Collaborative Chemistry

In honor of rare disease day later this week, I am raising awareness of some of the rare diseases as brief posts. Following on from past installments of “A rare disease a day” Hunter syndrome, Gaucher disease, Tay-Sachs, Morquio syndrome, Fabry disease, Sanfilippo syndrome, Krabbe Disease, Niemann-Pick Disease, Batten disease , Hurler Syndrome, Charcot-Marie-Tooth, Fibromuscular dysplasia, Huntington’s disease,  Giant Axonal Neuropathy (GAN). Neuroendocrine tumor, it is now the turn of Amyloidosis. 

Amyloidosis is a rare disease caused by deposits of amyloid protein fibrils in one or more organs ultimately causing their malfunction. The three  main types are Primary Amyloidosis (AL), Secondary Amyloidosis (AA) and Familial Amyloidosis (FAP).

AL is the most common form  in the US however only 1200 to 3200 new cases are reported each year in the United States (2/3 in men). The disease results from a person’s antibody-producing cells malfunctioning  to produce abnormal protein fibers made of light chains which then accumulate.  Symptoms are dependednt on the organ/s affected. Commonly the kidneys are affected leading to kidney disease and renal failure. Other symptoms may include heart complications, stroke, gastrointestinal disorders, enlarged liver, diminished spleen function, diminished function of the adrenal and other endocrine glands, skin color change or growths, lung problems, bleeding and bruising problems, fatigue and weight loss. Diagnosis may be via blood, urine and a biopsy of the affected organ. Treatment of the disease is often via bone marrow transplants or chemotherapy e.g. bortezomib and dexamethasone or melphalan and dexamethasone.

Secondary amyloidoses are those occurring as a complication of a chronic inflammatory or tissue destructive disease (reactive systemic amyloidosis, secondary cutaneous amyloidosis).

FAP is a rare group of autosomal dominant diseases wherein the autonomic nervous system and/or other nerves are compromised by protein aggregation and/or amyloid fibril formation. Proteins involved include: transthyretin, apolipoprotein A1, and gelsolin. The European Medicines Agency approved Tafamidis in 2011, as did the Japanese regulators in 2013. The drug stabilizes the folding of transthyretin tetramers, halting the progression of peripheral neuropathy and autonomic nervous system dysfunction.

There are efforts to design other molecules to target FAP including polymer conjugates. A recent multicenter clinical trial suggests that the NSAID diflunisal may be repurposed for FAP as it reduced the rate of progression of neurological impairment and preserved quality of life. Other NSAIDs as well as additional classes of drugs like antibiotics may also be repurposed for this disease. 

The first global, multicenter, longitudinal, observational survey that collects data on the natural history of TTR amyloidosis has also recently been published. The study highlighted considerable phenotypic heterogeneity for neurological and cardiac manifestations in patients with hereditary and wild-type TTR amyloidosis.