Huntington's disease – from gene mapping to gene therapy

Huntingtonova bolest nasljedna je neurodegenerativna bolest. Mutacija gena HTT temelji se na povećanome broju sljedova CAG, što dovodi do povećane sklonosti agregiranju proteina huntingtina (HTT) u živčanim stanicama mozga. Bolest se očituje u nekontroliranim pokretima, problemima u osnovnim fizičkim aktivnostima i mentalnoj nazadnosti. U ovome radu prikazan je pregled istraživanja Huntingtonove bolesti. Nakon što je gen HTT mapiran na četvrtome kromosomu čovjeka i uspješno kloniran, krenuo je cijeli niz istraživanja o samoj mutaciji i njezinu učinku na fenotip oboljele osobe na molekulskoj razini. U početku se liječenje ove bolesti svodilo samo na ublažavanje simptoma, no pokušani su i razni molekularni pristupi liječenja poput ciljane razgradnje mutiranoga oblika huntingtina ili utišavanja njegove ekspresije djelovanjem RNA i specifičnim protutijelima. U najnovije vrijeme nastoji se razviti genska terapija koja bi konačno mogla spriječiti napredovanje ove bolesti. Iako su terapije molekulama DNA, RNA i protutijelima pokazivale određene pozitivne učinke, potencijalno najboljim lijekom doima se tominersen, antisense specifični oligonukleotid (ASO) koji razgrađuje mutirani HTT, a još je u fazi II kliničkoga ispitivanja.Huntington's disease is a hereditary neurodegenerative disease. The HTT gene mutation is based on increased CAG sequences, leading to an increased tendency to aggregate huntingtin protein (HTT) in brain neuron cells. The disease manifests itself in uncontrolled movements, problems in basic physical activities, and mental retardation. This paper presents an overview of Huntington's disease research. After the HTT gene was mapped on the fourth chromosome and successfully cloned, a whole series of research began on the mutation itself and its effect on the phenotype of the affected person at the molecular level. In the beginning, the treatment of this disease was limited to alleviating the symptoms, but various molecular treatment approaches were also tried, such as the targeted degradation of the mutated form of huntingtin or the silencing of its expression by the action of RNA or specific antibodies. Recently, efforts are being made to develop a gene therapy that could finally prevent the progression of this disease. Although therapies with DNA and RNA molecules and antibodies have shown some positive effects, the potentially best drug at this moment seems to be tominersen, an antisense specific oligonucleotide (ASO) that degrades mutated HTT, which is still in the phase II of clinical trial