DS0412 - Innovation médicale, nanotechnologies, médecine régénérative, thérapies et vaccins innovants

ANGIOGENESIS, A NEW THERAPEUTIC TARGET IN OSTEOARTHRITIS (OA) AND ASSOCIATED PAIN – OA-ANGIO-ANALGESIA

Angiogenesis, a new therapeutic target in osteoarthritis and associated pain

Osteoarthritis (OA) is a degenerative joint disease which affects 630M people worldwide for which there is currently no cure. Exploration of the mechanisms involved in OA has highlighted the contribution of angiogenesis to the structural damage and progression of OA. This project proposes to target osteochondral angiogenesis with vascular disrupting agents to treat OA. We anticipate that VDA may also be beneficial to relieve osteoarthritic pain.

The ambition of this project is to develop first-in-class NCE with dual activity: prevention of osteochondral angiogenesis and pain (analgesia).

OA, a major public health issue worldwide, will affect 20% of the world population by 2050. To date, there is no approved safe and effective disease-modifying OA drug (DMOAD). The current therapeutic arsenal treats the symptoms (inflammation, pain); they do not halt the disease progression, neither do they reverse the process. Current treatment options for chronic osteoarthritis and related pain are insufficient. Angiogenesis (AG) is the growth of new capillary blood vessels from pre-existing vasculature. It occurs during essential (normal) physiological processes (embryogenesis, wound repair, female menstrual cycle). AG also contributes to a variety of pathologies involving “unwanted” neovascularisation including OA where it contributes to the structural damage of joints and associated pain. <br />This original project will aim to target osteochondral AG with Vascular-disrupting agents (VDA) to treat OA, prevent its progression and manage associated pain. <br />In order to fulfill this ambitious objective, we propose to: <br />1) Exploit our knowledge and expertise in the design and synthesis of VDA to develop new chemical entities (NCE) able to counteract the process of angiogenesis in OA; <br />2) Develop screening tools to assess the ability of the NCE to act as VDA in vitro and ex vivo. Appropriate animal OA models involving angiogenesis will be developed.<br />3) Use our expertise in pain pharmacology to evaluate the analgesic effect of the NCE in OA animal models; <br />4) Screen the NCE for toxicity (cardiotox- hERG assay, genotox- Ames and nicronucleus), considering the toxicities often associated with VDA.<br />5) Develop alternative administration routes of the NCE: oral vs transdermal or intra-articular injections to avoid any unwanted side-effects (cardio-, hepato-, nephro-toxicities).

Our efforts will concentrate on identifying lead molecules from existing VDA (Task 1). We envisage selecting five VDA and evaluating their in vivo efficacy on OA models (T5) to select suitable scaffold for OA application.
The lead(s) will serve to design and synthesize New Chemical Entities (Task 2). The designed molecules will be prepared using modern synthetic routes and characterized (NMR, MS, purity, stability, solubility).
The NCE may not be selectively delivered to the affected part of the body if orally administered. Given their track record (toxicity, side-effects), we ought to develop a more selective drug (Task 3). Hence we imagined two possibilities: 1) Oral administration with a cartilage-targeted delivery; 2) Local administration through transdermal administration.
The NCE will be evaluated in vitro for their ability to act as VDA and confirmed ex vivo (Task 4).
The active NCE will undergo in vivo evaluation (Task 5) to attain the proof-of-concept of the dual action (VDA and analgesic).

The OA-ANGIO-ANALGESIA project will receive advice and support from the SATT GRAND CENTRE for the exploitation of the results.
- The intellectual property (IP) associated with this project will be protected by a patent filed by the inventors. Legal aspects will be discussed at the time of the filing, according to the contribution of each partner, with the help of the SATT GRAND CENTRE.
- The OA-ANGIO-ANALGESIA project will have immediate consequences on the technology transfer of drug candidates (license transfer). With the financial support of ANR, we will be able to bring the proof of concept necessary, and bring the molecules to the late stage of discovery. The fact that these molecules constitute first-in-class drug candidates is attractive in itself. This will render the molecules more attractive for licensing.
- If further development is necessary, the SATT may fund the maturation of the project, to bring it closer to the clinic. This will not only render the molecules more attractive for licensing but also add commercial value to the molecules (Average upfronts paid at license agreements according to the stage of development vary from 13 m$ at discovery stage to 21 m$ at preclinical stage). In that case, the Analgesia Institute partners would strongly contribute to the development activities: ANS Biotech (in vivo profiling, www.ans-biotech.com/), CERB (regulatory preclinical studies: study of toxicity and safety pharmacology, www.cerb.fr/), CREPTA (pharmacokinetic studies), Aptys Pharmaceuticals (drug formulation, aptys-pharmaceuticals.com/).

