Who will conquer Parkinson's?

In the second half of the 20th century, with the in-depth understanding of the pathological mechanism of Parkinson's disease, a variety of therapeutic drugs came out one after another, especially the development of new drugs based on the dopaminergic system.

However, the development of new drugs for Parkinson's disease has always been a difficult "hard bone". To this day, levodopa remains the core drug for the treatment of Parkinson's disease. Moreover, existing drugs to treat Parkinson's disease do not delay or change the course of the disease.

Because of this, people with lofty ideals are committed to promoting the disease research and new drug development of Parkinson's disease and solving the many mysteries of Parkinson's disease.

Based on the search and collation of ClinicalTrials.gov, the company's official website and public information, the authors found that there are currently about 50 new drugs under development for Parkinson's disease.

Happily, in addition to the development of new drugs that act on the dopaminergic system, new therapeutic mechanisms have emerged, making the development of new therapies possible.

1. α-synuclein-targeted therapy

The deposition of intracellular misfolded α-synuclein in the central nervous system and peripheral nervous system leads to the occurrence of synucleinopathies such as Parkinson's disease, Lewy body dementia and multiple system atrophy, and inhibition of α-synuclein may slow the progression of Parkinson's disease.

At this stage, the mechanism of action of drugs targeting α-synuclein mainly includes inhibiting the formation of α-synuclein oligomers, promoting the degradation and clearance of α-synuclein, and reducing cytotoxicity caused by α-synuclein.

According to the authors, 7 anti-Parkinson's disease drugs developed by α-synuclein have entered clinical trials.

2. Gene therapy

In recent years, gene therapy programs for central nervous system diseases have begun to rise, although the pathogenesis of Parkinson's disease is not clear, but environmental, genetic and other factors may be closely related to its pathogenesis.

Some genes have been found to be associated with the pathogenesis of PD, Parkinson's disease gene therapy drugs have received attention, and a number of gene therapy drugs have entered the clinical research stage. According to the author's search, there are currently 5 gene therapy drugs involved, which can be divided into three categories according to the mechanism of action:

• Nutritional factors, gene replacement therapy for key genes in dopamine synthesis or key enzymes in disease metabolic pathways, gene expression regulation.

Nutritional factors that express neurotrophic and regenerative factors to improve neuronal survival. For example, AAV2-GDNF, a neurotrophic factor GDNF derived from glial cell lines, is beneficial to support the survival of dopaminergic brain neurons, relieve symptoms and improve disease progression by nourishing dopamine neuronal cells.

Gene replacement therapy for key genes in dopamine synthesis or key enzymes in disease metabolic pathways, such as VY-AADC02, VY-AADC01, PR001.

Aromatic L-amino acid decarboxylase (AADC) is a key enzyme in dopamine synthesis, and its activity decreases with the degeneration of the substantia nigra in patients with Parkinson's disease, resulting in a decrease in endogenous dopamine production and a decrease in exogenous transformation. The two drug candidates, VY-AADC01 and VY-AADC02, consisting of adeno-associated virus-2 (AAV2) encoding the AADC transgene, are designed to deliver the AADC gene directly to the putamen where the dopamine receptor is located, bypassing the substantia nigra neurons and causing the putamen to express AADC, the therapy may permanently enhance the conversion of endogenous and exogenous levodopa to dopamine.

• In humans, the glucocerebrosidase (GBA) gene is responsible for encoding the production of glucocerebrosidase (GCase) protein, a protein whose role in lysosomes is essential for removing garbage from cells.

When the GBA gene is mutated, the protein activity of GCase decreases, and the glycolipids and some misfolded proteins that it is responsible for degrading will increase, inducing the death of dopamine-producing cells, allowing patients to have Parkinson's disease symptoms.

The new drug PR001, jointly developed by Prevail Therapeutics and Eli Lilly, is an innovative therapy for neurodegenerative diseases caused by specific gene variants associated with lysosomal dysfunction, which uses AAV9 as a carrier and carries the GBA1 gene, in addition to Parkinson's, PR001 is also a potential treatment for Gaucher disease, which is currently undergoing clinical trials.

