Peering into the preclinical realm

From diabetes and muscular dystrophy and cancer to post-traumatic stress disorder, we take a quick look at several recent presentations and papers on preclinical findings from researchers across the United States.

GERMANTOWN, Md.—Recently SERAXIS announced the successful production of stem cell-derived pancreatic cells, which are capable of regulating blood glucose in rodent models of insulin dependent diabetes. The results of a preclinical study describing the new, efficient method for the production of insulin-secreting beta cells in pancreatic islet-like clusters were published in September in PLOS ONE.

The investigators showed that the islet clusters functioned like mature pancreatic islets—shortly after being transplanted in a rodent model of diabetes, the clusters started secreting insulin in response to fluctuations in glucose. The patented stem cells were derived from human pancreatic islets using induced pluripotent stem cell technology, and selected for their ability to regain pancreatic identity. The proprietary cells were generated using (chromosomally) non-integrating reprogramming factors to create a stem cell line, SR1423, that generates islet-like clusters when exposed to the differentiation protocol.

“We are very proud of the progress of SERAXIS towards the development of an allogeneic therapy for insulin-dependent diabetes,” said Dr. William Rust, CEO of SERAXIS, “and we are actively working with SERAXIS scientific advisors and clinical domain experts to develop the remaining data necessary to complete an IND filing for clinical trial testing of the encapsulated cells.”

BERKELEY, Calif.—In early September, Aduro Biotech presented preclinical data for its first-in-class anti-APRIL (a proliferation-inducing ligand) antibody BION-1301 at the 5th European Congress of Immunology in Amsterdam. The data showed that BION-1301 was well-tolerated, and its pharmacological activity in binding to APRIL, a ligand for the receptors BCMA (B cell maturation antigen) and TACI (transmembrane activator and cyclophilin ligand interactor), was established in a dose-dependent fashion.

The pharmacokinetics and target engagement biomarkers were used to predict the first-in-human dose. APRIL mediates important B cell functions, including activation, survival and maturation, and serum levels of the ligand are enhanced in patients with multiple myeloma (MM) and correlate with a poor prognosis. APRIL in the bone marrow triggers a cascade of events to support MM to proliferate, survive, induce resistance to standard-of-care drugs and provide an immune-protective environment.

Aduro is now conducting a Phase 1/2 multicenter, open-label study to assess BION-1301’s safety and activity in patients with relapsed or refractory MM whose disease has progressed after at least three prior systemic therapies, including immunomodulatory drugs, proteasome inhibitors, chemotherapies or monoclonal antibodies.

BERKELEY, Calif.—Dynavax Technologies has published a preclinical study demonstrating that inhalation of a TLR9 agonist can stimulate effective immunity against lung tumors and complement the actions of PD-1 blockade to generate durable, systemic anti-tumor immunity. The paper, entitled “Inhaled TLR9 Agonist Renders Lung Tumors Permissive to PD-1 Blockade by Promoting Optimal CD4+ and CD8+ T cell Interplay,” was published in Cancer Research.

Administration of the TLR9 agonist SD-101 into the lungs of mice with metastatic tumors triggered anti-tumor responses that controlled or eliminated tumor growth in the lungs and in non-treated organs, including liver. Treatment also resulted in about a 90-percent decrease in tumor burden in both the lungs and liver, leading to a significant increase in survival time—a majority of mice survived beyond 90-100 days. Treatment with SD-101 and anti-PD-1 resulted in a large increase of tumor-reactive T cells, which were required for anti-tumor activity. The durable control of liver metastases shows that local administration of SD-101 to the lung generates an anti-tumor T cell response capable of controlling tumor growth beyond the lung itself.

Exonics research demonstrates gene repair technology restoring dystrophin expression CAMBRIDGE, Mass.—In late August, Exonics Therapeutics announced the publication of a preclinical study demonstrating that the company’s SingleCut CRISPR technology restored in-vivo dystrophin expression in a canine model of Duchenne muscular dystrophy. The research article, “Gene editing restores dystrophin expression in a canine model of Duchenne muscular dystrophy,” was published online in Science.

The study evaluated both intramuscular and systemic delivery of CRISPR gene-editing components in canines with a naturally occurring splice mutation that leads to deletion of exon 50 of the dystrophin gene. The study demonstrated that a single systemically delivered dose of adeno-associated viruses encoding the gene-editing enzyme CRISPR/Cas9 and a guide strand RNA efficiently restored the expression of dystrophin.

Eight weeks after treatment, canines receiving treatment demonstrated expression of dystrophin up to 90 percent of normal levels in skeletal muscle (depending on muscle type), compared to untreated animals. In the canine receiving the highest dose, cardiac muscle dystrophin expression was restored to 92 percent of normal levels. Notably, no off-target effects of gene editing were detected.

“The encouraging findings from this preliminary study using Exonics’ SingleCut CRISPR approach are very significant as a model for future translational studies,” remarked Dr. Eric Olson, a co-author of the paper, founder and chief science advisor of Exonics and professor and chair of the Department of Molecular Biology at UT Southwestern Medical Center. “These findings build upon our experience in correcting Duchenne mutations in cells from patients and mouse models of the disease. Longer-term studies will enable us to further assess safety and durability of the benefits as we advance our treatment toward clinical studies.”

EVANSTON, Ill.—On August 21, Aptinyx Inc. presented a poster entitled “A Novel NMDA Receptor Modulator, NYX-783, Shows Therapeutic Potential as a Treatment for PTSD and TBI” at the Military Health System Research Symposium, featuring results from preclinical studies of NYX-783, a novel NMDA receptor modulator. NYX-783 has been evaluated in a Phase 1 clinical study, and has demonstrated a favorable safety and tolerability profile in healthy volunteers. The FDA has granted Fast Track designation to the development of NYX-783 as a therapy for post-traumatic stress disorder (PTSD).

“We are encouraged by the robust preclinical activity observed with NYX-783 in models of PTSD and traumatic brain injury and we look forward to advancing it further in clinical development,” Dr. Joseph Moskal, chief scientific officer of Aptinyx, commented in a statement. “We believe NYX-783 may represent a paradigm shift in the treatment of PTSD, addressing the underlying cause of the disorder rather than just the symptoms. We appreciate the opportunity to present these data at a forum that is uniquely focused on finding solutions to challenges that disproportionately affect military personnel.”