Drugs for rare diseases: An example of modified glucocerebrosidase

Abstract

To date, circa 5000 rare diseases have been defined, which in sum affect approximately 6% of total population. The development of drugs for rare diseases is hampered by the limitation of specific knowledge availability and difficulties in patient recruiting for clinical trials. Moreover, pharmaceutical industry does not have a clear economic incentive for investment in these studies. However, a stimulating regulation enacted in USA in 1983 and in the European Union in 1999 has helped that the targeted drugs were introduced for more than 200 rare diseases in the meantime. Among them, many are characterized by high molecular masses and are produced by recombinant technology. This is also true for the modified glucocerebrosidase, aimed at an enzymatic substitution in Gaucher disease. Namely, in comparison with the natural enzyme, the modification of terminal residues of the glycosylated enzyme, in a manner to incorporate mannose, obtains a specific recognition between enzyme and macrophages and clinical efficacy in the forms of disease devoid of neurological affections. Alglucerase, the first modified glucocerebrosidase, was extracted from placentae and hence was hardly available. Imiglucerase, as a standard drug, was developed secondly, and then ensued velaglucerase alpha and taliglucerase alpha, which may assure more reliable market supply in the settings of potential accidents in production and also diminish the costs of the therapy.

Do danas je definisano oko 5000 retkih bolesti, od kojih u zbiru boluje približno 6% populacije. Razvoj lekova za retke bolesti suočen je sa ograničenim znanjima o njima i otežanim obezbeđivanjem pacijenata za klinička ispitivanja. Dodatno, farmaceutska industrija nema jasan ekonomski motiv da investira u ova istraživanja. Ipak, podsticajna regulativa, uvedena u SAD 1983. godine, a u Evropskoj uniji 1999. godine, doprinela je da više od 200 retkih bolesti dobije specifično razvijene lekove. Mnogi među njima imaju veliku molekulsku masu i dobijeni su rekombinantnom biotehnologijom. Ovo je i primer modifikovane glukocerebrozidaze, koja obezbeđuje enzimsku supstituciju kod Gaucher-ove bolesti. Naime, u poređenju sa prirodnim enzimom, modifikacija terminalnih ostataka bočnih glikozilovanih lanaca enzima, na način da sadrže manozu, obezbeđuje specifično prepoznavanje enzima od strane makrofaga i kliničku delotvornost kod oblika bolesti bez neuroloških deficita. Nakon algluceraze, koja je dobijana iz placenti i stoga bila teško dostupna, razvijeni su imigluceraza kao standardni lek, a zatim i velagluceraza alfa i taligluceraza alfa, koji uz sigurnije snabdevanja tržišta u uslovima eventualnih proizvodnih akcidenata mogu da obezbede i smanjenje cene terapije.