Recent research progress in the field of central nervous system diseases (03.13)
March 13, 2018 Source: WuXi PharmaTech
Window._bd_share_config={ "common":{ "bdSnsKey":{ },"bdText":"","bdMini":"2","bdMiniList":false,"bdPic":"","bdStyle":" 0","bdSize":"16"},"share":{ }};with(document)0[(getElementsByTagName('head')[0]||body).appendChild(createElement('script')) .src='http://bdimg.share.baidu.com/static/api/js/share.js?v=89860593.js?cdnversion='+~(-new Date()/36e5)];1. Treatment of Parkinson's disease, gene therapy improves motor function in patients
Voyager Therapeutics, Inc., which specializes in gene therapy for severe neurological diseases, has published an ongoing Phase 1b clinical trial to evaluate long-term data on VY-AADC in advanced Parkinson's disease.
Parkinson's disease is a chronic neurodegenerative disease that affects approximately 1 million people in the United States and has a population of 7-10 million people worldwide. There are currently no therapies that can effectively slow or reverse the progression of Parkinson's disease, and levodopa is the standard treatment for this disease. However, as the disease progresses, the patient's response to treatment is worse, and the long-term exercise is slow and stiff, and the medication is not optimal. This period is called "off-time."
VY-AADC is a gene therapy vector developed by Voyager Therapeutics. The progressive motor symptoms of Parkinson's disease are largely attributable to the death of dopamine neurons in the substantia nigra, which convert levodopa to dopamine under the catalysis of AADC enzymes and then release dopamine to Dopamine receptors in the putamen. In advanced Parkinson's disease, neurons in the substantia nigra degenerate, and AADC enzymes in the putamen are also significantly reduced, limiting the brain's ability to convert levodopa to dopamine. However, the intrinsic neurons in the putamen do not degenerate. VY-AADC consists of the adeno-associated virus-2 capsid and the cytomegalovirus promoter that initiates the expression of the AADC gene, which can directly deliver the AADC gene to the putamen neurons in which the dopamine receptor is located, bypassing the substantia nigra neurons, Neurons in the putamen express AADC enzyme, which converts levodopa to dopamine. Therefore, VY-AADC is expected to permanently enhance the conversion of levodopa to dopamine, providing a clinically meaningful improvement by restoring the patient's motor function and relieving symptoms in one application.
The latest results of this study indicate that after a single dose of gene therapy, multiple motor function measurements were sustained, dose- and time-dependently improved. These measurements included a log of patient reports, a Parkinson's disease rating scale, quality of life, and an open-time log of no troublesome dyskinesia at 12 months. The results also included a 2.1-hour improvement in the onset of the trouble-free dyskinesia from baseline to 3 years reported by the cohort 1 patient, a sustained and clinically significant 3.5-hour improvement in the cohort 2 from baseline to 18 months, and a cohort of 3 The baseline improved to 1.5 hours in 6 months and lasted from 6 months to 12 months.
"VY-AADC is satisfied with the continuous improvement and extent of the patient's multiple motor function and quality of life measurements, which is consistent with the mechanism of action of VY-AADC, indicating that patients are capable of manufacturing with little levodopa. More dopamine and improve their motor function," said Dr. Bernard Ravina, Chief Medical Officer of Voyager Therapeutics. "We look forward to reviewing the results of these Phase 1b studies with the FDA at the C-type meeting and look forward to being key in mid-2018. The first patient in the 2-3 project offered treatment."
2. Unique gene therapy for Parkinson's disease, lightning financing A round of $ 75 million
Prevail Therapeutics, a newcomer to neurological disease gene therapy, recently announced that it has received $75 million in Series A funding to advance the development of unique lysosomal function-related gene therapies to treat neurodegenerative diseases of specific gene subtypes. The financing was led by OrbiMed, Pontifax Fund, RA Capital Management, EcoR1 Capital, Omega Funds, BVF Partners, Boxer Capital, Adage Capital Management and Alexandria Venture Investments.
Prevail was founded in 2017 and was originally founded by Jonathan Silverstein, co-head of OrbiMed's global private equity fund. He was diagnosed with Parkinson's disease caused by a mutation in the glucocerebrosidase gene (GBA1) in 2016. The GBA1 gene variant subtype Parkinson's disease research fund was established. The special gene was reinvested with OrbiMed to establish Prevail, aiming to create a unique gene therapy to improve the treatment of genetic variants of neurodegenerative diseases.
In terms of core technology, Prevail has obtained a patent license for the adeno-associated virus (AAV) gene therapy vector technology developed by Regenxbio called NAV AAV9, which will be used to develop gene therapy candidates. Prevail's R&D pipeline is dedicated to neurodegenerative diseases caused by specific genetic variants associated with lysosomal dysfunction. Specific gene mutations related to lysosomal function can be found in Parkinson's disease (including young early onset), certain types of Alzheimer's disease, and frontotemporal dementia (dementia) in various clinical subtypes. The company is developing the lead gene therapy PR001, which targets the GBA1 gene mutation target, mainly for the treatment of Parkinson's disease associated with GBA1 mutation (the rate of GBA1 mutation in Parkinson's disease is about 10%), and hopes to expand PR001 for Parkinson's disease in the future. Therapeutic effect.
“This round of financing will help us advance the robust gene therapy product pipeline program, focusing on improving the lives of patients with specific genetic subtypes of neurodegenerative diseases,†said Dr. Asa Abeliovich, founder and CEO of Prevail. “Our The pilot gene therapy program will target patients with Parkinson's disease, and future plans will extend to other areas of the disease caused by lysosomal dysfunction."
