-
Categories
-
Pharmaceutical Intermediates
-
Active Pharmaceutical Ingredients
-
Food Additives
- Industrial Coatings
- Agrochemicals
- Dyes and Pigments
- Surfactant
- Flavors and Fragrances
- Chemical Reagents
- Catalyst and Auxiliary
- Natural Products
- Inorganic Chemistry
-
Organic Chemistry
-
Biochemical Engineering
- Analytical Chemistry
-
Cosmetic Ingredient
- Water Treatment Chemical
-
Pharmaceutical Intermediates
Promotion
ECHEMI Mall
Wholesale
Weekly Price
Exhibition
News
-
Trade Service
▎WuXi AppTec content team editor
The original drugs used to treat Parkinson's disease were antimuscarinoids (such as belladonna alkaloids), in the 40s of the last century, the artificial synthesis of anticholinergic drugs made a breakthrough, trihexyphenidyl (trihexyphenidyl) was approved for marketing in 1949, and is still used as a classic drug for the treatment of Parkinson's disease
.
In the second half of the 20th century, an in-depth understanding of the pathological mechanisms of Parkinson's disease laid the foundation for the birth of more drugs, especially dopamine-based drug development
.
To this day, levodopa remains the core treatment for Parkinson's disease, and for more than 60 years, successful drug development in the field of Parkinson's disease has focused on increasing the bioavailability of levodopa or using dopamine receptor agonists to mimic its action
.
Since the approval of the first treatment for Parkinson's disease, there has been a better understanding of the neurobiological mechanisms, genetics and environmental factors behind Parkinson's disease, but the development of new drugs for Parkinson's disease is still difficult, and pharmaceutical companies lack good targets when developing new drugs due to the lack of available biomarkers
。 In addition, there are many mysteries to be solved about the genetic basis of Parkinson's disease, and solving these challenges is key
to advancing research and drug development for the disease.
1.
Development strategies for Parkinson's disease therapeutics – innovative targets
In recent years, there has been a deeper understanding of the connection between brain, biology and genetics, and some of the links to Parkinson's disease have been identified Mutations in risk-related genes, such as the SNCA gene encoding α α-synuclein, LRRK2 (encoding leucine-rich repeat kinase 2), and the GBA gene encoding lysosomal enzyme β-glucocerebrosidase, will greatly increase the risk
of Parkinson's disease.
α-synuclein is a protein composed of 140 amino acids that is thought to be involved in the regulation of synaptic activity and intracellular transport, and the Lewy body structure closely related to Parkinson's disease is formed
by abnormal fibrotic aggregation of α-synuclein.
For patients, lowering levels of this protein can be expected to delay or stop the progression
of Parkinson's disease.
Image credit: 123RF
LRRK2 is a member of the ROC (ras-of-complex) protein family, and studies have shown a correlation
between upregulation of LRRK2 kinase activity and Parkinson's disease.
In addition, the researchers found that LRRK2 gene mutations were associated
with Parkinson's disease in 7 Parkinson's disease families.
Dr.
Stacy Henry, a senior scientist at Denali Therapeutics, said in an interview that the company's work on Parkinson's disease drugs for LRRK2 is based on the interaction
between LRRK2 and lysosomal dysfunction.
Lysosomes use digestive enzymes to break down other cellular components, and when lysosomes don't function properly, abnormal lipid buildup
occurs in the brain.
"Preclinical data suggest that LRRK2 is a bit of a central node, contributing to the onset
of Parkinson's disease.
I think this is a huge step forward for us to understand the physiological activity of this protein and how it actually causes Parkinson's disease," Dr.
Henry said
.
In addition to the risk genes mentioned above, mutations in GBA, the gene encoding lysosomal enzyme β-glucocerebrosidase, have also been found to be associated with Parkinson's disease, and patients with GBA mutations have similar phenotypes to idiopathic patients, but with earlier age of onset and faster
cognitive decline 。 Previous studies have shown that GBA mutation causes β-glucocerebrosidase to remain in the endoplasmic reticulum, reducing the concentration of this protein in lysosomes.
