The neurodegenerative disease therapeutics market is undergoing a transformation. The segment is estimated to reach $216.6 billion by 2026. Numerous pharmaceutical companies across the globe have been laying the groundwork to develop NDDs drugs, mainly focusing on agonist or analog research on targets such as Tau proteins, beta-amyloid proteins, and alpha-synaptic core proteins for the treatment of Alzheimer's disease, acromegaly, Parkinson's disease, and Huntington's disease, among other disorders.
Several new drugs have already been approved in 2023, such as Biogen and Ionis' Qalsody for the treatment of a subtype of amyotrophic lateral sclerosis (ALS), Otsuka and Lundbeck's Rexulti became the first drug for the treatment of Alzheimer's disease bipolar disorder, and Eisai and Biogen's Leqembi was approved for the treatment of Alzheimer's disease. Similarly, drug development for neurodegenerative diseases is risky, and Alzheimer's disease in particular is often seen as a graveyard for drug development. One study found nearly 100 drugs failed in Phase II or Phase III studies between 2004 and 2021.
Neurodegenerative diseases (NDDs) are neuron loss diseases of the central or peripheral nervous system that have adversely affected the health and lives of millions of people worldwide. Brain and spinal cord cells are generally non-renewable, and excessive damage can be irreversible, worsening over time and leading to dysfunction. 2023 The Dewachter Laboratory in Belgium published an article in the journal Cell entitled "Hallmarks of neurodegenerative diseases ", providing an overview of the hallmark features of NDDs.
In this article, the characteristics, biomarkers, and their interactions of NDDs were described from multiple dimensions, such as molecular, protein, cellular, metabolic, and inflammatory, and there are eight main ones:
(1)pathological protein aggregation
(2)Synaptic and neuronal network damage
(3)Abnormal protein homeostasis
(4)Cytoskeletal abnormalities
(5) Imbalanced energy metabolism
(6)DNA and RNA damage
(7)Inflammatory response
(8)Neuronal cell death
Protein aggregation is a key pathological hallmark of several NDDs and is commonly used for diagnosis and disease classification, such as Alzheimer's disease, Parkinson's, frontotemporal lobe dementia, amyotrophic lateral sclerosis, and Huntington's disease. Mutations in related genes leading to aggregation of their encoded proteins are a common feature of several NDDs, including APP, tau, α-synuclein, and SOD1. In most NDDs, pathological protein aggregation is associated with symptom progression and affects neuronal function.
Abnormal protein homeostasis and protein aggregation are closely related, and the ubiquitin-proteasome system (UPS) and autophagy-lysosome pathway (ALP) are the major cellular mechanisms to maintain cellular homeostasis. The UPS mainly degrades labeled proteins, and the ALP scavenges protein aggregates and defective organelles. Tau, TDP-43, α-synuclein, and polyQ-containing proteins that aggregate can impair UPS function. Abnormal protein homeostasis and protein aggregation result in the loss of normal physiological function of proteins, thus preventing their physiological activities in processes such as cytoskeletal dynamics, synaptic function, and energy homeostasis. In addition, ALP is closely associated with synapses and axons (dysfunction). Thus, protein destabilization disorders can negatively interact with a variety of NDD features and induce neurodegeneration.