Optimizing plasma use to address orphan diseases.

Optimizing plasma use to address orphan diseases. Dr. Caricasole, Kedrion.

As the fifth largest plasma-derived therapies manufacturer in the world, Kedrion collects and processes plasma, selecting and purifying proteins of medical interest and developing them into therapies, currently serving thousands of patients suffering from rare diseases worldwide. These protein replacement therapies address not only rare diseases such as Primary Immunodeficiencies and Hemophilia, but also ultra rare conditions such as less common Coagulation Disorders and Plasminogen Deficiency. Blood is life, and plasma represents a gift from donors to patients: from Life to Life. Blood plasma is a rich and complex biological material, comprising thousands of proteins of which a couple of dozen are currently used to make therapies. Kedrion has a commitment to optimize plasma use to the maximum, to serve as many patients as possible and especially those suffering from ultra-rare, orphan conditions. In 2020 we had a conversation with Andrea Caricasole, Chief Research and Innovation Officer at Kedrion, on plasma as a resource for therapeutics development and the context of the biopharmaceutical sector in Italy. What has happened since then?

What efforts are in place in Kedrion for optimizing the use of plasma? Dr. Caricasole, Kedrion.

Working with plasma from donations, the plasma-derived therapeutics industry has a strong ethical drive to make full use of plasma by leveraging every possible opportunity to develop new therapies, particularly for patients suffering from rare/ultra rare and orphan conditions. The manufacturing of high-demand plasma-derived therapies from plasma fractionation, namely Immunoglobulins for Primary Immunodeficiencies and Autoimmune Neurological conditions, and Albumin for Critical Care, absorbs a significant proportion of the plasma collected by the industry and all manufacturers are striving to optimize the production of these key proteins. However, the manufacturing of these products generates unused intermediates, which are often discarded as industrial waste. These intermediates are rich in proteins, which Kedrion is characterizing through proteomics studies, and which can be prioritized based on medical opportunity and therapeutic potential through bioinformatics and data mining analyses. With 7000+ rare diseases there are many opportunities for plasma proteins to provide meaningful protein replacement therapies for patients suffering from rare/ultra rare conditions. Prioritized proteins can then be purified, characterized, and validated in preclinical models of relevant diseases, to provide a therapeutic proof-of-concept which constitutes the foundation for full industrial and clinical development of a new protein replacement therapy. The recycling of an otherwise unused intermediate into the industrial R&D and manufacturing process represents a virtuous approach from many perspectives: ethical (optimization of the use of plasma coming from donations), medical (new therapies for orphan diseases), industrial (source material does not impact the production of other plasma-derived products) and ecological (recycling of unused industrial waste).

Concretely, how is this work translating into benefit for the scientific community and for patients? Dr. Caricasole, Kedrion.

Kedrion is keen to share with the scientific community and the industry the knowledge gathered in the process, as represented by a recent publication in Communications Biology, one of Nature Portfolio’s Journals, where a number of proteins of potential interest for therapeutics development from these unused intermediates was reported. These proteins can be further characterized and explored for their therapeutic value and eventually progressed into industrial development projects, leading to new potential therapies. An example of how these proteins can be studied and their efficacy explored in models of human diseases is also reported in the publication. A key element emerging from the work is once again the importance of a strong network of solid collaborations between Industry, Academia, and Foundations, where each partner contributes its specific know-how and technological platforms. It is networks such as these which bridge the gap between academic research efforts and translational value for patients and society, bringing the scientific knowledge and technical expertise present in Universities and Foundations together with the industrial development mindset and expertise present in pharma and biotech companies.

What is aceruloplasminemia and how can this work provide a platform for the development of future therapies for this disease?- Dr. Alessio, Group Leader and Head of the Proteome Biochemistry Unit, Omics Sciences, at the San Raffaele Hospital in Milan.

