Asthma research leads to Gaucher’s Disease treatment approach

A new treatment was discovered unexpectedly for Gaucher’s Disease, an inherited enzyme disease, while carrying out a regular research on asthma at the NYU Langone Medical Center based in New York City.

The researchers were conducting experiments to study the action of proteins in protecting lungs from asthma related damage.

Inherited Enzyme Disease, also known as Gaucher’s Disease, is a rare genetic disease in which fatty substances keep on piling up in cells and certain organs.

It is caused due to genetic mutation of genes that encodes lysosomal enzymes which digests glycolipids and is mostly seen in Jews originating in Eastern and Central European countries.

Gaucher’s Disease symptoms include joint pain, blood disorders, enlarged spleen and liver, memory loss and lung damage.

It is associated with very low production of a protein named progranulin as the enzyme beta-glucocerebrosidase or GBA is produced outside lysososmes at high levels instead of inside where it is required.

Gaucher's Disease
Image of lung cell in mice with Gaucher’s disease shows “tubular-like” lysosomes (in dark purple, zigzagging lines). Normal lysosomes (unshown) are round. (PRNewsFoto/NYU Langone Medical Center)

When the manufactured progranulin protein is used in a new research done by researchers of NYU Langone Medical Center, it showed that the protein has reversed the effects of Gauchers’s disease in mouse and human cells. It also lowered the GBA accumulation.

Chuanju Liu, PhD, senior study investigator and a professor in the Departments of Orthopaedic Surgery and Cell Biology at NYU Langone said: “Our results suggest a new way to treat Gaucher’s disease that corrects abnormal enzyme delivery by progranulin to lysosomes, as opposed to current treatment strategies that temporarily replenish lysosomal GBA stores, which are then steadily consumed”.

Both NYU Langone Medical Center and the research team hold a patent for related, potential therapies.

An important finding of the research was that progranulin has to bind to other molecules to transport the enzyme to lysosomes, in particular, the protective heat shock protein 70. If there is no protection, then the cellular GBA fold up and stick on to the external surface of the lysosomes.

Synthetic progranulin or Pcgin, when added to the blood cells obtained from Gaucher’s Disease patients, led to a 40% reduction of GBA clumping in just a week of research.

Pcgin, asynthetic progranulin, is more stable than the actual protein. So its use has no risk of uncontrolled tumor-like cell growth in test animals.

Jian Jinlong, MD, PhD, a lead study investigator and an associate research scientist at NYU Langone said: “Our new experiments are the first to explain why reduced progranulin is a key characteristic of Gaucher’s, and why the mice engineered to lack the protein serve as such a good model to test new therapies”.

Progranulin deficiency leads to brain disorders and is also related to cell swelling in asthmatic lungs.

When Pcgin was added to progranulin-deficient mice, it was found to have reduced the lung-tissue swelling by more than 60%, an effect that has been observed with current GBA-replacement treatments.

Further research has to be carried out to understand the complete mechanism in which progranulin reduces cell swelling, through which more drug targets for Gaucher’ disease can be found.

National Institute of Health grants R01 AR062207, and R01 AR 061484, and a grant from Atreaon are funding the study.

NYU Langone also has a drug-licensing agreement with Atreaon, a pharmaceutical company based in Newton, Massachusetts which develops drugs for treating arthritis.

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