Jiksak Bioengineering focuses on the neuromuscular junction (NMJ) in developing new approaches for neurodegenerative disease diagnosis and therapy.
Animals, including us humans, are mobile beings. Most probably, few people are consciously aware of the habitual things that we do in our daily lives involves movement.
We can enjoy a walk or operate our smartphones is because we can move our fingers and legs.
“Movement” is achieved when the brain sends a signal to the skeletal muscles. Upon receiving the signal the skeletal muscle contracts. The controlled contraction and relaxation of skeletal muscles creates “movement”. The electrical signals from the brain are conveyed through the nerves to the skeletal muscles and these nerves are called motor neurons. Even though we are not conscious of it, these motor neurons are very important for muscle contraction in order for physical movement to be possible in our daily lives.
Electrical signals from the brain are conveyed to the muscles by motor neurons. The motor neuron and muscle constitutes a unique structure, known as neuromuscular junction (NMJ). At the NMJ, the motor nerve terminal (MNT) and the muscle are in close proximity to enable the transmission of these electrical signal.
Each time our body moves, these electrical signals are transmitted at the NMJ.
The maintenance of the NMJ requires a transfer of electrical signals from the motor neuron to the muscle. At other times, it requires the muscle to supply nutrients to the motor neurons. These exchanges at the NMJ are essential for the maintenance and proper function of motor neuron and muscle.
To maintain the interaction between motor neurons and skeletal muscle, the NMJ must be in a functional and structural conformation. In healthy NMJ, motor neurons are closely connected to skeletal muscle so that efficient chemical interactions are carried out without delay. On the other hand, in neuromuscular diseases, motor neurons are detached from skeletal muscle, resulting in a decrease in chemical interaction efficiency at the NMJ.
When motor neurons are detached from skeletal muscle, electrical signals from the motor neurons are not correctly transmitted to the skeletal muscle. At this stage, the motor neurons and skeletal muscle are still viable and are able to maintain their function. When electrical signals from the motor neurons are not efficiently transmitted to the skeletal muscles, the muscle cannot contract, which result in a state of motor paralysis. The detachment of NMJ, also disrupts the nutrient supply from skeletal muscle to motor neurons
Sarcopenia is an age-related muscle atrophy disease, if left untreated it will leads to progressive loss of motor function. The prevalence of sarcopenia in Japan is reported to be 8.2%, with an estimated 3.7 million patients. The number of sarcopenia patients continue to increase every year, which reflects an aging population. Currently, the absence of diagnostic and therapeutic methods for sarcopenia is a major roadblock to achieve quality of life with aging. We hope that our science can be applied to diagnose and treat sarcopenia as well.
In neuromuscular disease as well as sarcopenia, motor neurons are detached from skeletal muscle. The therapeutic strategy we are developing has two objectives
In healthy NMJ, signals from motor neurons are efficiently transmitted to skeletal muscle so that muscle contraction is generated. In addition, nutrient from skeletal muscle can be supplied to motor neurons, thus preserving the health of the motor neurons.
Therefore our therapeutic strategy is to target the NMJ by preserving functionality of the motor neurons and skeletal muscle.
Jiksak Bioengineering‘s Drug Linked Carrier (DLC) technology uses molecules that specifically deliver diagnostic and therapeutic drug molecules to motor neurons at the NMJ.
Jiksak Bioengineering DLC technology developed a tissue-specific delivery prototype (JB-00). JB-00 specifically targets the motor neuron terminal (MNT) at the NMJ. This was confirmed by fluorescence imaging (images below) and electron microscopy (data not shown).
Intravenous injection of JB-00 (Prototype of Jiksak DLC）
Collection of mouse skeletal muscle（72h post injection)
Visualization of JB-00
Jiksak Bioengineering’s DLC has many potential applications. For example, small molecules can be delivered as payloads to the site of action to modulate motor neuron function. Alternatively, gene expression in motor neurons can be controlled by incorporating miRNA, siRNA, or gRNA payloads.
Labeling of the DLC with radioisotope (RI) or other labeling method is also another promising tool for non-invasive visualization of NMJs.
Therefore, by modifying the payload components of our DLC has tremendous potential for a variety of applications
