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MIAMI—The possibility that Parkinson’s disease is a prion disorder has led investigators to begin clinical trials of drugs that target misfolded α-synuclein, according to an overview provided at the First Pan American Parkinson’s Disease and Movement Disorders Congress. Other potential therapies targeting the protein are in preclinical studies. 
Researchers are exploring four main treatment approaches: immunization, enhancing protein clearance, knocking down host α-synuclein, and inhibiting the prion conformer reaction, said C. Warren Olanow, MD, Professor and Chairman Emeritus of the Department of Neurology and Professor Emeritus of Neuroscience at the Mount Sinai School of Medicine in New York City.
Inhibiting the prion conformer reaction is the approach that Dr. Olanow believes is most likely to be effective. “But I also strongly believe every one of these approaches needs to be tested,” he said.
The Prion Hypothesis
A prion is an infectious particle composed solely of misfolded protein. It replicates by a process whereby the misfolded protein causes the native unfolded protein to misfold through a process called the prion conformer reaction. Misfolded proteins form beta-rich sheets that contain oligomers and rods, which are thought to be toxic, and polymerize to form aggregates. Prions can cause neurodegeneration and be transmitted from one species to another.
Researchers “have shown that α-synuclein can … replicate the prion biology,” and there are many reasons to suspect that α-synuclein “is integral to the pathology” of Parkinson’s disease, Dr. Olanow said. For instance, mutations as well as excess levels of wild type α-synuclein can cause Parkinson’s disease.
An α-synuclein monomer can misfold for various reasons, including a genetic mutation, a toxic or inflammatory event, or sporadically by chance. “As you get older, more and more proteins spontaneously misfold,” Dr. Olanow said.
The ubiquitin–proteasome and the autophagy–lysosomal systems normally clear misfolded proteins. If these systems cannot adequately clear the misfolded proteins—either because the clearance systems are not working enough or too much protein is being formed—the aggregates accumulate and can block the clearance systems, creating a vicious cycle that leads to further accumulation of misfolded α-synuclein, he said.
Removing Toxic Protein
One therapeutic approach based on the prion hypothesis involves targeting and removing toxic α-synuclein species by way of active or passive immunization.
Tran et al reported that α-synuclein immunotherapy blocks propagation of misfolded α-synuclein and neurodegeneration in an animal model. Several immune therapies are currently being tested in clinical trials. Trials by Prothena and Biogen are using passive immunization (ie, administering monoclonal antibodies targeted to a specific α-synuclein species), whereas trials by AFFiRiS are using active immunization (ie, stimulating the immune system to produce antibodies). “The good news so far is that there has been no major safety issue or tolerability concern,” Dr. Olanow said. “There have not, however, been long-term safety or efficacy data as yet.”
Challenges in immunization trials include uncertainty about whether antibodies reach the brain and which α-synuclein species should be targeted. Some α-synuclein species may be protective, said Dr. Olanow. “By no means are we assured that we are targeting exactly what we want.”
Enhancing Protein Clearance
Another approach entails facilitating protein clearance through the ubiquitin–proteasome system or the autophagy–lysosomal system, which are defective in Parkinson’s disease. Drugs that activate or enhance glucocerebrosidase (GCase) activity and promote lysosomal function have attracted particular attention.
Mutations in GBA, the gene that encodes for GCase, can cause Gaucher disease with features of parkinsonism, and as many as 10% of patients with Parkinson’s disease have GBA mutations. GCase levels are reduced by as much as 50% in patients with Parkinson’s disease.
When GCase is decreased, lysosomal function is reduced, and α-synuclein consequently increases. Likewise, overexpression of GCase can reduce α-synuclein, and overexpression of α-synuclein reduces GCase. Ambroxol, a molecular chaperone that has been shown experimentally to increase GCase levels, has entered clinical trials. More robust GCase-promoting agents are in development and will enter clinical trials in the near future, Dr. Olanow said.
Removing Host Protein
A third approach involves knockdown of host α-synuclein with, for example, iRNAs and antisense oligonucleotides directed at α-synuclein production or with chemicals that bind to α-synuclein. “If you knock down host α-synuclein, then you do not have any to participate in that prion conformer reaction,” he said.
Investigators are using high-throughput screening to identify chemicals that bind to α-synuclein. However, α-synuclein’s physiologic role is not completely known, nor is what happens if the protein is lowered in humans, or by how much α-synuclein would need to be reduced to provide benefit.
Blocking the Prion Conformer Reaction
If neurologists could block the prion conformer reaction, it might be the best approach. “We could stop the formation of misfolded protein, and we could preserve the host α-synuclein and its physiologic function,” Dr. Olanow said. “The problem is that we do not know the precise mechanism underlying the presumed templating in Parkinson’s disease.”
