GOF vs. LOF

On October 16th, the Karolinska Institute in Stockholm, Sweden held what may come to be remembered as the seminal debate in our attempts to treat degenerative brain diseases. The issue on the (virtual) table: Is Protein Aggregation as A Therapeutic Target in Neurodegenerative Diseases Still Valid?

On one side were Prof. Simon Mead and Prof. Janne Johansson defending the commonly held position that protein aggregates have a toxic gain-of-function (GOF) that makes them a principal driver of neurodegeneration. Disputing this were Prof. Alberto Espay and Dr. Kariem Ezzat arguing that the problem is not the aggregates themselves but the loss-of-function (LOF) of the proteins they suck up.

The issue strikes at the core of our attempts to treat these diseases as many ongoing clinical trials, driven by the GOF hypothesis, aim to either break up or prevent these aggregates, and most drug candidates in the pipeline are validated on the basis of how effectively they impact protein aggregation.

In many ways the story is one of science itself. The GOF hypothesis was built up over decades of experiments that produced multiple lines of evidence that seemed to point in its direction. Then a small group of dedicated and skeptical researchers came along to argue that we set off on the wrong path from the beginning.

In the end, it does not matter who or how many people believe one side or the other. The truth is there waiting to reveal itself if we just ask the right questions and are thorough enough in our investigations. At the moment we do not have conclusive evidence for one side or the other (or if it is a combination of the two). But, we do know that almost all resources spent trying to modify the course of these diseases have been based on GOF, with nothing to show for it thus far. In Alzheimer’s alone there have been 35 clinical trials testing GOF, none have succeeded. There has not been a single trial yet testing LOF.

This is not just some esoteric debate among academics. It is essential that we get this right if we are going to effectively address the rising number of people with neurodegenerative diseases worldwide. A number that may spike astronomically over the decade to come if recent findings of a link between COVID-19 infections and neurological disorders turns out to be true. (Here is just one of many studies that show a potential connection.)

Now, there is a lot more nuance to this debate than I have outlined. For a much deeper dive into the scientific arguments supporting both sides watch the recording of the debate below. It’s lengthy but well worth it.

Has time come to test LOF? More to follow.

1 comment

  1. Is there an open discussion on this, as this is what I said to you at the end of the WPC in Kyoto. I think our paper will show this. If you also look at the paper we discussed at the Research Arm of the PD Avengers with Dr Simon Stott, from the CPT, the majority of research is palliative, as the GOF theory fails, and my heart sank at the very beginning of this discussion, as the LOF research percentage is so very low. See, Parkinson’s Disease Drug Thérapies in the the Clinical Trial Pipeline: 2020, with reference to K. McFarthing et al./ Parkinson’s Drug Development Review, page 763, to 766. By phase 3, “same old, same old”. The mind set has to change.

    Joy

    Joy ________________________________

    Liked by 2 people

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