- Continued expansion of IP portfolio related to RNA delivery
- Treatment of rheumatoid arthritis as one of the key therapeutic indications
The provisional patent application describes novel nanoparticle compositions based on OligoPhore, Altamira’s peptide-based oligonucleotide delivery platform, or derivatives thereof in combination with siRNA sequences designed to silence p65. Activation of p65 has been observed in multiple types of cancer as well as in many inflammatory diseases and its function has been implicated in the pathogenesis of these diseases. For instance, p65 is a well-known key checkpoint in rheumatoid arthritis (RA) inflammation, and thought to regulate cell proliferation, cell death, and stimulate metastasis in cancer. The new filing is intended to extend Altamira’s intellectual property related to its AM-411 development program for RA treatment, among others.
“We consider the treatment of arthritis one of the most promising applications of our OligoPhore RNA delivery platform,” commented Covadonga Pañeda, Ph.D., Altamira Therapeutics’ Chief Development Officer. “With our AM-411 program, we have demonstrated in vivo that we can deliver siRNA specifically to inflamed tissues, which in the case of RA is primarily the inflamed joints. The treatment is thus sparing non-inflamed tissues and avoiding the systemic side effects frequently observed with current treatment options. In addition, using siRNA to knock down the p65 protein allows to control a key inflammatory checkpoint, and promises not only potent treatment effects, but also a much-reduced risk of developing treatment resistance, another frequent issue with current treatment options.”
Rheumatoid arthritis is a major autoimmune disease
RA is a chronic inflammatory condition causing joint swelling and pain which may also affect other areas, including the skin, eyes, brain, and cardiovascular system. In the US, approximately 1.3 million adults suffer from RA; according to the
Effective and specific suppression of inflammation in animal arthritis model
AM-411’s therapeutic potential in RA was demonstrated in a study using a collagen antibody–induced arthritis model in mice, where OligoPhore nanoparticles with siRNA targeting NF-κB (p65) potently suppressed early inflammatory arthritis.1 The treatment effectively reduced the expression of inflammatory cytokines and cellular influx into the joints, protected against bone erosions and preserved cartilage integrity. Importantly, the treatment did not affect p65 expression in off-target organs or elicit a humoral response after serial injections.
Positive outcomes of NF-κB knock-down also in cancer animal models
In cancer, treatment with OligoPhore nanoparticles delivering p65 siRNA showed positive outcomes in animal models of melanoma lung metastasis and of Adult T-cell Leukemia Lymphoma (ATLL). Three-serial i.v. injections of nanoparticles retarded growth of lung metastasis within one week by 76% (p=0.003) as compared to saline control treatments.2 In the second study, tumor size was significantly lower in treated mice compared to controls, tumor growth was reduced to near zero in the most aggressive tumors and late-stage ATLL tumors were sensitized to conventional chemotherapy.3
About OligoPhore
OligoPhore is a versatile platform for safe and effective delivery of oligonucleotides such as siRNA (small interfering ribonucleic acid) into target cells. It is based on a proprietary 21-amino acid peptide that can engage any type of RNA in rapid self-assembly into a polyplex. The polyplex has a size, charge, and other physical features that allow it to escape hepatic clearance and thus to reach other target tissues than the liver. OligoPhore protects the RNA payload from degradation in the circulation and allows for rapid cellular uptake, while enabling pH-dependent nucleotide endosomal escape and cytoplasmic delivery. Effective delivery and positive treatment outcomes have been demonstrated in more than 10 murine models of disease for targets in the NF-κB family, various members of the ETS transcription factor family, and targets in the JNK and TAM pathways.
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1 Zhou et al. (2014), Peptide-siRNA nanocomplexes targeting NF-κB subunit p65 suppress nascent experimental arthritis, J Clin Invest 124(10):4363-74.
2 Stansel et al. (2020), NF-κB Inhibition Suppresses Experimental Melanoma Lung Metastasis, J Cancer
3 Rauch et al. (2021), Targeting NF-κB with nanotherapy in a mouse model of adult T-cell leukemia/lymphoma, Nanomaterials 11(6):1582.
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