Interest in RNA-based therapeutics shows no signs of slowing down anytime soon. One of the newest entrants into the market, Aptadir recently announced its plans to develop RNA therapies for rare cancers and genetic disorders based on a new class of RNA inhibitors called DNMTs Interacting RNAs (DiRs) that are capable of blocking aberrant DNA methylation in a single gene. The company also shared results from a pre-seed funding round that raised about $1.6 million.
Details of the discovery were published in a 2013 Nature paper titled, “DNMT1-interacting RNAs block gene-specific DNA methylation.” Giovanni Amabile, PhD, who has been appointed executive chairman and acting CEO, is a co-author on the paper as are two of Aptadir’s four co-founders including Annalisa Di Ruscio, PhD, an assistant professor in medicine at Beth Israel Deaconess Medical Center at Harvard Medical School (HMS). She discovered DiRs while working in the lab of Aptadir co-founder Daniel Tenen, MD, head of the blood program at Harvard Stem Cell Institute and professor of medicine at HMS. The other co-founders are Vittorio De Franciscis, PhD, a research director at the Italian National Research Council, and Marcin Kortylewski, PhD, a professor in the department of immuno-oncology at City of Hope Research.
Initially, when the scientists discovered DiRs, which are a type of long noncoding RNA, they were not immediately sure of its function. Additional experiments revealed that they provide protection against hypermethylation in key genes. They theorized that it might be possible to use these noncoding RNAs to reactivate genes silenced by hypermethylation. Potentially, DiRs might be able to target and reactivate pathways in diseases like myelodysplastic syndrome (MDS) and fragile X syndrome that are associated with hypermethylation in a single gene.
Figuring out how to transform the RNAs into a therapeutic product was the first challenge given how long the sequences of these noncoding RNAs can be, Amabile told GEN. The researchers solved this issue by identifying the binding region of DNMT-1, which is just a few nucleotides long, Amabile explained. This sequence is then attached to RNA aptamers resulting in “an investigational molecule of very few nucleotides, but with the key sequence to inhibit DNMT-1.” The complex also includes a sequence that specifically recognizes the target hypermethylated gene.
A second paper, published in early 2023 in Nature Communications by Di Ruscio and others, described the results of testing DiRs against a key gene in a myeloid leukemia model. They showed that the investigational treatment not only reactivated the gene, but also induced tumor regression. Like many companies in the space, the biotech startup is relying on lipid nanoparticles to deliver its treatment.
For the myeloid experiment, the researchers engineered the LNPs to target a specific antigen on the myeloid cells. This solves the problem of particle accumulation in the liver. Details of their work in engineering LNPs for the myeloid case are described in a paper published in Inflammation and Cancer. That work was led by Kortylewski. Amabile added that the company continues to improve the precision of its particles and also to explore ways of targeting other kinds of cells and tissues depending on the disease they want to treat. For example, LNPs that target neurons in the case of fragile X syndrome. In those other disease cases, the particles will be engineered to target antigens specific to the relevant cells.
The results from the myeloid leukemia study proved that Aptadir’s treatment is “even more effective than the standard of care in this disease model,” Amabile said. Buoyed by this success, the scientists began seeking funding to develop and launch therapeutics. So far Aptadir has received pre-seed funding from the EXTEND initiative—the Italian National Technology Transfer Hub which supports biopharmaceutical companies’ efforts to develop new therapeutic approaches for commercialization. It is the first biotech company to receive funding from the initiative which was launched by CDP Venture Capital SGR with co-investors, Angelini Ventures and Evotec.
Aptadir’s first DiR-based therapeutic called Ce-49, which will target MDS cases, will hopefully move into clinical trials by the end of 2025. The drug, so named because it was the 49th molecule that the company screened for this use case, has proven quite resistant and has a strong affinity for its target, according to both in vitro and in vivo studies. At the moment, the company is running preliminary toxicity tests on the drug to ensure that there are no negative effects on other organs. Additionally, the manufacturing risk assessment for the therapy looks quite positive, Amabile said.
The therapy will include RNA that targets a specific gene associated with MDS as well as an LNP delivery-based system engineered to target a specific cell compartment. It is a unique precision approach to treating MDS, unlike other approaches which rely on a more systemic approach to treatment. Their uniqueness excites Amabile. “That’s the real innovation and why I liked this project,” he told GEN. Besides its targeted efficacy, “This represents an [advancement] in the field and a strong impact on the quality of life of the patients.”
Besides its efficacy, the targeted therapy is less toxic than the first-line MDS drug Azacitidine which has significant side effects. Ideally, Aptadir envisions Ce-49 as a standalone therapy for MDS but that of course depends on several factors. When the time comes for testing in patients, “we are open to investigating the best clinical strategy for the patient population to have the best clinical trials.”
Similarly, Aptadir is working on a DiR therapeutic that will target fragile X syndrome, a neurological condition that affects mostly children resulting in symptoms like mental retardation and neurological dysfunction. Other diseases that could benefit from the technology include amyotrophic lateral sclerosis and myotonic dystrophy, which have links to hypermethylated genes. As with many small biotechs, a lot of those efforts are funding-dependent. But staying small also has advantages as the company is nimble and able to move quickly on its therapeutic programs.
The post Aptadir Therapeutics Pioneers RNA Inhibitors That Target Hypermethylation in Rare Genetic Disorders appeared first on GEN – Genetic Engineering and Biotechnology News.