In addition, the decreased activity of mutant β-glucocerebrosidase leads to an imbalance of the homeostasis of glycosphingolipids in cells, further causing lysosomal dysfunction, abnormal vesicle trafficking, and aggregation of α-synuclein, all of which may be associated with Parkinson's disease, making GBA a candidate target for drug development for Parkinson's disease
.
Dr.
Todd Carter, senior vice president of research at Voyager Therapeutics, mentioned in an interview that the company's preclinical gene replacement therapy targets GBA, a gene genetically linked to a 20-fold increased risk of Parkinson's disease, and the target can be tested by cerebrospinal fluid to determine whether the treatment is effective without waiting for the results of
cognitive tests or motor function analysis.
Obviously, the discovery of new targets is of great significance
for the upgrading and innovation of Parkinson's disease-related therapies.
Image source: 123RF
Speaking about the development of innovative therapies for Parkinson's disease, Dr.
Todd Sherer, Executive Vice President of Research Strategy at the Michael J.
Fox Parkinson's Research Foundation, and Andrew Siderowf, Professor of Neurology at the Perelman School of Medicine at the University of Pennsylvania, shared their outlook at the recent WuXi AppTec Health Industry Forum, noting that over the past decade, A major advance in Parkinson's disease has been the discovery of potentially disease-causing accessible targets, making it possible
to develop therapies against these targets.
Related reading: Parkinson's disease is not just "hand trembling", experts teach you to correctly understand Parkinson's disease 2.
Current development strategy for Parkinson's disease
treatment drugs - biomarkers
The discovery of biomarkers has changed treatment strategies for many intractable diseases, such as ROS1/HER2-positive cancer, and researchers and healthcare workers can better understand which patients are more likely to benefit
from therapies through biomarker testing.
But research on Parkinson's disease biomarkers is far less rapid than cancer, and as experts say in an interview with Endpoints News, "Parkinson's disease biomarkers are still hard to find, making them the holy grail
of this research.
"
Dr.
Patrik Brundin, head of movement disorder research and research and development at Roche, said that when he began working in the field of Parkinson's disease more than 40 years ago, the dominant position in the scientific community was that Parkinson's disease began the day
when patients went to a neurologist and were diagnosed.
We now know that the disease began 10 to 20 years before that
.
Experts further pointed out in interviews that Parkinson's disease is a very variable and difficult to predict
.
For this reason, if genetic tools can be used to explore biomarkers and other characteristics related to different stages of the disease, it can be expected to be managed before the onset of the disease and obtain the best results
.
In addition to assisting in diagnosis, preliminary research suggests that certain biomarkers are promising for evaluating potential drugs and guiding clinical trials
.
Regarding the importance of biomarkers for drug clinical trials, experts bluntly said in an interview that "if you can't effectively and objectively detect changes in signs, it is very difficult
to get a drug into clinical trials.
" "For diseases with highly heterogeneous clinical manifestations such as Parkinson's disease, if reliable and effective biomarkers are found and further clinically classified accordingly, it is expected to screen out the potential benefit of certain therapies and achieve precise treatment
.
"
123RF Alzheimer's
disease research took 20 to 30 years to identify a biomarker, and no one knows exactly how much time we need to find the ideal marker for Parkinson's disease
.
However, it is foreseeable that its emergence will inevitably change the existing Parkinson's disease treatment pattern, making early diagnosis and early treatment and individualized precision treatment possible
.
Looking ahead, the development of Parkinson's disease drugs still faces some challenges
.
First, industry experts still debate the best way to conduct clinical trials in patients with Parkinson's disease: on the one hand, recruiting patients after they have developed physical symptoms can be risky; On the other hand, early patient enrollment means that clinical trial researchers may have to wait years, or even decades, for trial results
.
