There is a growing recognition that the immune system plays a key role in damaging brain cells during the progression of Alzheimer’s disease (AD). While the immune system is normally protective against foreign invaders, such as viruses or bacteria, it can become dysregulated in diseases like AD, leading to the attack of neurons and subsequent neurodegeneration. An attractive approach to counter these harmful effects is to reduce the activation of microglia, the brain’s immune cells. One approach to achieve this is to reduce the expression of a master regulator of microglia, the transcription factor PU.1 (Spi1), as reduced PU.1 (Spi1) expression is associated with a lower risk of AD.
While small nucleic acids called antisense oligonucleotides (ASOs) can be used to reduce PU.1 expression, it has been challenging to deliver such ASOs to the brain after injection into the bloodstream for several reasons. These include that i) ASOs are rapidly cleared from the bloodstream within minutes after administration, ii) ASOs are unable to cross the blood-brain barrier and enter the brain, and iii) highly invasive routes of ASO administration that bypass the blood-brain barrier, such as injection into the spinal cord, are too risky, specialized, and expensive to be highly impactful to the global aging population. To address these challenges, we propose chemically attaching ASOs to a binding protein, known as a bispecific antibody, that recognizes two different target molecules. The first target recognized by the bispecific antibody is a specific protein (CD98hc or transferrin receptor) at the blood-brain barrier, facilitating the transport of antibodies and other biologics across this barrier and into the brain. The second target recognized by the bispecific antibody is a highly expressed protein (CD11b) on microglia, which ensures the targeting of the brain’s immune cells.
We hypothesize that brain delivery of PU.1-targeted ASOs after intravenous administration will reduce PU.1 expression and microglia activation, thereby reducing damage to brain cells caused by activated microglia in mouse models of AD. To test this hypothesis, we will generate ASOs that reduce the expression of PU.1, chemically attach them to microglia-targeted bispecific antibodies that efficiently cross the blood-brain barrier, and test their activity in cell culture. Next, we will test the ability of bispecific antibody-ASO conjugates, as a function of dose and dosing frequency, to reduce PU.1 expression in microglia after intravenous administration in two AD mouse models, all while minimizing safety risks. Time permitting, we will also begin evaluating the ability of bispecific antibody-ASO conjugates to protect against AD in animal models, which is a key step toward translating this technology into a treatment for AD patients.
