Intrathecal drug delivery is changing how we approach diseases of the central nervous system

The late 1890s set the historic footprints for what we now know as infantile spinal muscular atrophy. Dr. Guido Werdnig, an Austrian neurologist, and Dr. Johann Hoffmann, a German neurologist, investigated the cause of decreased muscle tone observed in many newborns within their first months of life. These initial descriptions of this deteriorating condition were hereditary, with seemingly normal parents. Several more cases were examined by the early 1900s; scientists were perplexed and excitedly anxious by the elusive symptoms.  The syndrome was of a progressive atrophy and frailty of the motor muscles, leading to paralysis and death, stemming from the degeneration of the anterior horn cells of the spinal cord. 

This is where the story would end without the revolutionary work that led to the discovery of DNA and the blood-brain barrier (BBB). This is where childhoods would fade without the prospect of intrathecal drug delivery. 

Beyond the last century, the BBB was conceived to be a passive, impermeable barrier that shielded the brain from the blood’s trajectories. However, pioneering research over the years has given way to the idea that the BBB is an active, selectively permeable channel for transport between the blood and the brain for proteins, cells, and substrates that have access to transport systems localized within the BBB membrane. Techniques were optimized to disrupt the BBB (using, for instance, interaction or alteration of cells) or engineering transport carriers to deliver the agents and increase permeability of the barrier. Another emerging avenue was the focal delivery of drugs through routes that bypass the BBB entirely, including intrathecal delivery. 

A unique opportunity for CNS drug makers

With these innovations in motion, cerebrospinal and in particular intrathecal delivery of the drug to the central nervous system (CNS) by circumventing the BBB offers some unique opportunities for developers of CNS drugs. It permits, among other things, the administration of genetically-engineered vectors into the CNS. These vectors transport targeted proteins or oligonucleotides that modulate the expression of genes in order to address unmet medical needs for neurodegenerative and often rare diseases. In doing so, they can potentially overcome challenges with intravenous administration, which isn’t always able to deliver sufficient therapeutic levels across the BBB or where systemic administration may result in undesirable toxicities outside the therapeutic target.

Charles River’s passion and strive for improving the quality of lives through continued, exceptional science and accomplishments, is well exemplified in the efforts and dedication towards intrathecal drug delivery. Our Montreal-based Director of Infusion, Parenteral and Neurotoxicology, Dr. Julie Douville, is steering this expertise with a highly-trained and experienced team. 

Dr. Douville’s experience spans over eight years in this field, with knowledge and stature gained steadily over the years. Her mandate extended beyond the scope of a heavily-involved Study Director and it engaged associations with the surgeons for method development to expand the portfolio and optimization of the intricacy of the procedures. The portfolio cultivated, scientific meetings attended, and the market demand grew.

The challenge of large-molecule drugs

I recently conversed with Dr. Douville to gain valuable insight on this exciting journey. Firstly, the cerebrospinal delivery process, which can be conducted in all standard laboratory species, was described. For intrathecal delivery, a catheter with an access port can be implanted (via surgery), which allows administration of the test material to an unanesthetized animal in the testing room via the access port and may be more frequently employed in large laboratory species. For rats, a catheter can be surgically implanted with immediate dose delivery. The catheter provides a more definitive answer to the injection’s location because the catheter tip’s position is proven with histopathologic evaluations. 

An alternate approach employs a direct injection/direct stick: an injection performed at the lumbar level in the intrathecal space while under anesthesia. No prior surgery is required for direct stick approach. With direct stick, the cerebrospinal fluid’s flow through the needle confirms the needle’s position.    

The frequency of administration will often drive the decision on which approach to use; for single doses, the direct stick is generally used, but with repeat doses, the catheter approach is appropriate as it limits the number of anesthesia events. Furthermore, the frequency of test material administration and level at which the injection will be performed is targeted to mimic that of the clinical setting. However, because the use of the catheter approach is not commonly used in the clinic; most preclinical testing where possible supports the use of the direct stick. Depending on the therapeutic avenue you choose, and following thorough discussions during the study design development, some preclinical work will still use the catheter approach.

With regards to injectable volumes, as the administration is within a compartment and as the intrathecal space is not proportional to the animal’s body weight; fixed volumes not adjusted to body weight is typically administered to all animals on a given study. In general, the recommended dosing volume for large animal is ≤ 1 mL, and ≤ 50 µL for rats.

Although delivery into the cerebrospinal space is not a novel methodology, there is a resurgence and abundant attention for use of these methodologies because of the growing number of large molecule drugs in the CNS pipeline. Because of their size, these proteins cannot cross the BBB. Thus, a physical means to traffic through the barrier commands use of cerebrospinal, more often intrathecal delivery modes. Also, with the US Food and Drug Administration’s recent approval of SpinrazaTM (nusinersen) in December 2016, a first-ever approved intrathecal delivery treatment for spinal muscular atrophy in pediatric and adult patients, the industry is realizing that there are many neurologic defects that can be, with great potential, may have opportunity for correction using exon skipping approaches. Dr. Werdnig and Dr. Hoffmann’s story continues.

Intrathecal studies may be similar in design, but each offers a different outcome, and unexpected reactions or findings. The knowledge bank lends to a vast amount remaining to be gained, but all with enthusiasm and motivation with the prospect of improving or saving a life.These types of studies command a heavy involvement, increased Study Director presence in the animal room, and discussions with surgeons and technicians who are in tune with animals’ behaviors and reactions. Similarly, extensive communication lines are open with the pathologists to gain visibility on the subtle and specific effects as well as ensuring close monitoring and understanding of procedure-related contributions to microscopic changes. The bioanalytical and biodistribution data are studiously evaluated to landscape the injected test material’s deposition and diffusion.

Prospects for the intrathecal delivery are on the rise what with the increasing need to treat patients and genetic diseases, including rare orphan diseases affecting pediatric and juvenile populations. Neurological diseases, in general, are largely untreated; innovative treatments and advances in research, along with conventional concepts of the BBB’s permeability, are developing rapidly. 

I asked Dr. Douville what the most important thing she learned and appreciated about intrathecal drug delivery and she said, quite simply:

“Gives you direct access to the brain…with the stick of a needle.”