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ʻOiai kakaʻikahi, ʻo ka nui o ka nui o ka mālama ʻana i ka lysosomal ma kahi o 1 i kēlā me kēia 5,000 hānau hānau. Eia kekahi, ma kahi kokoke i 70 i ʻike ʻia nā maʻi mālama mālama lysosomal, 70% e pili ana i ka ʻōnaehana nerve waena. ʻO kēia mau maʻi maʻi hoʻokahi ke kumu o ka lysosomal dysfunction, ka hopena i ka metabolic instability, dysregulation o ka protein target mammalian o rapamycin (mTOR, ka mea maʻamau e pale ai i ka mumū), autophagy impaired, a me ka make o ke aʻalolo. Ua ʻae ʻia kekahi mau lāʻau lapaʻau e pili ana i nā ʻano pathologic kumu o ka maʻi mālama lysosomal a i ʻole ke kūkulu ʻia ʻana, e komo pū ana me ka enzyme replacement therapy, substrate reduction therapy, molecular chaperone therapy, gene therapy, gene editing, and neuroprotective therapy.

ʻO ka maʻi ʻo Niemann-pick type C kahi maʻi lysosomal storage cellular cholesterol transport ma muli o nā hoʻololi biallelic ma NPC1 (95%) a i ʻole NPC2 (5%). ʻO nā hōʻailona o ke ʻano C o ka maʻi Niemann-Pick e pili ana i ka emi wikiwiki o ka neurological i ka wā kamaliʻi, ʻoiai ʻo nā ʻōpio hope loa, nā ʻōpio, a me nā ʻano hoʻomaka o nā pākeke he splenomegaly, supranuclear gaze paralysis a me cerebellar ataxia, dysarticulationia, a me ka dementia holomua.

Ma kēia pukana o ka puke pai, hōʻike ʻo Bremova-Ertl et al i nā hopena o kahi hoʻāʻo crossover ʻelua makapō, placebo-controlled. Ua hoʻohana ka hoʻokolokolo i kahi mea neuroprotective hiki, ka amino acid analogue N-acetyl-L-leucine (NALL), e mālama i ka maʻi ʻo Niemann-Pick type C. Ua kiʻi lākou i 60 symptomatic ʻōpio a me nā maʻi makua a ua hōʻike nā hopena i ka hoʻomaikaʻi nui ʻana i ka helu helu (primary endpoint) o ka Ataxia Assessment and Rating Scale.

ʻO nā hoʻokolohua lapaʻau o N-acetyl-DL-leucine (Tanganil), he racemic o NALL a me n-acetyl-D-leucine, me he mea lā ua alakaʻi nui ʻia e ka ʻike: ʻaʻole i wehewehe maopopo ʻia ke ʻano o ka hana. Ua ʻae ʻia ʻo N-acetyl-dl-leucine no ka mālama ʻana i ka vertigo acute mai ka makahiki 1950; Hōʻike nā hiʻohiʻona holoholona e hana ka lāʻau lapaʻau ma ke kau hou ʻana i ka overpolarization a me ka depolarization o nā neurons vestibular medial. Ma hope mai, ʻo Strupp et al. hōʻike i nā hopena o kahi haʻawina pōkole i ʻike lākou i ka hoʻomaikaʻi ʻana i nā hōʻailona ma 13 nā mea maʻi me ka degenerative cerebellar ataxia o nā ʻano etiologies, nā ʻike i hoʻonui i ka hoihoi i ka nānā hou ʻana i ka lāʻau.

ʻAʻole maopopo ke ʻano o ka n-acetyl-DL-leucine e hoʻomaikaʻi ai i ka hana aʻalolo, akā ʻo nā ʻike i ʻelua mau ʻiole, ʻo kekahi o ka maʻi Niemann-Pick type C a me ka maʻi ʻē aʻe o GM2 ganglioside storage disorder Variant O (Sandhoff maʻi), kekahi maʻi neurodegenerative lysosomal, ua hoʻohuli i ka nānā ʻana i ka NALL. ʻO ke ʻano, ʻoi aku ka maikaʻi o ke ola ʻana o nā ʻiole Npc1-/- i mālama ʻia me ka n-acetyl-DL-leucine a i ʻole NALL (L-enantiomers), ʻoiai ʻaʻole i ola ke ola o nā ʻiole i mālama ʻia me n-acetyl-D-leucine (D-enantiomers), e hōʻike ana ʻo NALL ke ʻano hana o ka lāʻau. Ma kahi noiʻi like ʻana o GM2 ganglioside storage disorder variant O (Hexb-/-), n-acetyl-DL-leucine i hopena i kahi hoʻonui haʻahaʻa akā nui o ke ola o nā ʻiole.

No ka ʻimi ʻana i ke ʻano hana o ka n-acetyl-DL-leucine, ua noiʻi nā mea noiʻi i ke ala metabolic o ka leucine ma ke ana ʻana i nā metabolites i loko o nā kiko cerebellar o nā holoholona mutant. Ma kahi ʻano ʻokoʻa O o ka GM2 ganglioside storage disorder, n-acetyl-DL-leucine normalizes glucose a me ka glutamate metabolism, hoʻonui i ka autophagy, a hoʻonui i nā pae o ka superoxide dismutase (he scavger oxygen active). Ma ka C model o ka maʻi Niemann-Pick, ua ʻike ʻia nā loli i ka glucose a me ka metabolism antioxidant a me ka hoʻomaikaʻi ʻana i ka metabolism ikehu mitochondrial. ʻOiai ʻo L-leucine kahi mea hoʻoulu mTOR ikaika, ʻaʻohe hoʻololi i ka pae a i ʻole phosphorylation o mTOR ma hope o ka mālama ʻana me ka n-acetyl-DL-leucine a i ʻole kona mau enantiomers i kēlā me kēia ʻano ʻiole.

Ua ʻike ʻia ka hopena neuroprotective o NALL i kahi kiʻi kiʻi o ka cortical impingement induced brain injury. Hoʻopili kēia mau hopena i ka hoