Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - ASTROCIT (Development and validation of an innovative nutritional solution to fight muscle atrophy during human space flights, application of the acquired knowledge to prevent muscle degeneration down on earth)

Teaser

Inactivity in most mammals lead to atrophy of skeletal muscle. In humans, prolonged periods of immobilization, as in the cases of bed rest or space flights, result in muscle weakening and atrophy. This muscle atrophy in space can not only affect the performance of astronauts...

Summary

Inactivity in most mammals lead to atrophy of skeletal muscle. In humans, prolonged periods of immobilization, as in the cases of bed rest or space flights, result in muscle weakening and atrophy. This muscle atrophy in space can not only affect the performance of astronauts during missions, but it can also lead to severe muscle injuries upon return on Earth, reduce their aerobic capacity and slow down their immune and cardiovascular systems. Without regular exercise, astronauts can lose up to 20% of their muscle mass in just 5 to 11 days and up to 50% for long duration missions. In addition, posture-related slow twitch endurance fibers are replaced by fast twitch rapidly contracting fibers that are insufficient for any heavy labor.
To reduce muscle atrophy, the international space station has on board devices allowing astronauts to perform at least 2.5 h/day of muscle training. In addition, space programs are also focusing on food and nutriment regimens to sustain astronaut musculoskeletal health. Nevertheless, current countermeasures are hardly effective at mitigating muscular atrophy and do not succeed at maintaining neither protein homeostasis, nor muscle mass, function nor strength. This is exactly the problem. CITRAGE, a French biotechnology SME founded in 2009 and specialized in the development of solutions for degenerative diseases, proposes to tackle in the AstroCIT project by developing an efficient nutraceutical. By combining the L-Citrulline, an amino acid the SME and its academic partner has proven to improve muscle protein synthesis, muscle mass, strength and function on earth (resulting in the commercialization of a product for age-related muscular dystrophy since 2012) and its hitherto unseen polyamine, a precursor affecting red muscle fibers, CITRAGE aims at providing astronauts and the general population with a mean to care for muscle loss.

It has been estimated that each shuttle flight costs 1.4 Bi$ or 7.5 M$ per person-day on the international space station. The economic benefit then appears clearly by calculating spending linked to time taken by each astronaut to exercise in order to fight against muscle atrophy (781.3 k$ per day). If AstroCIT consumption leads to 10 % time saving (15 min per day), this would allow an economic benefit of 78 k$ per day per astronaut, along with the clear medical advantages. Although it costs from 11,538 to 50,847 $ to send a kg of equipment into geostationary transfer orbit and taking into account the weight of a typical treadmill (about 100kg), financial equilibrium would be reached after sending the daily dose of the proposed nutraceuticals for 18 astronauts during 3 years.
In healthcare applications (age-related muscular dystrophy or disuse muscle atrophy after injury, immobilization or surgery), direct and indirect expenditures cost more than 800 € per person per year. Because a portion of the proposed nutraceuticals could be charged up to 1,2 € a day, a 3 months cure would be equivalent to less than 13,5% of the cost induced by caring for the disease and still yield a positive impact due to a decrease in falls, invalidity or time required to care for patients. Taking into account that muscular degeneration will affect 500 million people by 2050, key prescribers will be public and private insurers, along with nursing homes, clinics and hospitals.

The overall objectives of AstroCIT are answering two key EU challenges: (a) fighting more efficiently muscle atrophy during human space flights by developing and validating a breakthrough nutritional solution and (b) preventing muscle degeneration on earth by applying this new knowledge into a second generation product.

Work performed

Five tasks have been performed:

Task 1: Thorough analysis of the literature and formulation tests, it was concluded that:
- solid and compact formulations with high density, such as tablets and oral lyophilisation, are the best appropriate formulations for a consumption under spaceflight conditions and it will be also suitable for consumption on earth
- two options could be retained : the compression after wet granulation, and wetting followed by a freeze-drying process. These two manufacturing processes did not alter the stability of L-citrulline
- given the important size related ti the high daily dose of L-citrulline to be administered, a dosage form to be crunched should be envisaged, or still several units of smaller size to be swallowed.

Task 2: Review of existing data through exchanges with laboratories and institutions involved in previous studies in the field of astronaut nutrition and muscle atrophy allowed to define a data management plan. Data were collected on astronaut\'s nutritional requirements, space food form and manufacturing, effects of microgravity on muscles, available countermeasures and their impact, international space station facilities, microgravity studies in MEDES, ongoing studies and points to address in a future clinical trial.

