Science Science

Engineering Brain Delivery

The human brain contains approximately 400 miles of blood vessels. These blood vessels are lined by closely linked endothelial cells to form the Blood-Brain Barrier (BBB), which protects the brain from toxins by regulating the transfer of proteins, nutrients and waste products. Delivering therapeutics across the BBB has been a major obstacle to successful drug development in neurodegeneration, and is critical to enabling effective treatments.

Engineering

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

Crohn's Disease

DNL975 (LRRK2 Peripheral)

Program Target

LRRK2

Development Stage

Drug Discovery

ALS Parkinson's

CH1

Program Target

Undisclosed

Development Stage

Drug Discovery

ALS

GB1

Program Target

Undisclosed

Development Stage

Drug Discovery

Parkinson's

DNL151

Program Target

LRRK2

Development Stage

Early Clinical

ALS Alzheimer's MS

DNL788

Program Target

RIPK1

Development Stage

Early Clinical

ALS FTD

DNL343

Program Target

eIF2B

Development Stage

Early Clinical

Cutaneous Lupus Erythematosus (CLE) COVID-19

DNL758

Program Target

RIPK1

Development Stage

Early Clinical

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

Drug Candidates

Alzheimer's

ATV:Abeta

Program Target

Abeta

Development Stage

Drug Discovery

Parkinson's

AAV:LF2

Program Target

Undisclosed

Development Stage

Drug Discovery

Oncology

ATV:HER2

Program Target

HER2

Development Stage

Drug Discovery

Parkinson's, Gaucher disease

ETV:GCase

Program Target

GCase

Development Stage

Drug Discovery

MPS IIIA (Sanfilippo Syndrome)

DNL126 (ETV:SGSH)

Program Target

Sulfamidase

Development Stage

IND-Enabling

MPS II (Hunter Syndrome)

DNL310 (ETV:IDS)

Program Target

Iduronate 2-sulfatase

Development Stage

Early Clinical

Parkinson's DLB MSA

ATV:aSyn

Program Target

Alpha-Synuclein

Development Stage

Drug Discovery

Frontotemporal Dementia

DNL593 (PTV:PGRN)

Program Target

Progranulin

Development Stage

IND-Enabling

Alzheimer's

DNL919 (ATV:TREM2)

Program Target

TREM2

Development Stage

IND-Enabling

Alzheimer's

ATV:Tau

Program Target

Tau

Development Stage

Drug Discovery