• Regulation of gene expression

At present, it has been found that mutations in the α synuclein gene (SNCA) and leucine-rich repeat kinase 2 (LRRK2) gene encoding lead to increased protein expression and the pathogenesis of Parkinson's disease, and gene therapy based on antisense oligonucleotides (ASOs) technology reduces the expression of mutant genes by blocking the translation of abnormal proteins or inducing their degradation.

Biogen's investigational drug BIIB094, an antisense oligonucleotide drug of the LRRK2 gene, blocks the protein translation of the LRRK2 mutant gene to control the disease.

3. Amino acid system: NMDAR, mGluRs, AMPAR

The neurotransmitter system is responsible for the flow of information in the complex circuits of the brain and central nervous system.

Glutamate is the main excitatory neurotransmitter in the central nervous system and is widely distributed in the brain. Glutamate receptors are divided into ionic receptors and metabolic receptors, the former including N-methyl-D-aspartate receptor (NMDAR), α-amino-3-hydroxy-5-methyl-4 isoxazole receptor (AMPAR), etc.; Metabolic glutamate receptors (mGLuRs) consist of three types and eight subtypes, involved in the regulation of synaptic transmission and neuronal excitability throughout the central nervous system.

According to the authors, there are currently 3 NMDA receptor antagonists, 1 mGluR5 allosteric modulator and 1 AMPA receptor antagonist in the clinical research stage.

4. Kinase inhibitor: C-Abl kinase inhibitor

Related studies have found increased levels and activity of the non-receptor tyrosine kinase Abelson (c-Abl) in dopaminergic neurons in the brain of Parkinson's disease patients.

c-AbI has protein substrate phosphorylation activity that phosphorylates α-synuclein, which affects the structure and aggregation behavior of α-synuclein.

C-ABL kinase inhibitors can play a neuroprotective role and provide a good application prospect for the treatment of patients with Parkinson's disease.

5. GLP1 receptor agonist

At present, GLP1 (Glucagon-Like Peptide 1) is mainly used clinically to treat type 2 diabetes.

Related studies have shown that GLP-1 agonists have neuroprotective effects, can reduce the breakdown of dopamine in the brain, and are potential treatment players for Parkinson's disease.

Neuraly's NLY01 and Peptron's PT320 are GLP1 receptor agonists and are currently in Phase 2 clinical studies.

6. Brain-gut axis mechanism

Relevant studies have found that α synaptic proteins produced in the intestine travel up the peripheral nerves to the central nervous system, and cause inflammation and destruction of some brain tissue, eventually leading to Parkinson's disease.

Based on this pathogenesis, Enterin's product ENT-01 is designed to competitively detach α-synuclein from the inner membrane by infiltrating and adhering to the intestinal nerve cell lining, thereby inhibiting α-synaptic protein accumulation.

At present, ENT-01 has completed the phase 2 clinical trial of Parkinson's-related constipation, and will carry out Parkinson-related mental disorders, Parkinson's dementia, and even autism-related clinical trials in the future.

7. Other mechanisms of action: immunotherapy, Sigma-1 receptor agonists...

In addition to the above new therapies, immunotherapy, cell therapy, Sigma-1 receptor agonists, cholinergic systems and other research fields have also emerged many potential new drugs for Parkinson's disease.

In addition to the exploration of new mechanisms, there is also the innovation of R&D strategies.

For example, B&A Therapeutics is conducting a Phase 2 clinical trial of Bumetanide. Butmetanide is a diuretic that has been used for decades to reduce edema due to heart failure, liver or kidney disease. Brametanide regulates the ability of cells to absorb sodium and chloride ions, and in addition to regulating the body's water balance, it also plays an important role in transmitting electrical signals to nerve cells in the brain.

"Old drugs for new use" is undoubtedly a highly effective research and development strategy to discover better treatments for Parkinson's disease.

brief summary

Looking ahead, the development of Parkinson's disease drugs faces many challenges, and researchers do not know enough about the genetic basis, etiology and pathological process of the disease.

However, the exploration of Parkinson's disease continues, the road is blocked and long, and the road is coming! It is believed that treatments that improve or even cure Parkinson's disease will eventually become available.