LRRK2 & GBA Gene Targeting to Slow PD Progression

Research Research discussion
1

Let’s start with some (ahem) light reading about LRRK2 and GBA gene mutations in PD to set the stage for further comparison as to treatment options being studied that target them, and that may also work for people with PD without either of those mutations.
https://www.parkinson.org/understanding-parkinsons/causes/genetics/common-genetic-mutations

Targeting LRRK2 we have DNL151 (which may also help those without that mutation):
https://www.alzforum.org/therapeutics/dnl151

DNL151 is being moved into late stage trials next year based on trial findings to-date as follows:
“Results to date in DNL151 also show a target engagement of over 50%, and up to a 50% reduction of the lysosomal marker BMP (22:6-bis-monoacylglycero-phosphate) in urine samples, with this drop dependent on the DNL151 dose given. These data indicated that the study’s pharmacological goals were being met.”
https://parkinsonsnewstoday.com/2020/08/10/denali-biogen-partner-to-move-dnl151-into-late-stage-parkinsons-trials/

To me DNL151 results sound promising, but I for one would like a little more clarity on how its goals translate into metrics used to snapshot PD cognitive and motor progression. If that is available, I would really appreciate someone posting it in reply.

Targeting the GBA gene we have Ambroxol, on which a trial was just completed with the following statements:
“Mean (SD) scores on part 3 of the Movement Disorders Society Unified Parkinson Disease Rating Scale decreased (ie, improved) by 6.8 (7.1) points (95% CI, –10.4 to –3.1; P = .001). These changes were observed in patients with and without GBA1 mutations.”
“we confirm that ambroxol has potential as a drug to target the glucocerebrosidase (GBA) pathway in PD and increase GCase activity in the brain. These findings concur with cell and animal modeling, which indicate that ambroxol modulates α-synuclein levels. We believe ambroxol therapy has promise for further investigation as a drug to improve outcomes, particularly in patients who have PD with a GBA1 mutation and potentially in those without a GBA1 mutation.”
https://jamanetwork.com/journals/jamaneurology/fullarticle/2758317

With a significant trial underway ending next year - Ambroxol as a Treatment for Parkinson’s Disease Dementia:
https://clinicaltrials.gov/ct2/show/NCT02914366?term=ambroxol&draw=4&rank=7

My thoughts:
As some of you know, I am currently taking Ambroxol for my PD, and have posted here about its positive impact on my progression which I believe is continuing at the 7 month+ mark, as I have noted fewer daily freeze episodes, and in fact have discontinued taking Ropinirole (Requip) without much movement change. Hopefully DNL151 if/when available will bring even more to our battle against PD, but until then I have something now that is working for me. I remain very hopeful that will continue, at the very least until something better comes along!

2

Hi DHP,

sorry, don’t have much time to elaborate these but perhaps you have. Have you read about the recent results of the PASSEDENA trial and the nearing completion MOVES-PD trial? Both GBA targeted.

Dave

3

Hi Dave, thanks very much! brief search yielded me the following:

Targeting GBA a 2nd candidate Prasinezuma, its Pasadena trial did not find slowing PD progression

https://parkinsonsnewstoday.com/2020/04/24/prasinezumab-fails-to-slow-symptom-worsening-in-parkinsons-trial-finds/

Targeting GBA a 3rd candidate Venglustat, in a Gauchar model in mice found that it “reduced brain glucosylceramide levels, as well as accumulation of hippocampal α-synuclein and tau deposits. Treatment reportedly improved memory deficits.” Looks like the human Moves trial does not complete until early 2023 (treatment stage ends in December this year).

https://www.alzforum.org/therapeutics/venglustat

Planning to look more closely at Venglustat, willl post my thoughts next week.

Thanks again!

4

Hi DHP, here is a ink to PDUK I found easier to follow https://medium.com/parkinsons-uk/results-from-pasadena-a-phase-2-clinical-trial-of-a-vaccine-for-parkinsons-e63fbf63883e .
Moves-PD initial phase 2 results from year 1 double blind should be released December 2020. Although two year follow-up not published till 2023. It’s the double blind that most trials fall down on. That’s why December 2023 is so significant. Fingers crossed.
Hopefully Covif-19 doesn’t hold things up.

Dave.

5

Thanks Dave!

