Treating neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, among others) is a challenging project from the start. Not only do scientists have to counteract multiple problems, they also have to deal with the fact that the brain is a complex organ with: 1) different areas that perform different functions and have different cell types and 2) defense mechanisms not present in other organs to protect it from toxins.

Important brain regions for neurodegenerative diseases. (Credit

Important brain regions for neurodegenerative diseases.

First, most neurodegenerative diseases involve cell death in multiple brain regions: for example, Alzheimer’s affects several parts of the cerebral cortex and hippocampus; Huntington’s disease affects the cortex and basal ganglia; and Parkinson’s disease affects primarily a subarea of the basal ganglia called the substantia nigra.   Each area of the brain has specialized cells that are regulated differently and perform unique functions relative to those in other areas of the brain. So any problem with multiple areas of the brain needs a treatment that can work on multiple cell types or target just the right cell types.

Second, the brain’s complexity and defense mechanisms make it difficult to get treatments (a small molecule, a therapeutic antibody, a synthetic growth factor) *into* the brain in the first place, and then to the correct location once they’re already inside. In contrast to the rest of the body’s tissues, which are exposed to whatever molecules find their way into the blood stream, the brain has a specialized blood-brain-barrier composed of support glial cells that wrap around the brain’s blood vessels and restrict the molecules that can enter the brain.   This prevents toxic molecules from entering the brain, but also means that large therapeutic molecules (antibodies, growth factors) or certain drugs have to be injected directly into brain tissue to have an effect. On top of this, the brain’s complex structure means it has an equally complicated protein skeleton known as an extracellular matrix (ECM) that helps structure the connections between neurons, but also can act as a “sink” or barrier preventing molecules in one part of the brain from reaching another. So even if you try to get around the blood-brain barrier by directly injecting your drug of choice into the brain, the complicated brain ECM makes it difficult for your molecule to spread widely in the brain.


Diagram showing the blood-brain-barrier that surrounds blood vessels in the brain along with proteoglycan “nets” that surround neurons

A recently issued patent by a company called NTF Therapeutics shows one way scientists are discovering new therapeutic molecules and improving their properties to deal with the unique challenges the brain poses to treating neurodegenerative diseases.

The patent covers the use of specially engineered, less “sticky” variants of a natural growth factor called Neurturin. Previously, Neurturin (under the name CERE-120) was the subject of a high-profile trial by Celgene that failed to improve symptoms in Parkinson’s patients. Many commenters were surprised by this outcome, because the Celgene therapeutic addressed many of the problems with treating neurodegenerative disease: 1) Neurturin is a growth factor that protects multiple types of neurons from cell death (including the dopaminergic neurons that are the primary cause of Parkinson’s), and 2) Celgene’s scientists avoided blood-brain barrier delivery problems by using a gene therapy vector to induce neurons to produce Neurturin themselves and thus avoid the need for injection. Despite Celgene’s “solving” these problems however, patients still showed no improvement of motor symptoms after receiving of the treatment.

A key factor that showed up in an analysis of why this trial failed was the lack of delivery of Neurturin to the correct spot in the brain. As it turns out, just engineering neurons to produce Neurturin doesn’t solve the delivery issues: Neurturin is probably “captured” in regions of the brain by molecules in the ECM called proteoglycans, preventing it from diffusing far enough to affect enough diseased cells.

The key improvement in the NTF Therapeutics patent is the discovery of a way to engineer this proteoglycan binding out of Neurturin without inhibiting its therapeutic efficacy. A previous patent by NTF described the mutations that can be introduced into Neurturin to accomplish this, but because proteoglycan binding is supposed to help Neurturin function, it wasn’t clear that these altered versions would still be effective therapeutics. This latest patent shows data indicating that these engineered versions of Neurturin can still activate the correct receptors and survival functions in cultured neurons, while showing dramatically reduced “stickiness” to cells. The assumption is that this will dramatically improve the ability of Neurturin to diffuse in the brain, meaning that future gene therapy trials or trials with direct injection may be much more efficacious. Neurturin variants with improved spreading through the brain could turn out to be useful for a wide variety of other degenerative diseases, as it also has the ability to improve survival of glial cells (which are needed to support neurons) and survival of cortical cholinergic neurons (which are important for cognitive processes).

These molecules are currently preclinical; they have yet to be tested in humans. But we’re eagerly awaiting data to see if engineering protein drugs to “slip” through the ECM is genuinely a way to make brain therapeutics better.  If so, the mutational strategy developed by NTF therapeutics may prove extremely useful for engineering future protein-based therapeutics for the brain.