Aceruloplasminemia is an ultra-rare monogenic disease, with about around 110 patients described in the world so far, of which about 10% have so far been diagnosed in Italy. As for most rare and ultra-rare diseases it is likely underdiagnosed. The disease is caused by the absence or lack of functionality of Ceruloplasmin, a plasma enzyme that mainly plays a role in iron homeostasis, leading to the accumulation of iron in various organs, including liver, pancreas, eyes, and brain. This results in systemic damage such as liver dysfunction, diabetes and retinopathy associated with reduced erythropoiesis, the latter caused by the limited availability of circulating iron. The most serious damage, however, is reflected in neurological symptoms produced by the neurodegeneration caused by iron deposition in the brain. Being an accumulation disease, Aceruloplasminemia has a typically progressive, adult onset with systemic symptoms that can be confusing for a correct diagnosis. The onset of the disease is followed approximately ten years later by progressive and devastating neurological symptoms which quickly lead to the patient's death. This time window is potentially valuable for treatments aimed at preventing, halting, or delaying neuronal damage. Currently, there is no effective therapy for this pathology. Patients are treated with iron chelators which partially reduce systemic iron deposits (e.g. in the liver) but are largely ineffective on the accumulation of iron in the brain. Furthermore, these therapies aggravate Anemia in patients, further limiting the availability of iron for erythropoiesis, and must be periodically interrupted. Ceruloplasmin was selected as an example for a protein replacement therapy approach. The role of Ceruloplasmin in neurodegenerative diseases has been a focus of studies for many years at the San Raffaele Hospital, where we initially proposed and examined the effectiveness of Ceruloplasmin replacement therapy in mitigating neuronal damage in a preclinical model of Aceruloplasminemia (the Ceruloplasmin knock-out mouse). The collaboration with Kedrion enabled the further examination of Ceruloplasmin protein produced from an industrial plasma processing waste fraction.

What is the role of a Foundation such as TLS in this collaboration?- Dr. Cicaloni, Bioinformatics specialist, Toscana Life Sciences (TLS) Foundation, Siena.

The Fondazione Toscana Life Sciences (TLS) is a not-for-profit Foundation engaged in in-house research activities and business incubation. TLS acts as aggregator and facilitator of an innovation ecosystem in the biotechnology sector by managing projects and handling structures on behalf of its stakeholders, which include the Regione Toscana, through national and international networking activities. Such activities connect the know-how and technology platforms of research centers with the development expertise of companies to encourage the creation of synergies and partnerships to address major public health challenges and to make a decisive contribution to the development of a valuable ecosystem. In this context of the collaboration with Kedrion, TLS is involved in providing its research experience in an in-depth characterization of the proteome composition of industrial plasma fractionation followed by a bioinformatic analysis, representing the first steps for unused intermediates optimization and use. Although the unfractionated plasma proteome has been widely studied, information on qualitative proteome composition in discarded fractions obtained during the production process of plasma derivatives is still poorly represented in the literature. To address this, the network coordinated by Kedrion leveraged the established expertise of the Mass Spectrometry Unit (MSU) of TLS in mass spectrometry, combined with advanced data mining techniques, to enable the identification of plasma proteins present in waste fractions by advanced "shotgun proteomics" techniques. The continuous growth of proteomics involves both opportunities and challenges. The collective richness of the data allows researchers to answer complex biological questions and to gain new scientific insights in disease mechanisms, treatments development and precise medicine applications. However, one of the main challenges in this field is to customize and tailor bioinformatics applications to the scientific tasks by transforming available data into scientifically and translationally relevant information. Once the hundreds of proteins in plasma fractions were identified, an in-depth, cross-sectional bioinformatics analysis was performed. This pipeline allowed a "prioritization" of the proteome in order to select the proteins characterized by the most promising therapeutic potential. The identification and selection of these candidate proteins proves that industrial waste plasma fractions may be used as a starting point for the production of novel treatments, with particular attention to rare diseases. Working in the field of rare diseases is exactly one of the main missions carried out by TLS, an institution devoted to supporting research in the field of orphan diseases for many years. The collaboration with Kedrion has allowed us to further this particularly important aspect of our mission.

Italy has a number of initiatives promoting innovation and public-private partnerships at both National and Regional level. How is Kedrion contributing? Dr. Caricasole, Kedrion.

The Italian Piano Nazionale di Ripresa e Resilienza (PNRR) is a key National instrument of the Next Generation EU programme aimed at promoting innovation and competitiveness at both the National and European level, following the COVID-19 pandemic. Kedrion is contributing in several ways. For instance, to facilitate the exchange of scientists and know-how between Academia and Industry (in particular young scientists at the beginning of their careers), Kedrion is an active and enthusiastic participant to the Dottorati Innovativi initiative of the Italian Ministry of Universities (MUR). In terms of initiatives aimed at promoting industrial innovation within the perimeter of the Accordi di Innovazione by the Ministry of Manufacturing and Made in Italy (MIMIT), Kedrion is the Coordinator of a major grant co-financed by MIMIT and the Regione Toscana aimed at expanding the characterization of unused plasma fractionation intermediates and developing new candidate therapies for rare and orphan diseases from proteins obtained from these intermediates. Again, a network of collaborations involving academic institutions, contract research organizations and foundations will be the instrument for achieving the ambitious objectives of the project.