Task 3: Efficiency of citrulline as a nutritional countermeasure to prevent disuse muscle atrophy in a model of hindlimb unloading in mice was performed. Although CIT is effective to protect against muscle atrophy during aging, results showed that CIT does not prevent body mass, muscle mass, myofiber cross sectional area and protein synthesis decrease in soleus and gastrocnemius muscles after 14 days of hindlimb unloading. Thus, in these conditions, CIT treatment does not appear to be efficient to prevent muscle deconditioning. However, it has been demonstrated in other models that citrulline can potentialized the effects of exercise, and further studies are needed in the present model to evaluate combined effect of citrulline with exercise.
In addition, collection of financial data to further quantify CITRAGE’s breakthrough technology’s benefit in space (as a spin-in) and back down on earth (as a spin-off), along with potential risks, showed that the size market of disuse muscle atrophy is estimated to be of around $46 billion in Europe and €7 million in France, that current solution are incomplet and that positioning of CITRAGE\'s product should be during in patient care to reduce rehabilitation duration after a period of muscle disuse. Potential co-development and commercialization partners have been identified and a complete review of CITRAGE’s business plan has been conducted during the AstroCIT project and will be leveraged in the frame current actions in equity crowdfunding.

Task 4: - A “bed rest” protocol has been defined in order to evaluate the product’s efficiency and its fit with regard to astronauts’ needs and environment in order to control for confounding variables. In particular, a state of the art of existing models and countermeasures was described and a study design was proposed: objectives, choice of investigator centers, choice of the model, criteria of inclusion/non-inclusion, arms to be studied and outcomes to be assessed.

Task 5: Analysis of the current IP of CITRAGE showed a protection for the treatment of malnutrition related to immobilization, which will be of importance to protect CITRAGE’s technology’s benefit down on earth. This is an European patent EP2081564 Use of citrulline for treating undernutrition conditions.
Freedom to operate have been studied and it was not identified any patent which would block the main activities as they are envisioned by CITRAGE as of today, i.e. treating malnutrition related to immobilization. We don’t have data specific of its use in space.
In addition, several patent applications relate to methods for producing citrulline. They should be taken into account when CITRAGE starts working

Final results

We learned from this project that :
- a citrulline basis product intended to astronauts can be successfully formulated and then consumed down on earth
- citrulline alone as a nutritional countermeasure to prevent disuse muscle atrophy is not efficient to prevent muscle deconditioning. However, since it has been demonstrated in other models that citrulline can potentialized the effects of exercise, and knowing that astronauts required training during space flights, further studies are needed to evaluate combined effect of citruline with exercise.

The AstroCIT innovative solution would mainly target/benefit astronauts, whom have clearly expressed a critical need to better preserve their muscle mass, function and strength. On earth, the AstroCIT solution would target/benefit patients with muscle atrophy due to aging or muscle disuse, whom also have expressed this need.
When looking at the economic side and the usual decision making process in the field, space agencies and space doctors will be the main payers and prescribers. Indeed, it has been estimated that each shuttle flight costs 1.4 Bi$ or 7.5 M$ per person-day on the international space station. The economic benefit then appears clearly by calculating spending linked to time taken by each astronaut to exercise in order to fight against muscle atrophy (781.3 k$ per day). If AstroCIT consumption leads to 10 % time saving (15 min per day), this would allow an economic benefit of 78 k$ per day per astronaut, along with the clear medical advantages. Although it costs from 11,538 to 50,847 $ to send a kg of equipment into geostationary transfer orbit and taking into account the weight of a typical treadmill (about 100kg), financial equilibrium would be reached after sending the daily dose of the proposed nutraceuticals for 18 astronauts during 3 years.
In healthcare applications (age-related muscular dystrophy or disuse muscle atrophy after injury, immobilization or surgery), direct and indirect expenditures cost more than 800 € per person per year. Because a portion of the proposed nutraceuticals could be charged up to 1,2 € a day, a 3 months cure would be equivalent to less than 13,5% of the cost induced by caring for the disease. Taking into account that muscular degeneration will affect 500 million people by 2050, key prescribers will be public and private insurers, along with nursing homes, clinics and hospitals.During the AstroCIT projet, the size market of disuse muscle atrophy has been estimated to be of around $46 billion in Europe and €7 million in France.

If further study confirms that citrulline combined to exercise is efficient to reduce immobilization-related muscle atrophy, AstroCIT project presents wider societal implications since it would allow to decrease time required to care for patients, to fight against dependency, to improve quality of life, allowing to return to work, if not retired, to practice physical activities and have social relations.

Website & more info

More info: http://www.citrage.com.