Denali Paves the Way for Brain Disease Treatment with Transport Vehicle Technology – BioSpace

California-based Denali Therapeutics is known for its work with transport vehicle technology for the development of treatments for Hunter Syndrome, a deadly disease. However, CEO Ryan Watts recently told the San Francisco Business Times that this technology could one day also be used to shuttle other large molecules into the brain, including enzymes, antibodies, proteins and oligonucleotides. This opens up the possibility of the company developing treatments for other brain diseases.

In a paper published on Wednesday, Denali detailed the engineering of its transport vehicles. These vehicles are designed to move across the blood-brain barrier, a tightly packed maze of capillaries and cells that protects the brain from damage by foreign invaders. While some drugs are able to make it through the barrier, they are often in low doses by the time they reach the brain.

Denali has engineered part of the fragment crystallizable region, or Fc region, to interact with cell surface receptors expressed on cells that line the brains blood vessels to carry drugs across the barrier.

The transport vehicle technology is currently in use in DNL-310, a Phase 1/2 clinical trial looking into Hunter Syndrome. Denali expects to see data from the study in late 2020, and it could potentially develop a competitor to Elaprase, an enzyme replacement therapy Takeda Pharmaceutical Co.'s Shire unit.

The technology that Denali is working on could also one day be used to address conditions, such as Alzheimers disease. A recent study published in May by scientists from the University of Southern California (USC) took a closer look at the blood-brain barrier and how better understanding it can lead to more effective treatments.

To investigate the connection between the blood-brain barrier and the APOE4 variant, which is found in people who go on to develop Alzheimers disease, the scientists used a specialized form of MRI. They examined the blood-brain barrier in people with mild cognitive impairment, which can be a precursor to the disease. In addition, they analyzed those with normal cognitive function, both with and without APOE4.

The researchers ultimately discovered that people with the APOE4 variant had a leaky blood-brain barrier in parts of the brain that are essential for memory function, such as the hippocampus. This was regardless of whether they were cognitively healthy at the time of the scan. Individuals who experienced cognitive decline had even worse damage to their blood-brain barrier.

The scientists also took a closer look at pericytes, a particular group of cells, which wrap around blood vessels in the brain to form a critical barrier. When they used a biomarker of pericyte injury, they discovered higher levels of damage in people with the APOE4 variant.

This study sheds light on a new way of looking at this disease and possibly on treatment in people with the APOE4 gene, looking at blood vessels and improving their function to potentially slow down or arrest cognitive decline, said senior author Berislav Zlokovic, director of the Zilkha Neurogenetic Institute at the Keck School of Medicine of USC. Severe damage to vascular cells called pericytes was linked to more severe cognitive problems in APOE4 carriers. APOE4 seems to speed up the breakdown of the blood-brain barrier by activating an inflammatory pathway in blood vessels, which is associated with pericyte injury.

Previous experimentation in mice has already shown that blocking the inflammatory process that APOE4 triggers can restore the blood-brain barrier and improve neuronal function. However, there is still extensive research that needs to be done in this area.

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Denali Paves the Way for Brain Disease Treatment with Transport Vehicle Technology - BioSpace