Developing Novel Treatments for CNS Diseases

The discovery and development of drugs to treat diseases of the central nervous system (CNS) is particularly challenging compared to other disease areas. The blood–brain barrier restricts access to the brain, making the targeted delivery of drugs arduous, and in many cases, we are yet to have a complete understanding of the biology behind CNS disorders – for example, Alzheimer’s disease.  

Technology Networks recently spoke with Brad Margus, CEO at Cerevance, to find out how the company is addressing key drug development challenges. In this industry insight, Margus tells us more about the company’s drug development pipeline and their lead candidate CVN424, which is currently being developed to treat Parkinson’s disease. He also explains how Cerevance’s Nuclear Enriched Transcript Sort sequencing (NETSseq) platform is helping to discover promising targets that could be exploited therapeutically.

Laura Lansdowne (LL): What would you consider to be the key challenges that have led to low success rates in novel drug development for diseases affecting the nervous system?

Brad Margus (BM): Ensuring that a drug can cross the blood–brain barrier can be a challenge, metabolic differences between animal models and humans can lead to erroneous predictions of human pharmacokinetic profiles, and safety concerns in clinical development can certainly present problems. But by far, the most frequent reason for a CNS drug’s failure is a lack of efficacy caused by our very limited understanding of the brain. There is still too much guesswork involved in the industry about what mechanisms will be beneficial.

The brain is composed of hundreds of different brain cell types intermingled in intricate circuits and pathways, making it hard to know which protein or pathway to target to treat a disease. For example, there is still a lack of understanding of why specific cell populations are more vulnerable or resilient in many brain diseases. Animal models can help but often yield data that do not translate to human disease. Induced pluripotent stem cells made from human tissue samples and then differentiated into neurons and grown into organoids are still quite immature and function in an artificial environment. Single-cell analysis is powerful for identifying highly expressed genes that can serve as markers for a cell type can miss many potential drug targets that are expressed at lower levels. A method for deeply profiling transcriptional and epigenetic differences between specific cell types in mature human tissue has been missing.

LL: What is Nuclear Enriched Transcript Sort sequencing (NETSseq) and how can this technique be used to identify novel therapeutic targets for disease affecting the central nervous system?

BM: Cerevance’s proprietary NETSseq platform was invented by Nat Heintz and Xiao Xu at Rockefeller University and is being used to comprehensively profile-specific brain cell types, including both neurons and glial cells, in mature human brain tissue. Importantly, this technique is being used to study donated tissue from healthy people as well as those who had CNS disorders. The NETSseq approach involves using antibodies against nuclear proteins, endoplasmic reticulum proteins and membrane proteins, as well as RNA probes against any cell-type-specific transcripts in brain tissue to allow for sorting of each cell type’s nuclei. The nuclei from each cell type are then captured by florescence-activated sorting (FACS) to obtain the sequence of the nuclear messages, with the goal of quantifying the expression levels of genes in that cell type.

Cerevance has collected RNAseq data from specific cell populations that have proven to be robust and highly reproducible, even with human brain tissue samples that were frozen as long as 48 hours after death. This approach allows for the measurement of the expression of significantly more genes, including genes expressed at lower levels, than single-cell or single-nuclei analysis, a crucial attribute for the identification of potential therapeutic targets that may be expressed at low levels in the mature brain, particularly in late-onset degenerative diseases.

LL: Can you tell us more about the development and mechanism of CVN424, Cerevance’s drug candidate for Parkinson’s disease?

BM: CVN424 is an orally bioavailable, brain penetrant small molecule that selectively targets the dopamine D2 receptor-dependent, indirect pathway associated with Parkinson’s disease. It was designed to generate the positive effects of L-dopa and deep brain stimulation, the current standard of care for Parkinson’s disease (PD), without the adverse effects. CVN424 acts as a potent modulator of a novel target, confirmed using the NETSseq platform, that is selectively expressed in striatal neurons and has demonstrated improved locomotor activity in animal models of PD.

Cerevance is currently conducting a Phase 2, double-blind, multicenter, randomized, placebo-controlled trial that will evaluate the efficacy and safety of CVN424 in patients with PD and motor fluctuations who are currently being treated with levodopa (L-dopa). The trial is assessing two dose levels of CVN424 and is expected to enroll approximately 70 patients. Efficacy endpoints include reduction in “off time”, which refers to periods of the day when PD symptoms recur despite medication, as well as other functional outcome measures.

LL: Can you highlight some of the other indications you have discovered therapeutic targets for?

BM: Preclinical drug discovery and development programs are underway to advance therapeutics against novel targets that have been identified by the NETSseq approach for other neurodegenerative diseases. One such novel target is selectively expressed only in the immune cells of the brain, called the microglia. Inhibiting this target selectively dampens the inflammatory process in the brain, which is critical for diseases like Alzheimer’s that require chronic administration of treatment, where broad suppression of the inflammatory response would be harmful.

Cerevance entered a collaboration agreement with Takeda in late 2019, to assess gene expression in two cell types that may play a role in mediating certain gastrointestinal disorders in healthy people. The goal is to identify drug targets that are expressed highly selectively only in those cell types. Partnerships like this one will be important for the identification of novel therapeutic targets in other disease areas.

Brad Margus was speaking with Laura Elizabeth Lansdowne, Senior Science Writer for Technology Networks.