Oligonucleotides are short strands of DNA or RNA that can bind to specific sequences of genetic material and modulate their expression. They have emerged as a promising class of drugs for various diseases, especially those affecting the central nervous system (CNS), such as spinal muscular atrophy, Alzheimer's disease, and Huntington's disease.
Cerebrospinal fluid (CSF) is a clear fluid that fills and surrounds the central nervous system (CNS), consisting of the brain and spinal cord. CSF is produced mainly by the choroid plexus in the ventricles of the brain, and circulates through the ventricles, the subarachnoid space, and the dural sinuses, where it is reabsorbed into the blood.
However, delivering oligonucleotides to the CNS is not easy, as they have to overcome the blood-brain barrier, a protective layer that prevents most substances from entering the brain. One way to bypass this barrier is to inject the oligonucleotides directly into the CSF. This is called intrathecal injection. The oligonucleotide drugs targeting CNS choose intrathecal injection as a delivery method because:
- Intrathecal injection can bypass the blood-brain barrier (BBB), which is a major obstacle for CNS drug delivery, especially for large and negatively charged molecules like oligonucleotides.
- Intrathecal injection can reduce the systemic exposure and adverse effects of the drugs, as well as the required dose, by directly injecting them into the CSF.
- Intrathecal injection can benefit from the long half-life of the drugs in the CNS, which can reduce the frequency of administration and improve patient compliance.
Intrathecal injection has been used successfully for the first oligonucleotide drug approved for CNS diseases, Nusinersen. Nusinersen is an antisense oligonucleotide (ASO) that targets a gene involved in spinal muscular atrophy, a rare and fatal genetic disorder that causes muscle weakness and paralysis. By altering the splicing of the gene, Nusinersen increases the production of a protein that is essential for motor neuron survival and function. Nusinersen was approved by the FDA in 2016 and has shown remarkable efficacy and safety in clinical trials.
Nusinersen is not the only oligonucleotide drug that uses intrathecal injection to target the CNS. Several other ASOs and siRNAs, another type of oligonucleotide that silences gene expression, are in clinical development for various CNS diseases. These drugs have different mechanisms of action, but they share some common pharmacokinetic characteristics, such as rapid distribution and long half-life in the CNS tissues.
After ASO enters the blood circulation, its metabolism and excretion are similar to those of systemic administration, mainly metabolized by nuclease and excreted by kidney. According to the above characteristics, it is suggested that the research method of intrathecal administration of oligonucleotide drugs is similar to other systemic administration methods when studying its systemic pharmacokinetics characteristics. In addition to routine identification of metabolites in plasma, liver and kidney, identification of metabolites in brain tissue and CSF can be increased as appropriate because it targets CNS. For oligonucleotide drugs in the early stage of research and development, the study on the stability of brain homogenate can be increased to screen compounds at an early stage.
Because oligonucleotide drugs are rapidly eliminated in cerebrospinal fluid circulation, the PK-PD study of oligonucleotide drugs targeting CNS is mainly based on the dose-effect relationship between drug concentration in CNS tissue and pharmacodynamic biomarkers in CNS tissue. After intrathecal administration, the dose conversion of drugs among various genera is based on the volume of cerebrospinal fluid, rather than the conventional body surface area or equivalent free system exposure.
Intrathecal administration is a technically difficult means of administration. With the continuous warming of drug research in central nervous system in recent years, the demand for intrathecal drug delivery technology has gradually increased. Prisys has a complete technology of intrathecal administration and cerebrospinal fluid collection, and has established a comprehensive platform for intrathecal administration and intraventricular administration. Relying on a complete platform for nervous system drug research, it is expected to help customers quickly promote new drug research and development projects targeting the nervous system.