The successful outcomes of the proposed research project will serve several beneficiaries:
1) Academics. Scientific results will be disseminated via scientific journals and refereed conference proceedings. We will publish in a number of international scientific journals (Medicinal chemistry, pharmacology). Academics will benefit from knowledge acquired from this project: targeting angiogenesis with VDA as a novel approach to treat OA and associated pain.
2) Students in Higher Education. We anticipate recruiting project students (Master) to contribute to the project. Students will benefit from training in R&D on a real-world topic. The multidisciplinary character of the project is well appreciated by the students involved in this type of project.
3) Technology transfer. The project is expected to generate new intellectual property (IP) which will present novel compounds to treat OA. Technology transfer will be managed by SATT Grand Centre.
4) The pharmaceutical industry will benefit from the results of this project which will bring the proof-of-concept necessary to develop VDA as drugs for the treatment of OA.
5) Societal impact. We will contribute to discover new ways of OA treatment for both human and veterinary health (one-health). Both teams are members of the Analgesia Institute (www.institut-analgesia.org) dedicated to innovate against pain in human & animal health. Existing collaboration with the Institut Bourgelat (http://icbl.vetagro-sup.fr/) could provide proof-of-concept of the NCE in a dog spontaneous OA-model.
6) Patients suffering from OA. Last but not least patients suffering from OA should finally find long lasting relief in the newly developed drug(s).

The strong need of a better understanding of the pathophysiology of OA, the high interest of the identification of new targets for OA treatment, and the clinical perspective of this project will certainly lead to the publication of several articles in high impact journals. Dissemination of the project and its results is important to promote and raise awareness of the research. Dissemination will be careful planned between the partners to ensure that all parties are made aware of the disseminated content and that the intellectual property is protected.
? Results will be published in peer-reviewed international journals from the chemistry and/or pharmacology fields.
? Partners will present their findings at national and international conferences: International Conference on Medicinal Chemistry organized each year by the French Medicinal Chemistry Society, Annual meeting of the American Society for Neuroscience.
? The partners will update their respective websites with published data as they emerge.
Regular articles in regional and national newspapers with national/international diffusion are very likely to help promote our project and attract potential licensors. This will be strengthened by the dynamic image of Auvergne in research, development and innovation of new medicines. Auvergne is now in the forefront of French regions for its pharmaceutical industry. The Group of Industries of Medicine in the Auvergne Region (GIMRA, www.gimra.info) regroups 40 members ranging from start-ups to subsidiaries of large international groups. Its goals are to promote exchanges and partnerships between members; promote members’ activities by lobbying local and regional authorities; develop cooperation with other organizations of health professionals.

Osteoarthritis (OA) is a chronic degenerative joint disease which affects 630 M people worldwide. There is currently no specific cure for OA. Recent exploration of the mechanisms involved in OA has highlighted the contribution of an important phenomenon: the angiogenesis, i.e. the development of new vessels in the whole affected joints. This mechanism participates to OA symptoms and the joint structural damages.
Our innovative project proposes to target angiogenesis (never exploited as a therapeutic target for OA) with vascular disrupting agents (VDA inhibit the tubulin assembly causing a rapid change in shape of endothelial cells, resulting in selective neovasculature shutdown) to prevent OA progression. We anticipate that VDA may also be beneficial to relieve osteoarthritic pain. The ambition of this project is to develop first-in-class new chemical entities. This multidisciplinary project will benefit from the complementary expertise of two institutions (Chemistry/Pharmacology).

Project coordination

Sylvie DUCKI (Institut de Chimie de Clermont-Ferrand)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

ICCF Institut de Chimie de Clermont-Ferrand
Neuro-Dol Neuro-Dol

Help of the ANR 381,472 euros
Beginning and duration of the scientific project: September 2015 - 36 Months

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