Second, the goal of Parkinson's disease diagnostic research is to one day be able to diagnose patients earlier, but this begs the question: Do people want to know that they will develop Parkinson's disease 10 to 15 years from now? Finally, we don't know enough about the genetic basis, etiology, and pathological process of Parkinson's disease at this stage, and as Dr.
Brundin said in an interview, in his opinion, researchers only know about about 25%
of the genetic basis of the disease (i.
e.
, what causes Parkinson's disease, or what makes some patients more severe or mild).
Despite these difficulties, the search for Parkinson's disease continues
.
Scientists are also hoping to develop combination therapies to better treat Parkinson's disease, and given the number of clinical targets and the heterogeneity of Parkinson's disease, they think a more effective treatment for Parkinson's disease may be a combination therapy
.
Dr.
Tien Dam, head of Biogen's Parkinson's disease research and development program, is a proponent of this view, arguing that "combination therapies are likely to benefit patients, especially if a patient has multiple dysfunctional genes or proteins, such as α-synuclein and LRRK2
.
" "
The road is obstructive and long, and the line is coming
.
There is still a lot to be done to develop new drugs for Parkinson's disease, but experts are optimistic about the next decade
.
As Dr.
Mudra Kapoor, vice president of AbbVie, said in an interview, "Witnessing the current speed of scientific innovation and knowledge transfer, I believe we have access to treatments that improve Parkinson's disease
.
" "
WuXi AppTec provides integrated, end-to-end new drug development and manufacturing services to the global biopharmaceutical industry, covering chemical drug development and manufacturing, biological research, preclinical testing and clinical trial development, cell and gene therapy development, testing and manufacturing
.
If you have related business needs, please click the picture below to fill in the specific information
.
▲If you have any business needs, please long press to scan the QR code above, or
For the pharmaceutical industry, the research and development of new drugs for Parkinson's disease (PD) has always been a difficult "hard bone", although pharmaceutical companies have invested a lot of money and manpower over the years, but the clinical trials of new drugs for Parkinson's disease are often unsatisfactory
.
At present, most of the treatment drugs for Parkinson's disease are "old drugs"
approved for marketing decades ago.
Recently, pharmaceutical industry media Endpoints News invited several industry experts and external observers to discuss the bottlenecks that restrict the development of Parkinson's disease drugs and the way to
break the situation in the future.
In today's article, WuXi AppTec's content team reviewed the research and drug development process of Parkinson's disease, and combined with the content of this discussion, it analyzes the current challenges and future development trends
of new drugs for Parkinson's disease.
Parkinson's disease is an ancient neurodegenerative disease that has a history behind it dating back two centuries
.
In 1817, Dr.
James Parkinson published an essay entitled "An Essay on the Shaking Palsy," which first described and documented the disease
.
In honor, the disease was named
after Dr.
Parkinson's last name.
As the global ageing trend and the incidence of Parkinson's disease continue to rise globally, the medical, social and economic problems caused by the high incidence of the disease highlight the urgent need
for new drugs and treatments.
Thanks to innovative research methods, we now have a better understanding of Parkinson's disease, but researchers have not yet found an effective cure
.
Image source: 123RF
Drug development for Parkinson's disease
The original drugs used to treat Parkinson's disease were antimuscarinoids (such as belladonna alkaloids), in the 40s of the last century, the artificial synthesis of anticholinergic drugs made a breakthrough, trihexyphenidyl (trihexyphenidyl) was approved for marketing in 1949, and is still used as a classic drug for the treatment of Parkinson's disease
.
In the second half of the 20th century, an in-depth understanding of the pathological mechanisms of Parkinson's disease laid the foundation for the birth of more drugs, especially dopamine-based drug development
.
To this day, levodopa remains the core treatment for Parkinson's disease, and for more than 60 years, successful drug development in the field of Parkinson's disease has focused on increasing the bioavailability of levodopa or using dopamine receptor agonists to mimic its action
.
