Small Molecules

ENGINEERING AND DESIGN

Delivery of small molecule therapeutics to the brain has been challenging as most small molecule drugs are actively excluded by efflux pumps. It has been estimated that approximately 98% of small molecule drugs do not cross the BBB.

We are focused on engineering small molecule therapeutics that achieve exposure levels in the brain sufficient to bind to protein targets and drive a therapeutic effect. Efficacious orally administered small-molecule medicines for brain diseases must be readily absorbed from the gut into the blood and penetrate the BBB while avoiding transporter-mediated efflux. Our small molecule drug discovery scientists have many years of experience designing small molecules for brain diseases

Cns Drug

Overview

For small molecules, we follow a rigorous approach in designing these molecules to cross the Blood-Brain Barrier.

Blood Brain Barrier

Drug Candidates


Parkinson's

DNL201


Program Target

LRRK2

Development Stage

Early Clinical

Parkinson's

DNL151


Program Target

LRRK2

Development Stage

Early Clinical

ALS, Alzheimer's, MS

DNL747


Program Target

RIPK1

Development Stage

Early Clinical

Neurodegeneration

CH1


Program Target

Undisclosed

Development Stage

Drug Discovery

RA, Psoriasis

DNL758


Program Target

RIPK1

Development Stage

IND-Enabling


Large Molecules

Transport Vehicle Platform Technology

Brain uptake of therapeutic antibodies and recombinant enzymes is severely limited by their size. For example, the concentration of most therapeutic antibodies in the brain is only 0.1% of the concentration in the blood. We are developing proprietary platform technologies to actively transport these molecules across the BBB through receptor-mediated transcytosis (RMT). RMT through the BBB is the process by which macromolecules in the blood bind to receptors on the endothelial cells that make up the BBB and are actively transported and released into the brain.

Our large molecule transport vehicle (TV), platform technology engineers BBB receptor binding into an Fc domain. We have selected transferrin receptor (TfR), which is a highly-expressed BBB receptor that we believe has the ability to substantially improve brain uptake of therapeutic molecules. This construct can be integrated and fused to therapeutic molecules as described below, without disrupting the binding of transferrin to TfR.


Overview

For large molecules, we have developed proprietary drug delivery platform technologies, Antibody Transport Vehicle (“ATV”) and Enzyme Transport Vehicle (“ETV”), designed to deliver large molecules across the BBB.


Drug Candidates


MPS II (Hunter Syndrome)

DNL310 (ETV:IDS)


Program Target

Iduronate 2-sulfatase

Development Stage

IND-Enabling

Parkinson's, DLB, MSA

ATV:aSyn


Program Target

Alpha-Synuclein

Development Stage

IND-Enabling

Neurodegeneration

LF1


Program Target

Undisclosed

Development Stage

Drug Discovery

Alzheimer's

ATV:TREM2


Program Target

TREM2

Development Stage

Drug Discovery

Alzheimer's

ATV:Tau


Program Target

Tau

Development Stage

Drug Discovery