Research is being done by Prevail Therapeutics in NYC. (I have the mutation and so does my boss's husband. Hopefully he will get into the study and I will try to report on the results)
We are developing a broad pipeline of gene therapies for a range of neurodegenerative diseases including Parkinson’s disease, frontotemporal dementia, Alzheimer’s disease, and ALS. The first indication for our lead program, PR001, the treatment of Parkinson’s disease with GBA1 mutation (PD-GBA), illustrates our precision medicine approach to treating neurodegenerative disease.
Parkinson’s disease is a chronic, progressive neurodegenerative disorder that affects up to one million people in the United States and more than 7 million people worldwide. While Parkinson’s disease is a movement disorder that is most commonly characterized by resting tremor, bradykinesia, rigidity and gait difficulty, it is now known to impact other aspects of nervous system function, and patients can suffer from a range of non-motor symptoms including psychosis, dementia, and cognitive impairment. Pathologically, Parkinson’s disease is characterized by inclusions called Lewy bodies, which are found within neurons and are comprised predominantly of an aggregated protein called α-Synuclein. There are no treatments available that modify the progressive underlying disease process of Parkinson’s disease.
Gene mapping in recent years has led to the identification of dozens of causative and risk genes for Parkinson’s disease. Many of these genes are involved in lysosomal function or lysosomal trafficking, indicating that lysosome dysfunction is the common denominator that underlies Parkinson’s disease pathology.
For example, mutations in the glucocerebrosidase (GBA1) gene are now known to play an important role in Parkinson’s disease. It is estimated that seven to ten percent of Parkinson’s patients worldwide, and up to 10 percent of Parkinson’s patients in the United States carry a GBA1 mutation. GBA1 encodes the lysosomal enzyme glucocerebrosidase (GCase), which is required for the disposal and recycling of glycolipids, a type of cellular lipid component that is known to accumulate with aging. Reduced levels of GCase activity in Parkinson’s patients with GBA1 mutations may lead to accumulation of glycolipids, which is toxic and can cause inflammation, leading to lysosomal dysfunction and aggregation of α-Synuclein in cells.
We are also developing PR001 for the treatment of neuronopathic Gaucher disease. PD-GBA and Gaucher disease share the same underlying genetic mechanism, as Gaucher disease is defined by the presence of mutations in both chromosomal copies of GBA1, and we believe they represent a continuum of disease.
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pmmargo
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Thanks pmmargo. My husband doesn't have your "garden variety" PD. I'm wondering if he has this mutation. He has extreme apathy, which was initially diagnosed as depression, then LBD. He was put on Madapar with little effect. Then put on the Neupro patch and within a few weeks rediagnosed with PD. The effect of the patch was amazing...mentally back to normal. That was in 2013. The patch is no longer working and he is now struggling with apathy again. He been on Xadago, since May 2018, which has helped, but not enough. He's now on 250mg B1 (high dose sent his blood pressure thru the ceiling), magnesium, B6, B12 and even more recently, Mannitol. There is definitely more improvement since the Mannitol. He is no longer foggy at all. Previously he had days where he was wanting to shake his head to clear the fogginess. I can only put this change down the combination of these supplements or the Mannitol in particular. ( He actually started on the Mannitol in the hope that it might restore his sense of taste. That can take some time apparently). His blood pressure is a problem and was also an early symptom (very low when he stands, but can get high in the night). We are managing this with a patch in the night to bring it down, (taken off before rising). Seems to work. His PD mask is worse currently.
Anyway pmmargo, I thank you for your input. Our neurologist is very open minded to anything I throw at him, including B1 protocol., so the GBA1 mutation is now on my list. Anything you think might help us would be appreciated.
Hi Gwendolyn, Your husband is so lucky to have you working so hard to look for things that might help with his PD! I learned I had the mutation from 23 and me (23andme.com). I also do not have typical symptoms and really thought I had Parkinsons Plus in some form (PSP or MSA) since I have only a little bit of tremor. Supposedly the genetic form progresses a little quicker than the non-genetic form. Of course he should regard himself as fortunate not to have Parkinsons-Plus since the expected lifespan is probably at least 10 years shorter than PD. Neupro worked well for me except the patches hurt after maybe 19 hours..So I'm now on Mirapex and Rasagiline which is supposedly a synergistic combination that is so good that Teva is designing a drug which features the combination. (By the way my balance was really bad and I could not smell and everything was salty...Mirapex fixed all of these issues for me..really remarkable.) It is known as the libido drug so that may help with apathy. You should be sure he takes less than 50 mg of B6. B6 helps the nerves but interacts with some of the PD drugs in an unfavorable way.
My movement specialist is at Georgetown U (Yasar Torres-Yaghi). There are lots of experts in the DC area. There is an Ashkenazi Genetics in PD expert at NIH Ellen Sidransky: irp.nih.gov/pi/ellen-sidransky Best Wishes! Paul
If it turns out that your husband has the GBA form Dr Sidransky might want to meet him and include him in one of of her studies. My boss's husband has met her and she is super cool intelligent kind person.
We have had great success with the methyl B12, and magnesium L-Threonate. We also are using Methyl-Max, which contains small doses of B6 and B9. He's only been on this combination a few weeks and is functioning a lot better. We went out to friends home for dinner for the first time in 12 months and he chatted all night and was still going at 11pm, when I took him home..apathy gone.
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