Severe neurodegeneration that starts in childhood is a defining feature of Sanfilippo syndrome. To treat this neurodegeneration and other neurological symptoms, a potential therapy must first overcome the blood-brain barrier (BBB).
The BBB is a thin layer of cells that separates the central nervous system (CNS) from the blood. The CNS is made up of the brain and spinal cord. By allowing only selected molecules to enter from the bloodstream, the BBB helps to protect the CNS from harmful bacteria, viruses and substances.
The BBB is vital for healthy brain function; however, its selectivity can lead to challenges when delivering therapies to the brain. In their natural state, most cells, genes, large molecules like enzymes, and even some smaller molecules cannot pass from the bloodstream to the CNS.
Researchers developing brain-targeting therapies for Sanfilippo have a few options: they can administer a therapy directly into the CNS, adapt a therapy to cross the BBB from the blood, or use a delivery vehicle to carry a therapy across the BBB.
Direct administration into the CNS
One option to efficiently target the brain is via direct administration to the CNS. A few active clinical trials involving gene or enzyme replacement therapies have taken this approach.
Gene therapy trials for Sanfilippo type A run by Lysogene and Esteve involve surgery to inject the therapy into the brain. Both of these trials also rely on harmless viruses as a vehicle to carry the genes into cells in the brain.
Allievex’s enzyme replacement therapy clinical trial for Sanfilippo type B involves enzyme administered directly into the fluid of the brain via a port implanted under the scalp. The enzyme is also fused to another protein called IGF-II, which helps the enzyme to enter cells and get into the lysosome.
Direct injection efficiently delivers therapies to the brain where they are most needed. However, this is invasive and can lead to adverse side effects like infections, and device malfunction may occur if a device is used.
Adapting a therapy to enter the CNS
Some potential therapies, especially those involving small molecule drugs or enzymes, may be modified to cross the BBB from the blood.
Small molecule drugs are under development for avenues like pharmacological chaperone therapy, substrate reduction therapy, and those targeting inflammation. They are generally more likely to cross the BBB, but sometimes, even slight changes in the chemical structure of a drug can make it more suitable to cross the BBB.
It is very hard to get large molecules like enzymes across the BBB. JCR Pharmaceuticals and Denali Therapeutics have potential enzyme replacement therapies for Sanfilippo type A and/or B in their pipeline that have been specially engineered to cross the BBB. Both companies have plans to start clinical trials to deliver enzyme to the brain with intravenous administration, commonly via a vein in the arm.
By adapting therapies to enter the CNS, it may be possible to treat the neurological symptoms of Sanfilippo with fewer adverse side effects compared to direct injection into the CNS. This is particularly important for therapies that will need to be administered repeatedly throughout a patient's life.
Using a drug-delivery vehicle to enter the CNS
Another way to deliver therapies to the brain via the bloodstream is by using a delivery vehicle, such as viruses or nanoparticles, that can cross the BBB.
Viral vectors have been used to deliver gene therapy in the clinic and in clinical trials, like in Ultragenyx’s gene therapy clinical trial for Sanfilippo type A—a gene therapy carried by the harmless AAV9 virus, which can cross the BBB after intravenous injection via a vein in the arm.
Nanoparticle drug delivery systems involve minuscule components—for example, tiny droplets of fat—that can be engineered to enter the CNS. One example includes a project led by Dr Maria Francisca Coutinho, funded by the Sanfilippo Children’s Foundation, to use nanoparticles to get substrate reduction drugs to the brain.
While less invasive than direct injection into the brain, using a drug-delivery vehicle like a virus may require much more material to ensure enough reaches the brain. For gene therapy, in particular, this approach can be expensive and may lead to a stronger immune response against the therapy. Nanoparticle delivery is thought to be less likely to generate an immune response.
- The blood-brain barrier is an important structure that separates the brain and spinal cord (the central nervous system, or CNS) from the bloodstream
- The blood-brain barrier allows only selected molecules to pass, which makes therapy delivery to the brain more difficult
- Overcoming the blood-brain barrier may involve direct injection into the CNS, adapting a therapy to cross the blood-brain barrier from the blood, or using a delivery vehicle to carry a therapy across