Any attempts to treat Parkinson’s disease with therapies aimed at α-synuclein likely should be initiated as early as possible in the disease process, and biomarkers will be crucial to initiating timely treatment, Dr. Olanow noted.
“This, to me, is one of the most exciting periods in Parkinson’s therapeutics,” he said. Over the next decade, neurologists may see “a revolution of therapies directed at α-synuclein that may ultimately prove to be disease modifying and fundamentally change the nature of the disease.”
—Jake Remaly
Suggested Reading
Dehay B, Bourdenx M, Gorry P, et al. Targeting α-synuclein for treating Parkinson’s disease: mechanistic and therapeutic considerations. Lancet Neurol. 2015;14(8):855-866.
Olanow CW, Kordower JH. Targeting α-synuclein as a therapy for Parkinson’s disease: The battle begins. Mov Disord. 2017;32(2):203-207.
Olanow CW, Brundin P. Parkinson’s disease and alpha synuclein: is Parkinson’s disease a prion-like disorder? Mov Disord. 2013;28(1):31-40.
Schenk DB, Koller M, Ness DK, et al. First-in-human assessment of PRX002, an anti-α-synuclein monoclonal antibody, in healthy volunteers. Mov Disord. 2017;32(2):211-218.
Tran HT, Chung CH, Iba M, et al. α-synuclein immunotherapy blocks uptake and templated propagation of misfolded α-synuclein and neurodegeneration. Cell Rep. 2014;7(6):2054-2065.
MIAMI—The possibility that Parkinson’s disease is a prion disorder has led investigators to begin clinical trials of drugs that target misfolded α-synuclein, according to an overview provided at the First Pan American Parkinson’s Disease and Movement Disorders Congress. Other potential therapies targeting the protein are in preclinical studies.
Researchers are exploring four main treatment approaches: immunization, enhancing protein clearance, knocking down host α-synuclein, and inhibiting the prion conformer reaction, said C. Warren Olanow, MD, Professor and Chairman Emeritus of the Department of Neurology and Professor Emeritus of Neuroscience at the Mount Sinai School of Medicine in New York City.
Inhibiting the prion conformer reaction is the approach that Dr. Olanow believes is most likely to be effective. “But I also strongly believe every one of these approaches needs to be tested,” he said.
The Prion Hypothesis
A prion is an infectious particle composed solely of misfolded protein. It replicates by a process whereby the misfolded protein causes the native unfolded protein to misfold through a process called the prion conformer reaction. Misfolded proteins form beta-rich sheets that contain oligomers and rods, which are thought to be toxic, and polymerize to form aggregates. Prions can cause neurodegeneration and be transmitted from one species to another.
Researchers “have shown that α-synuclein can … replicate the prion biology,” and there are many reasons to suspect that α-synuclein “is integral to the pathology” of Parkinson’s disease, Dr. Olanow said. For instance, mutations as well as excess levels of wild type α-synuclein can cause Parkinson’s disease.
An α-synuclein monomer can misfold for various reasons, including a genetic mutation, a toxic or inflammatory event, or sporadically by chance. “As you get older, more and more proteins spontaneously misfold,” Dr. Olanow said.
The ubiquitin–proteasome and the autophagy–lysosomal systems normally clear misfolded proteins. If these systems cannot adequately clear the misfolded proteins—either because the clearance systems are not working enough or too much protein is being formed—the aggregates accumulate and can block the clearance systems, creating a vicious cycle that leads to further accumulation of misfolded α-synuclein, he said.
Removing Toxic Protein
One therapeutic approach based on the prion hypothesis involves targeting and removing toxic α-synuclein species by way of active or passive immunization.
Tran et al reported that α-synuclein immunotherapy blocks propagation of misfolded α-synuclein and neurodegeneration in an animal model. Several immune therapies are currently being tested in clinical trials. Trials by Prothena and Biogen are using passive immunization (ie, administering monoclonal antibodies targeted to a specific α-synuclein species), whereas trials by AFFiRiS are using active immunization (ie, stimulating the immune system to produce antibodies). “The good news so far is that there has been no major safety issue or tolerability concern,” Dr. Olanow said. “There have not, however, been long-term safety or efficacy data as yet.”
Challenges in immunization trials include uncertainty about whether antibodies reach the brain and which α-synuclein species should be targeted. Some α-synuclein species may be protective, said Dr. Olanow. “By no means are we assured that we are targeting exactly what we want.”
Enhancing Protein Clearance
Another approach entails facilitating protein clearance through the ubiquitin–proteasome system or the autophagy–lysosomal system, which are defective in Parkinson’s disease. Drugs that activate or enhance glucocerebrosidase (GCase) activity and promote lysosomal function have attracted particular attention.