3. CRISPR technology helps discover new targets for the treatment of gradual freezing human disease
Amytrophic lateral sclerosis (ALS), commonly known as gradual freezing, is a progressive and fatal neurodegenerative disease. Due to the gradual death of motor neurons, the patient's muscle function is degraded, and simple muscle movements such as brushing, talking, and even breathing are ultimately impossible. Abnormal protein deposition in the brain of patients is one of the important hallmarks of ALS, but scientists are not sure how these protein deposits lead to neuronal death. Recently, researchers at Stanford University used CRISPR/Cas9 gene editing technology to screen genes affecting ALS symptoms. The results not only helped scientists understand the pathogenesis of ALS, but also provided new targets for the treatment of ALS. point. This result was published in Nature Genetics.
â–²Image source: 123RF
In ALS patients, a common cause is the hexanucleotide repeat expansion on the C90RF72 gene, and the mutated gene expresses a dipeptide repeat (DPR) that is very easy to polymerize. protein. Deposition of DPR in cells is thought to be responsible for nerve cell death. The researchers used CRISPR/Cas9 gene editing technology to perform genome-wide knockout screens in the human cell line K562. The researchers then added DPR protein to the culture medium and tested whether the knockdown of specific genes would be more sensitive or resistant to DPR-induced cytotoxicity. Using this method, the researchers found that hundreds of genes have a positive or negative effect on the cytotoxicity of DPR. To test the function of these genes in a cell environment closer to ALS, the researchers further examined approximately 200 genes that have the greatest impact on DPR toxicity in human cells in a mouse neuron cell culture model that mimics ALS. After two rounds of screening, the researchers found that more than a dozen genes have the greatest impact on the cytotoxicity of DPR.
Among these dozens of genes, several genes are knocked out and have a strong protective effect on cells. For example, the gene named RBA7A is an endolysosomal trafficking gene that may play an important role in mediating DPR invasion and transduction between cells. Another gene of interest is Tmx2. When it is knocked out, almost 100% of cells survive in the presence of DPR, and usually only 10% of cells survive. The Tmx2 protein is a protein in the endoplasmic reticulum of the cell and its function has not been fully clarified. Studies have suggested that it may play an important role in the response of the mediator endoplasmic reticulum to stress factors in the environment, especially as it may induce cell death.
The CRISPR screening technique used in this study can be used to study signaling pathways in other diseases. The team is currently using the same technology to study other neurodegenerative diseases caused by toxic protein deposition, including Huntington's disease, Parkinson's disease, and Alzheimer's disease. “I think this is a very exciting application for CRISPR screening, and it has only just begun,†said Dr. Michael Bassik, a senior author of the article and a professor of genetics at Stanford University.
4. The jet lag is very painful? The new drug that solves the trouble is coming soon.
In this era of globalization, cross-border travel has become the norm for business people. However, travel across time zones can disturb people's biological rhythms, making people feel less energetic during the day and difficult to sleep at night. Such a state is neither good for work nor good for health. A few days ago, Vanda Pharmaceuticals, a biotech company based in Washington, announced the good news – its new drug Hetlioz (Tasimelteon) achieved good results in a phase 3 clinical trial and was one step closer to approval. If all goes well, this new drug is expected to bring the gospel to millions of people around the world who are troubled by jet lag.
Hetlioz, who achieved excellent clinical results this time, is a melatonin receptor agonist. In the human body, melatonin activates its receptors to produce a sleep aid effect. Melatonin receptor agonists such as Hetlioz can help people sleep with a similar mechanism. In 2014, it was approved by the US FDA to treat “Non-24-hour sleep–wake disorderâ€. This is also a disorder in which the sleep cycle is disordered.
In the latest study, Vanda Pharmaceuticals set the jet lag to Heltioz's main direction. The efficacy of Hetlioz was confirmed in a phase 3 clinical trial involving 318 healthy volunteers. In the trial, these volunteers went to bed 8 hours in advance, artificially causing jet lag. Studies have shown that compared with the placebo-treated group, the total sleep duration of the experimental group of 20 mg Hetlioz increased by 60.3 minutes in 2/3 of the test days, which was significantly improved and reached a pre-set clinical setting. end. In addition, this new drug has achieved remarkable results in a number of secondary clinical endpoints - the volunteers in the experimental group improved their distress and improved their awareness during the day.
"We are very pleased with the results of this study. It shows that Heltioz can overcome the 8-hour biorhythm advance. This is a significant change, equivalent to flying from Los Angeles to London, flying from Washington, DC to Moscow, flying from Paris to Tokyo, or It is flying from London to Singapore,†said Dr. Mihael H. Polymeropoulos, President and CEO of Vanda Pharmaceuticals. “Hetlioz is expected to treat the time difference and provide significant benefits to millions of travelers.â€
Reference materials:
[1] Voyager Therapeutic's Parkinson's Trial Shows Positive Results
[2] Prevail Therapeutics Announces $75 Million Series A Financing to Advance Gene Therapies for Patients with Parkinson's and Other Neurodegenerative Diseases
[3] CRISPR reveals possible ALS drug target
[4] Vanda Pharmaceuticals' Hetlioz Shows Promise for Treating Jet Lag
Original Title: Recent Research Progress in the Field of Central Nervous System Diseases (No. 51)
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