Funding Boost From MJFF Advances Lysosome-targeting Therapies

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Caraway Therapeutics was awarded a new research grant from the Michael J. Fox Foundation (MJFF) to further work on therapies that increase flux, or movement, into the lysosome, a tiny cell compartment that helps clear away the alpha-synuclein toxic clumps that are known to cause Parkinson’s disease.

This is the MJFF’s third grant to the U.S.-based company, which will use the money to advance the development of small molecules that act as agonists to TRPML1, an ion channel that is present on lysosomes and controls their activity.

“It has been a pleasure to work with The Michael J. Fox Foundation and we are thrilled to continue our partnership with this third grant,” Martin D. Williams, CEO at Caraway, said in a press release.

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The lysosome acts as a cell’s recycling center: it contains enzymes that break down unwanted materials into building blocks that can be reused and built upon by that cell or others in the body.

One such enzyme is glucocerebrosidase, known as GCase, which breaks down fatty molecules. The cell keeps the instructions to make this enzyme in a gene called GBA. Mutations in this gene are linked to an increased risk of developing Parkinson’s. They also can cause Gaucher, a disease passed down from parents to children that is marked by a buildup of fatty molecules, which accumulate in tissues instead of being broken down and cleared away.

TRPML1 reduces the buildup of fatty molecules by increasing the levels and activity of GCase. The company believes that making TRPML1 even more active by means of agonists could help the lysosomes clear away those unwanted materials from cells.

“By agonizing TRPML1, we aim to restore the activity of the lysosome and improve cell health,” said Magdalene Moran, chief scientific officer at Caraway.

Earlier work has shown that TRPML1 agonists are able to reduce the levels of fatty molecules and alpha-synuclein in neurons (nerve cells) derived from patients with Parkinson’s who have mutations in GBA.

“Understanding the role TRPML1 plays in alpha-synuclein clearance will be important as we advance our TRPML1 program towards the clinic and further our understanding of how our TRPML1 agonists impact disease processes in GBA-PD, one of the most common genetically-defined forms of PD [Parkinson’s disease],” Williams said. The program currently is in a preclinical stage, according to a page on the company’s website.

Another way the company will use the new grant is by identifying biomarkers that may be used to see how well patients in upcoming clinical trials respond to potential TRPML1 agonists.

“MJFF continues to invest in research that will improve our understanding of lysosomal function in PD,” said Marco Baptista, vice-president of research programs at MJFF.

“We are pleased to award this third grant to Caraway to increase our understanding of TRPML1, a target of high interest to the Foundation,” he added.

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