Since the approval of the first treatment for Parkinson's disease, there has been a better understanding of the neurobiological mechanisms, genetics and environmental factors behind Parkinson's disease, but the development of new drugs for Parkinson's disease is still difficult, and pharmaceutical companies lack good targets when developing new drugs due to the lack of available biomarkers
。 In addition, there are many mysteries to be solved about the genetic basis of Parkinson's disease, and solving these challenges is key
to advancing research and drug development for the disease.
1.
Development strategies for Parkinson's disease therapeutics – innovative targets
In recent years, there has been a deeper understanding of the connection between brain, biology and genetics, and some of the links to Parkinson's disease have been identified Mutations in risk-related genes, such as the SNCA gene encoding α α-synuclein, LRRK2 (encoding leucine-rich repeat kinase 2), and the GBA gene encoding lysosomal enzyme β-glucocerebrosidase, will greatly increase the risk
of Parkinson's disease.
α-synuclein is a protein composed of 140 amino acids that is thought to be involved in the regulation of synaptic activity and intracellular transport, and the Lewy body structure closely related to Parkinson's disease is formed
by abnormal fibrotic aggregation of α-synuclein.
For patients, lowering levels of this protein can be expected to delay or stop the progression
of Parkinson's disease.
Image credit: 123RF
LRRK2 is a member of the ROC (ras-of-complex) protein family, and studies have shown a correlation
between upregulation of LRRK2 kinase activity and Parkinson's disease.
In addition, the researchers found that LRRK2 gene mutations were associated
with Parkinson's disease in 7 Parkinson's disease families.
Dr.
Stacy Henry, a senior scientist at Denali Therapeutics, said in an interview that the company's work on Parkinson's disease drugs for LRRK2 is based on the interaction
between LRRK2 and lysosomal dysfunction.
Lysosomes use digestive enzymes to break down other cellular components, and when lysosomes don't function properly, abnormal lipid buildup
occurs in the brain.
"Preclinical data suggest that LRRK2 is a bit of a central node, contributing to the onset
of Parkinson's disease.
I think this is a huge step forward for us to understand the physiological activity of this protein and how it actually causes Parkinson's disease," Dr.
Henry said
.
In addition to the risk genes mentioned above, mutations in GBA, the gene encoding lysosomal enzyme β-glucocerebrosidase, have also been found to be associated with Parkinson's disease, and patients with GBA mutations have similar phenotypes to idiopathic patients, but with earlier age of onset and faster
cognitive decline 。 Previous studies have shown that GBA mutation causes β-glucocerebrosidase to remain in the endoplasmic reticulum, reducing the concentration of this protein in lysosomes.
In addition, the decreased activity of mutant β-glucocerebrosidase leads to an imbalance of the homeostasis of glycosphingolipids in cells, further causing lysosomal dysfunction, abnormal vesicle trafficking, and aggregation of α-synuclein, all of which may be associated with Parkinson's disease, making GBA a candidate target for drug development for Parkinson's disease
.
Dr.
Todd Carter, senior vice president of research at Voyager Therapeutics, mentioned in an interview that the company's preclinical gene replacement therapy targets GBA, a gene genetically linked to a 20-fold increased risk of Parkinson's disease, and the target can be tested by cerebrospinal fluid to determine whether the treatment is effective without waiting for the results of
cognitive tests or motor function analysis.
Obviously, the discovery of new targets is of great significance
for the upgrading and innovation of Parkinson's disease-related therapies.
Image source: 123RF
Speaking about the development of innovative therapies for Parkinson's disease, Dr.
Todd Sherer, Executive Vice President of Research Strategy at the Michael J.
Fox Parkinson's Research Foundation, and Andrew Siderowf, Professor of Neurology at the Perelman School of Medicine at the University of Pennsylvania, shared their outlook at the recent WuXi AppTec Health Industry Forum, noting that over the past decade, A major advance in Parkinson's disease has been the discovery of potentially disease-causing accessible targets, making it possible
to develop therapies against these targets.
Related reading: Parkinson's disease is not just "hand trembling", experts teach you to correctly understand Parkinson's disease 2.