Mutations in GBA, the gene that encodes for GCase, can cause Gaucher disease with features of parkinsonism, and as many as 10% of patients with Parkinson’s disease have GBA mutations. GCase levels are reduced by as much as 50% in patients with Parkinson’s disease.
When GCase is decreased, lysosomal function is reduced, and α-synuclein consequently increases. Likewise, overexpression of GCase can reduce α-synuclein, and overexpression of α-synuclein reduces GCase. Ambroxol, a molecular chaperone that has been shown experimentally to increase GCase levels, has entered clinical trials. More robust GCase-promoting agents are in development and will enter clinical trials in the near future, Dr. Olanow said.
Removing Host Protein
A third approach involves knockdown of host α-synuclein with, for example, iRNAs and antisense oligonucleotides directed at α-synuclein production or with chemicals that bind to α-synuclein. “If you knock down host α-synuclein, then you do not have any to participate in that prion conformer reaction,” he said.
Investigators are using high-throughput screening to identify chemicals that bind to α-synuclein. However, α-synuclein’s physiologic role is not completely known, nor is what happens if the protein is lowered in humans, or by how much α-synuclein would need to be reduced to provide benefit.
Blocking the Prion Conformer Reaction
If neurologists could block the prion conformer reaction, it might be the best approach. “We could stop the formation of misfolded protein, and we could preserve the host α-synuclein and its physiologic function,” Dr. Olanow said. “The problem is that we do not know the precise mechanism underlying the presumed templating in Parkinson’s disease.”
Any attempts to treat Parkinson’s disease with therapies aimed at α-synuclein likely should be initiated as early as possible in the disease process, and biomarkers will be crucial to initiating timely treatment, Dr. Olanow noted.
“This, to me, is one of the most exciting periods in Parkinson’s therapeutics,” he said. Over the next decade, neurologists may see “a revolution of therapies directed at α-synuclein that may ultimately prove to be disease modifying and fundamentally change the nature of the disease.”
—Jake Remaly
Suggested Reading
Dehay B, Bourdenx M, Gorry P, et al. Targeting α-synuclein for treating Parkinson’s disease: mechanistic and therapeutic considerations. Lancet Neurol. 2015;14(8):855-866.
Olanow CW, Kordower JH. Targeting α-synuclein as a therapy for Parkinson’s disease: The battle begins. Mov Disord. 2017;32(2):203-207.
Olanow CW, Brundin P. Parkinson’s disease and alpha synuclein: is Parkinson’s disease a prion-like disorder? Mov Disord. 2013;28(1):31-40.
Schenk DB, Koller M, Ness DK, et al. First-in-human assessment of PRX002, an anti-α-synuclein monoclonal antibody, in healthy volunteers. Mov Disord. 2017;32(2):211-218.
Tran HT, Chung CH, Iba M, et al. α-synuclein immunotherapy blocks uptake and templated propagation of misfolded α-synuclein and neurodegeneration. Cell Rep. 2014;7(6):2054-2065.
MIAMI—The possibility that Parkinson’s disease is a prion disorder has led investigators to begin clinical trials of drugs that target misfolded α-synuclein, according to an overview provided at the First Pan American Parkinson’s Disease and Movement Disorders Congress. Other potential therapies targeting the protein are in preclinical studies.
Researchers are exploring four main treatment approaches: immunization, enhancing protein clearance, knocking down host α-synuclein, and inhibiting the prion conformer reaction, said C. Warren Olanow, MD, Professor and Chairman Emeritus of the Department of Neurology and Professor Emeritus of Neuroscience at the Mount Sinai School of Medicine in New York City.
Inhibiting the prion conformer reaction is the approach that Dr. Olanow believes is most likely to be effective. “But I also strongly believe every one of these approaches needs to be tested,” he said.
The Prion Hypothesis
A prion is an infectious particle composed solely of misfolded protein. It replicates by a process whereby the misfolded protein causes the native unfolded protein to misfold through a process called the prion conformer reaction. Misfolded proteins form beta-rich sheets that contain oligomers and rods, which are thought to be toxic, and polymerize to form aggregates. Prions can cause neurodegeneration and be transmitted from one species to another.
Researchers “have shown that α-synuclein can … replicate the prion biology,” and there are many reasons to suspect that α-synuclein “is integral to the pathology” of Parkinson’s disease, Dr. Olanow said. For instance, mutations as well as excess levels of wild type α-synuclein can cause Parkinson’s disease.
