Matt’s Promise is dedicated to making a difference
in the lives of young people affected by terminal illnesses.
Our cornerstone project is to find a cure for Duchenne Muscular Dystrophy (DMD).

Matt’s Promise is dedicated to making a difference in the lives of young people affected by terminal illnesses.
Our cornerstone project is to find a cure for Duchenne Muscular Dystrophy (DMD).

Biologicals

One aspect of finding the right approach for a new treatment is choosing the best technology platform. Molecules used as active substances can be divided into two classes – small and large molecules. They differ not only in terms of size, but also in how they are made, how they behave, their mode of action in the body and their suitability for certain drug forms.

Biologics: pioneering drugs made of proteins

Biologics (or biopharmaceuticals) are a class of drugs based on proteins that have a therapeutic effect. These large protein molecules – which are composed of more than 1,300 amino acids and can be as heavy as 150,000 g/mol (or 150 kDa) – are essentially copies or optimized versions of endogenous human proteins.

Biologics bind to specific cell receptors that are associated with the disease process. Monoclonal antibodies are specialized in recognizing a very specific structure on the cell surface. Used in cancer therapy, they bind selectively – for example to the receptors of cancer cells, making it possible to mark and fight specific abnormal cells. Healthy cells are usually not attacked in this process, so that biologics often cause fewer side effects than classic chemotherapy.

Biologics researchers at Bayer also use antibodies as carrier molecules for toxic substances, with the aim of transporting cell poisons to their exact site of action – inside cancer cells – and not releasing them until they arrive there. Such combinations of antibodies and cell toxins are also known as antibody-drug conjugates.

Biopharmaceuticals are administered by injection or infusion – because if they were taken orally they would (like other proteins) be digested in the stomach and intestines, and therefore be ineffective (see also Galenics).

They are produced in biotechnological processes via genetically modified cells of microorganisms such as bacteria, or yeasts or in mammalian cell lines. Over 1,000 process steps may be necessary to assemble a complex protein.

The production of biologics for therapeutic use is preceded by an optimization process known as protein engineering, in which naturally occurring protein molecules are usually geared to a specific task. Before a protein can have its intended medical effect, the researchers at Bayer HealthCare have to alter its ‘blueprint’. The amino acids are systematically exchanged until the biologic candidate functions even better than the natural variant: for example, it might bind more tightly or specifically to its target molecule. About 80,000 different variants of a protein that is to be optimized are tested every day. Here, too, this is made possible by fully automated, robot-based high-throughput screening and the use of special testing systems.  Click here to learn more.


tivorsan

Tivorsan was co-founded by Dr. Justin Fallon, Professor of Neuroscience at Brown University, to develop biglycan as a therapy for Duchenne. Charley’s Fund was an early supporter of Dr. Fallon’s work, and we are founding shareholders in Tivorsan. The company plans to begin a phase 1 clinical study for healthy adult volunteers in 2015.

Pioneering Science to Treat Duchenne and Becker Muscular Dystrophies

One attractive therapeutic approach for DMD is to reactivate the alternate, dystrophin-independent programs that normally stabilize the muscle in young and regenerating muscle.  The intracellular linchpin of this alternative complex is utrophin.

The extracellular matrix protein biglycan is a critical regulator of utrophin in developing muscle. Tests in the most widely used mouse model of DMD have shown that systemically-delivered recombinant human biglycan (rhBGN) upregulates utrophin and activates the dystrophin-independent membrane stabilization program. Muscle in the mice exposed to rhBGN is healthier and has improved function.

Biglycan targets all forms of DMD, regardless of mutation. In addition biglycan should be synergistic with other therapies in development for DMD, such as exon skipping. This synergy comes from both its upregulation of utrophin as well as targeting nNOS (neuronal nitric oxide synthase), a key enzyme that is functionally compromised in Duchenne and Becker Muscular Dystrophy.

Importantly, the active form of rhBGN lacks the complex carbohydrate (GAG) side chains that are present in most forms of biglycan. This simplified structure greatly facilitates rhBGN manufacture and mitigates off-target effects.

Multiple lines of preclinical evidence also make biglycan a compelling candidate for moving into human testing.

For more information please visit Tivorsan Pharmaceuticals


minnUniversity of Minnesota

Dr. James Ervasti at the University of Minnesota has conceived of and developed a therapeutic approach that introduces proteins into the body using a cell-penetrating peptide. With support from Charley’s Fund and the Nash Avery Foundation.


retrophonRetrophin

Retrophin is an emerging biotechnology company focused on rare and life-threatening diseases. Retrophin’s lead compound, RE-001, is based on a therapeutic approach that was conceived of and developed by Dr. James Ervasti at the University of Minnesota.  Dr. Ervasti has conducted crucial animal studies that demonstrated the potential efficacy of Tat-utrophin as a treatment for Duchenne.  Please click here to view website