl tRNA synthetases. The latter are believed by many to be among the first enzymes to arise on this planet in the early stages of the evolution of life.

Having a longstanding interest in the application of basic biomedical research to human health, Schimmel is a Member of the US Academy of Sciences, National Academy of Medicine, National Academy of Inventors, American Academy of Arts and Sciences, American Philosophical Society. He holds numerous patents and is a co-founder or founding director of multiple biotechnology companies, of which seven became publicly traded on NASDAQ. These companies are developing new therapies for human diseases and disorders; one of them, Pangu Biopharma, is a joint venture with HKUST.

Led by Schimmel, the IAS-Scripps R&D Laboratory was the first of its kind, established in 2007 under the auspices of the IAS. Throughout the years, research projects in biomedical sciences have been carried out in collaboration with researchers and scientists from HKUST. In 2014, the research team of the IAS-Scripps R&D Laboratory discovered 250 previously unknown gene-transcript variants of aminoacyl tRNA synthetases. The findings, published in Science, highlight an intriguing oddity of protein evolution that has generated novel extracellular signaling proteins from these ancient enzymes, which may serve as the basis for many potentially valuable new protein therapeutics. Growth hormone and insulin are examples of widely used, approved injectable protein therapeutics.