So let’s explore this GBA (and non GBA) gene relationship and slowing PD progression topic a little further shall we?

“The current leading hypothesis posits that GBA‐mediated loss of function causes an abnormal glycosphingolipid environment, leading to cellular protein mishandling (proteinopathy) and neuronal dysfunction. In animal models of disease, decreased GCase activity results in increased CNS α‐synuclein/ubiquitin/tau aggregates and associated cognitive and motor deficits.73 These pathological and behavioral aberrations can be ameliorated (and even reversed) by viral gene therapy‐mediated overexpression of exogenous GCase in the CNS, which would act by restoring membrane glycosphingolipid balance (Fig. 1).73-75 These studies provide strong support for GBA augmentation as a therapy for GBA‐associated PD and conceivably for certain forms of sporadic PD disease. As a consequence, several therapeutic strategies aimed at increasing GCase activity in the CNS through gene therapy or small molecule activators of GCase activity are under active investigation.”

https://onlinelibrary.wiley.com/doi/full/10.1002/mds.27414

Ideally then what we are looking for to slow PD progression is a small molecule (say a pill) that can cross the blood-brain barrier and increase GCase activity in our brain, which will then decrease α-synuclein levels in our brain which are likely causing our progression. Simple right? Obviously not, but let’s look at Ambroxol first, as its available now over the counter in many countries as a pretty safe (well tolerated in pharma speak) cough medicine, and apparently it can do that for us in higher doses as used in this clinical trial just ended (with others still in-progress).

“In conclusion, we confirm that ambroxol has potential as a drug to target the glucocerebrosidase pathway in PD and increase GCase activity in the brain. These findings concur with cell and animal modeling, which indicate that ambroxol modulates α-synuclein levels. We believe ambroxol therapy has promise for further investigation as a drug to improve outcomes, particularly in patients who have PD with a GBA1 mutation and potentially in those without a GBA1 mutation.”

Did they measure its impact on their PD symptoms? Yes they did, and it improved them.

“Mean (SD) scores on part 3 of the Movement Disorders Society Unified Parkinson Disease Rating Scale decreased (ie, improved) by 6.8 (7.1) points (95% CI, –10.4 to –3.1; P = .001). These changes were observed in patients with and without GBA1 mutations.”

https://jamanetwork.com/journals/jamaneurology/fullarticle/2758317

Next I plan to take a closer look at Venglustat to see (if available) how well it did in mice as a clinical trial is still underway. If it in fact also increases GCase activity and is relatively safe, the problem for us is that it likely would still not be available to us for a few years yet, and can one afford to wait taking something to slow their PD progression that long?

The rub for us - a possible point of no return (from the first link above)
“it is not known when during the natural history of PD the first intracerebral a-synuclein pathology appears and whether there is a “point of no return” beyond which the damage to the neural systems affected by synucleinopathy can no longer be protected or revived, even with the most effective therapies. As mentioned earlier, it is currently believed that a-synuclein pathology begins to develop during the PD prodrome,20 and by the time motor symptoms have appeared the aggregates are widespread in the brain.”

My thoughts
I myself did not wait, Ambroxol is available now and I have been taking it for almost 7 months, most of that time at 600mg / day, and have observed a marked improvement in my symptoms, many of which I have reported in my posts, but I plan to summarize them later this week for your thoughts.

6

Update on Venglustat for PD:

“The venglustat Phase 2 trial in Parkinson’s disease with GBA mutations did not meet the primary endpoint (end-January) and the indication was halted. Safety profile continues to be favorable and the development moves forward as planned in other Rare Disease indications.”

https://www.globenewswire.com/news-release/2021/02/05/2170444/0/en/Sanofi-delivered-close-to-double-digit-Q4-2020-business-EPS-1-growth-at-CER.html

7

Update on DNL151 for PD, still not much info being shared re goals met & late stage trials have been moved to “the end” of this year:

“Denali recently announced completion of the Phase 1b study for BIIB122, otherwise known as DNL151, a small molecule inhibitor of LRRK2 which met target and pathway engagement goals. We expect to initiate late stage clinical development in Parkinson’s disease patients by the end of this year.”

https://seekingalpha.com/article/4403092-biogen-inc-biib-ceo-michel-vounatsos-on-q4-2020-results-earnings-call-transcript