2024-06-04

Q: Why are genetic modifiers challenging to identify using population genetics for rare genetic disorders and how does Scenic Biotech’s products exploring genetic modifiers using its proprietary platform technology?

Genetic modifiers are gene variants that affect the outcome of a disease-causing gene mutation. They can positively influence the severity of a disease and, in some cases, act as a ‘natural form of protection.’ By identifying genetic modifiers through its proprietary Cell-Seq platform, Scenic Biotech aims to develop powerful disease-modifying therapies for metabolic diseases based on a completely novel class of drug targets.

In general, one can imagine that the search for genetic modifiers resembles finding a needle in a haystack. Individuals carrying strong modifier variants that significantly alter the course of a disease are exceedingly rare. Population genetics can identify gene variants associated with decreased or increased disease severity based on human genetics data, usually collected in large databases of healthy volunteers. These databases yield valuable insights into how genes contribute to human health but are more catered to study common diseases. For rare genetic diseases, the availability of sequencing data is oftentimes limited, so relying solely on human genetics data to identify modifier genes is challenging. The low patient numbers further complicate this search, as individuals carrying modifier variants may not be represented in such small population sample sets. Scenic Biotech’s proprietary Cell-Seq platform offers the opportunity to systemically explore genetic modifiers independent of prevalence by mimicking population genetics in a petri dish.

Q: How does Scenic Biotech's Cell-Seq platform address the challenges of identifying genetic modifiers?

Scenic’s proprietary target discovery platform, Cell-Seq, uses special human cells that carry a single copy of every gene. To mimic genetic diseases in this system, we introduce the underlying disease mutation and identify experimental read-outs that measure the critical disease-causing pathways in these cells. In Cell-Seq, mimicking the disease is combined with powerful genome-wide mutagenesis and deep sequencing to provide genetic landscapes to identify genes that affect the disease phenotype of interest. This way, we can identify and quantify those gene mutations that alleviate and worsen the selected disease phenotype. Constructing high-resolution “disease maps” from this data, Scenic Biotech has the opportunity to gain comprehensive insights into disease mechanisms and detect genetic modifiers completely independent of human genetics data. These subsequently undergo further validation in relevant cellular models as well as in vivo models.

Q: Can you explain how Scenic Biotech identifies potential targets for inherited disorders like HSAN1 and MacTel?

Scenic’s Cell-Seq platform enables us to perform highly sensitive and reproducible genetics in human cells. The power to identify modifier genes in rare inherited disorders comes from comparing all identified genes that affect a disease-relevant phenotype between ‘healthy’ cells and those carrying a disease mutation. Scenic’s proprietary data warehouse subsequently enables the rapid prioritization of potential drug targets that affect cells carrying a disease mutation. With close to 400 Cell-Seq maps in over 70 genetic backgrounds, Scenic Biotech has been able to establish an elaborate data warehouse that displays detailed phenotype-genotype landscapes for a multitude of diseases across immunological, metabolic, and neurological disorders. Together with our profound expertise in metabolic pathways, we are uniquely positioned to select highly specific genetic modifiers and develop small-molecule inhibitor-based therapies against such targets.

Q: What distinguishes Scenic Biotech's Cell-Seq platform from other methods of identifying genetic modifiers?

Cell-Seq can be applied to rare and common diseases, providing functional genomics insights in areas where population genetics currently fall short. The method further profits from its versatility in probing both viability and phenotypic disease features as a basis for identifying genetic modifiers. Often, a disease cannot be accurately modeled by solely relying on cellular fitness, as many other genome-wide screening efforts do. The read-out of fluorescently measurable intracellular disease phenotypes in combination with genome-wide perturbation is uniquely associated with Scenic’s platform due to patent protection and thus allows Scenic to mimic the broadest variety of disease mechanisms possible.

Q: How does SC-2882's mechanism of action impact the tumor microenvironment and what preclinical evidence suggests the potential of SC-2882 for cancer treatment?

SC-2882 is a small molecule inhibitor against a novel immuno-oncology (IO) drug target: the glutaminyl cyclase, QPCTL. This intracellular enzyme has been identified via the CellSeq platform as a modifier of the CD47-SIRPα “don’t eat me” checkpoint. Inhibiting QPCTL significantly reduced CD47-SIRPa binding and, thus, the ‘don't eat me signal.’ Furthermore, it has been shown to modify the action of several chemokines. SC-2882 potently inhibits these processes and thus lowers immune suppression in the tumor microenvironment.

SC-2882’s dual mechanism has shown effective means in several preclinical cancer models both as a single agent and in combination with other IO drugs and chemotherapy. To give an example, SC-2882 significantly reduced tumor cells in a Diffuse Large B-cell Lymphoma (DLBCL) mouse model, with the tumor microenvironment showing increased CD3+ T cell infiltration and a reduced number of tumor-associated macrophages and regulatory T cells (Di Siervi et al 2023). This suggests that the animal’s immune system is activated to kill cancer cells.

Q: What potential benefits does SC-2882 offer for the treatment of solid tumors and hematological malignancies?

To date, most IO therapies are focused on stimulating adaptive immunity, particularly T cells, to eliminate cancer cells. These therapies have revolutionized the treatment of certain cancer types, yet large groups of patients still do not respond or become resistant to IO treatment. This highlights the necessity for novel avenues in IO to provide patients with efficient cancer therapy.

Based on the available pre-clinical data, inhibiting QPCTL with SC-2882 has the potential to show efficacy in several indications, solid and hematological, as a single agent and/or in combination. Besides DLBCL, we have seen preclinical efficacy in pancreatic, colorectal, and liver cancer models. Due to SC-2882’s novel and dual mechanism of action, it is expected to have a unique efficacy profile compared to other IO agents. SC-2882 will be administered orally as a small-molecule drug, offering higher convenience and simplifying the combination with parenteral agents irrespective of dosing schemes.