An α-synuclein monomer can misfold for various reasons, including a genetic mutation, a toxic or inflammatory event, or sporadically by chance. “As you get older, more and more proteins spontaneously misfold,” Dr. Olanow said.
The ubiquitin–proteasome and the autophagy–lysosomal systems normally clear misfolded proteins. If these systems cannot adequately clear the misfolded proteins—either because the clearance systems are not working enough or too much protein is being formed—the aggregates accumulate and can block the clearance systems, creating a vicious cycle that leads to further accumulation of misfolded α-synuclein, he said.
Removing Toxic Protein
One therapeutic approach based on the prion hypothesis involves targeting and removing toxic α-synuclein species by way of active or passive immunization.
Tran et al reported that α-synuclein immunotherapy blocks propagation of misfolded α-synuclein and neurodegeneration in an animal model. Several immune therapies are currently being tested in clinical trials. Trials by Prothena and Biogen are using passive immunization (ie, administering monoclonal antibodies targeted to a specific α-synuclein species), whereas trials by AFFiRiS are using active immunization (ie, stimulating the immune system to produce antibodies). “The good news so far is that there has been no major safety issue or tolerability concern,” Dr. Olanow said. “There have not, however, been long-term safety or efficacy data as yet.”
Challenges in immunization trials include uncertainty about whether antibodies reach the brain and which α-synuclein species should be targeted. Some α-synuclein species may be protective, said Dr. Olanow. “By no means are we assured that we are targeting exactly what we want.”
Enhancing Protein Clearance
Another approach entails facilitating protein clearance through the ubiquitin–proteasome system or the autophagy–lysosomal system, which are defective in Parkinson’s disease. Drugs that activate or enhance glucocerebrosidase (GCase) activity and promote lysosomal function have attracted particular attention.
Mutations in GBA, the gene that encodes for GCase, can cause Gaucher disease with features of parkinsonism, and as many as 10% of patients with Parkinson’s disease have GBA mutations. GCase levels are reduced by as much as 50% in patients with Parkinson’s disease.
When GCase is decreased, lysosomal function is reduced, and α-synuclein consequently increases. Likewise, overexpression of GCase can reduce α-synuclein, and overexpression of α-synuclein reduces GCase. Ambroxol, a molecular chaperone that has been shown experimentally to increase GCase levels, has entered clinical trials. More robust GCase-promoting agents are in development and will enter clinical trials in the near future, Dr. Olanow said.
Removing Host Protein
A third approach involves knockdown of host α-synuclein with, for example, iRNAs and antisense oligonucleotides directed at α-synuclein production or with chemicals that bind to α-synuclein. “If you knock down host α-synuclein, then you do not have any to participate in that prion conformer reaction,” he said.
Investigators are using high-throughput screening to identify chemicals that bind to α-synuclein. However, α-synuclein’s physiologic role is not completely known, nor is what happens if the protein is lowered in humans, or by how much α-synuclein would need to be reduced to provide benefit.
Blocking the Prion Conformer Reaction
If neurologists could block the prion conformer reaction, it might be the best approach. “We could stop the formation of misfolded protein, and we could preserve the host α-synuclein and its physiologic function,” Dr. Olanow said. “The problem is that we do not know the precise mechanism underlying the presumed templating in Parkinson’s disease.”
Any attempts to treat Parkinson’s disease with therapies aimed at α-synuclein likely should be initiated as early as possible in the disease process, and biomarkers will be crucial to initiating timely treatment, Dr. Olanow noted.
“This, to me, is one of the most exciting periods in Parkinson’s therapeutics,” he said. Over the next decade, neurologists may see “a revolution of therapies directed at α-synuclein that may ultimately prove to be disease modifying and fundamentally change the nature of the disease.”
—Jake Remaly
Suggested Reading
Dehay B, Bourdenx M, Gorry P, et al. Targeting α-synuclein for treating Parkinson’s disease: mechanistic and therapeutic considerations. Lancet Neurol. 2015;14(8):855-866.
Olanow CW, Kordower JH. Targeting α-synuclein as a therapy for Parkinson’s disease: The battle begins. Mov Disord. 2017;32(2):203-207.
Olanow CW, Brundin P. Parkinson’s disease and alpha synuclein: is Parkinson’s disease a prion-like disorder? Mov Disord. 2013;28(1):31-40.
Schenk DB, Koller M, Ness DK, et al. First-in-human assessment of PRX002, an anti-α-synuclein monoclonal antibody, in healthy volunteers. Mov Disord. 2017;32(2):211-218.
Tran HT, Chung CH, Iba M, et al. α-synuclein immunotherapy blocks uptake and templated propagation of misfolded α-synuclein and neurodegeneration. Cell Rep. 2014;7(6):2054-2065.