Emerging treatment options for the mucopolysaccharidoses

Abstract

The mucopolysaccharidoses (MPS) are a group of diseases arising from one of eleven different enzyme defects, each one affecting one single step of the degradation pathway of glycosamynoglycans. Several developments in the understanding of the MPS have occurred since the first clinical report about their occurrence in 1917: the nature of the storage product was recognized, a useful biomarker (mucopolysacchariduria) was developed, the enzyme defects became identified, and the gene defects were elucidated. The first successful treatment for MPS diseases was bone marrow transplantation, which was introduced for the therapy in 1980. Over the last decade, a whole new set of therapeutic approaches have become available or are currently in development to address MPS. Intravenous enzyme replacement therapy, already approved for MPS I, II, and VI, will possibly be available for MPS IVA and for MPS VII within the next few years. Intrathecal enzyme replacement therapy (tested in animals and already reported in a few patients) may become a tool to treat or prevent the central nervous system (CNS) manifestations which occur in several MPS. Substrate inhibition therapy using small molecules which cross the blood-brain barrier is also being tested for MPS types with CNS manifestations. In vitro studies point out that chaperones may also be of therapeutic value when the main cause is protein misfolding and retention at the endoplasmic reticulum. Stopcodon read-through strategy has been tried in preclinical studies with MPS models caused by nonsense mutations. Preclinical studies assessing gene therapy also show quite encouraging results, and this modality of treatment is now moving toward clinical development. The use of neural stem cells in MPS types which have CNS involvement is also promising. It is important to point out that MPS diseases are hard to treat, and demand specific therapies with a broad range of supportive measures. An additional challenge arises from the high cost of these technology intensive approaches, and this needs to be addressed if the treatments are to become widely available. Finally, since there is evidence that early diagnosis followed by early treatment considerably improves the health outcomes for these patients, newborn screening is becoming increasingly important for the early diagnosis of affected patients.

Neuronopathic Types of Mucopolysaccharidoses: Pathogenesis and Emerging Treatments

“…рых катализирует одну из реакций пути распада ГАГ [4]. Результатом недостаточности данных ферментов явля-ется прогрессирующее накопление ГАГ в различных органах и тканях, в т. ч. в центральной нервной системе (ЦНС), оболочках головного и спинного мозга [1,5,6].…”

“…Для тяжелых форм МПС I, II, VII типа и МПС III характерно нейродегенеративное течение заболевания, характеризующееся регрессом когнитивных функций, нарушениями поведения и сокра-щением продолжительности жизни. При всех нейроно-патических типах МПС нарушен метаболизм гепаран-сульфата [3,4,7].…”

“…Существование механизма обратного захва-та лизосомных ферментов нейронами, так называемой кросс-коррекции, было неоднократно продемонстриро-вано на экспериментальных моделях животных с нейро-дегенеративными заболеваниями из группы лизосомных болезней накопления [4,8,10].…”

“…Накопление субстрата в нейронах, считающееся пер-вичным фактором каскада дальнейших патогенетических реакций, чаще всего происходит в перинуклеарных обла-стях [4,8,9]. В головном мозге экспериментальных мышей c МПС I, IIIA и B описано прогрессирующее увеличение размера лизосом.…”

“…Для обратного развития, остановки или, по край-ней мере, замедления деструктивного воздействия ГАГ на головной мозг и оболочки ЦНС необходимо уменьше-ние количества накапливаемого субстрата [4]. В зависи-мости от причины, лежащей в основе дефицита фермен-та, возможно применение различных тактик лечения: восполнение недостающего фермента или его стабилиза-ция в случае недостаточности, обусловленной нестабиль-ностью дефектного белка [8].…”