Current development strategy for Parkinson's disease
treatment drugs - biomarkers
The discovery of biomarkers has changed treatment strategies for many intractable diseases, such as ROS1/HER2-positive cancer, and researchers and healthcare workers can better understand which patients are more likely to benefit
from therapies through biomarker testing.
But research on Parkinson's disease biomarkers is far less rapid than cancer, and as experts say in an interview with Endpoints News, "Parkinson's disease biomarkers are still hard to find, making them the holy grail
of this research.
"
Dr.
Patrik Brundin, head of movement disorder research and research and development at Roche, said that when he began working in the field of Parkinson's disease more than 40 years ago, the dominant position in the scientific community was that Parkinson's disease began the day
when patients went to a neurologist and were diagnosed.
We now know that the disease began 10 to 20 years before that
.
Experts further pointed out in interviews that Parkinson's disease is a very variable and difficult to predict
.
For this reason, if genetic tools can be used to explore biomarkers and other characteristics related to different stages of the disease, it can be expected to be managed before the onset of the disease and obtain the best results
.
In addition to assisting in diagnosis, preliminary research suggests that certain biomarkers are promising for evaluating potential drugs and guiding clinical trials
.
Regarding the importance of biomarkers for drug clinical trials, experts bluntly said in an interview that "if you can't effectively and objectively detect changes in signs, it is very difficult
to get a drug into clinical trials.
" "For diseases with highly heterogeneous clinical manifestations such as Parkinson's disease, if reliable and effective biomarkers are found and further clinically classified accordingly, it is expected to screen out the potential benefit of certain therapies and achieve precise treatment
.
"
123RF Alzheimer's
disease research took 20 to 30 years to identify a biomarker, and no one knows exactly how much time we need to find the ideal marker for Parkinson's disease
.
However, it is foreseeable that its emergence will inevitably change the existing Parkinson's disease treatment pattern, making early diagnosis and early treatment and individualized precision treatment possible
.
epilogue
Looking ahead, the development of Parkinson's disease drugs still faces some challenges
.
First, industry experts still debate the best way to conduct clinical trials in patients with Parkinson's disease: on the one hand, recruiting patients after they have developed physical symptoms can be risky; On the other hand, early patient enrollment means that clinical trial researchers may have to wait years, or even decades, for trial results
.
Second, the goal of Parkinson's disease diagnostic research is to one day be able to diagnose patients earlier, but this begs the question: Do people want to know that they will develop Parkinson's disease 10 to 15 years from now? Finally, we don't know enough about the genetic basis, etiology, and pathological process of Parkinson's disease at this stage, and as Dr.
Brundin said in an interview, in his opinion, researchers only know about about 25%
of the genetic basis of the disease (i.
e.
, what causes Parkinson's disease, or what makes some patients more severe or mild).
Despite these difficulties, the search for Parkinson's disease continues
.
Scientists are also hoping to develop combination therapies to better treat Parkinson's disease, and given the number of clinical targets and the heterogeneity of Parkinson's disease, they think a more effective treatment for Parkinson's disease may be a combination therapy
.
Dr.
Tien Dam, head of Biogen's Parkinson's disease research and development program, is a proponent of this view, arguing that "combination therapies are likely to benefit patients, especially if a patient has multiple dysfunctional genes or proteins, such as α-synuclein and LRRK2
.
" "
The road is obstructive and long, and the line is coming
.
There is still a lot to be done to develop new drugs for Parkinson's disease, but experts are optimistic about the next decade
.
As Dr.
Mudra Kapoor, vice president of AbbVie, said in an interview, "Witnessing the current speed of scientific innovation and knowledge transfer, I believe we have access to treatments that improve Parkinson's disease
.
" "
WuXi AppTec provides integrated, end-to-end new drug development and manufacturing services to the global biopharmaceutical industry, covering chemical drug development and manufacturing, biological research, preclinical testing and clinical trial development, cell and gene therapy development, testing and manufacturing
.
If you have related business needs, please click the picture below to fill in the specific information
.
▲If you have any business needs, please long press to scan the QR code above, or
