AAN 2026 | GHF-201 mechanism of action in APBD and findings from a compassionate use program
Or Kakhlon, PhD, Hadassah University Medical Center, Jerusalem, Israel, discusses the mechanism of action of GHF-201 in adult polyglucosan body disease (APBD), highlighting how the compound targets lysosomal pathways to enhance autophagy and improve lysosomal function. He also outlines early findings from a compassionate use program demonstrating encouraging safety and efficacy signals. This interview took place at the 78th American Academy of Neurology (AAN) Annual Meeting in Chicago, IL.
These works are owned by Magdalen Medical Publishing (MMP) and are protected by copyright laws and treaties around the world. All rights are reserved.
Transcript
GHF-201 was discovered actually as a hit in high-throughput screening that we did on skin fibroblasts from APBD patients. And the mechanism of action consists of a specific binding to a membrane protein of the lysosomes called LAMP1, lysosomal-associated membrane protein 1. And LAMP1 actually inhibits a proton exporter, a lysosomal proton exporter called TMEM175. So when you bind, when GHF-201 binds to LAMP1, it effectively dilutes it so that you have actually inhibition of the inhibition of this proton exporter, and therefore you have more acidification of the lysosome, which makes them more active in APBD and in other diseases...
GHF-201 was discovered actually as a hit in high-throughput screening that we did on skin fibroblasts from APBD patients. And the mechanism of action consists of a specific binding to a membrane protein of the lysosomes called LAMP1, lysosomal-associated membrane protein 1. And LAMP1 actually inhibits a proton exporter, a lysosomal proton exporter called TMEM175. So when you bind, when GHF-201 binds to LAMP1, it effectively dilutes it so that you have actually inhibition of the inhibition of this proton exporter, and therefore you have more acidification of the lysosome, which makes them more active in APBD and in other diseases. So it activates the lysosomes, makes them more functional. This is one thing that LAMP1 does, that inhibition of LAMP1 does. The other thing is that when LAMP1 is inhibited, LAMP2 has a compensation, which is the binding partner of LAMP1. LAMP2 is increased, and LAMP2 actually engages a protein called GORASP2 on the autophagosomes. And so the LAMP2-GORASP2 interaction promotes autophagic flux. So these are the two ways by which inhibition or dilution of LAMP1 actually activates autophagy. And I just wanted to add that LAMP1 inhibition in other studies, on flies, for instance, and on cholesterol, was also shown to increase autophagy. So this is not the first time that we show that inhibition or dilution of LAMP1 actually enhances autophagy. So within a compassionate use program in APBD patients, three patients. One was just recruited this month. We show actually no issues of adverse effects. So there was no, I mean, the biochemical parameters were not modified, ECG, and we followed this for 12 patient years, okay? So this is for the safety. So there were no safety concerns in patients, no safety issues in patients. Also in mice, there were no safety issues observed. As for the efficacy, we have an increase in muscle strength in all patients. Some of them also report regaining of sensation in the feet, of cold and heat sensation, which we also confirmed in our mouse model, by the way. So to us, it is really a surprise because even slowing down the deterioration or stopping the deterioration would have been an achievement on its own, let alone the increased efficacy. So we’re very satisfied with this result.
This transcript is AI-generated. While we strive for accuracy, please verify this copy with the video.
Read more...
