Rare Metabolic Disorders

Rare metabolic disorders represent a broad class of life-threatening inherited diseases. They are mainly caused by genetic mutations affecting the function of specific enzymes, transporters, receptors or hormones involved in metabolizing and transporting the body’s building blocks such as sugars, proteins and lipids.

These malfunctions can impair either the assembly of crucial metabolic end-products which are needed for the normal function of the body or lead to harmful accumulations of intermediate metabolites. Diseases that are caused by harmful metabolite accumulation are also referred to as storage disorders.

Storage disorders and their impact on patients

Depending on the affected pathway, storage disorders can lead to harmful metabolite accumulations in different organs and body parts including, not exclusively, the liver, spleen, heart, kidney, skin, bones and brain. Symptoms therefore range anywhere from organ enlargement/dysfunction, abnormal bone growth, impaired hearing and vision, developmental delay, and cognitive dysfunction to neuropathological effects such as seizures and movement disorders. As these diseases are triggered by the relevant inherited mutations, mutation carriers can be affected early on, sometimes leading to premature death of newborns and young children. For some of these rare metabolic diseases, patients may reach adult age while affected with severe progressive morbidity.

Rare metabolic storage disorders are commonly classified according to the affected organelles, the nature of material accumulation and/or the affected enzyme. GM1 gangliosidosis and GM2 gangliosidosis (Tay-Sachs and Sandhoff diseases), Krabbe, Farber, Fabry and Gaucher diseases are examples of lysosomal lipid storage disorders. On the other hand, Hunter, Scheie and Sanfilippo syndromes affect different enzymes in the metabolism of sugars. Regardless of the defective pathway, early treatment is critical for these diseases given their hereditary nature and severity. Although specific therapies are now available for some of these diseases, there is still a large unmet medical need as many patients can only receive palliative care and with marginal or no improvements when it comes to neuronopathic conditions.

The picture on the left shows multilamellar bodies that form due to accumulation of degradation products (image from Dr. Jastrow’s EM-atlas).

The Azafaros approach to rare metabolic diseases

At Azafaros, we are applying our deep understanding of underlying metabolic pathways to develop new classes of oral small molecule compounds designed to counteract the pathological effects of accumulated metabolites in several rare metabolic disorders. With their mode of action, Azafaros’s compounds have the potential to offer disease-modifying modalities that are effective regardless of the genotypes of the patients. In addition, Azafaros’s small molecule compounds can readily distribute throughout the body organs to maximize their effectiveness.

With oral delivery, small molecule compounds offer the possibility of convenient administration and life-long treatment at home, significantly preserving the quality of life for patients, especially young ones. They also avoid the risks associated with gene or enzyme replacement therapies.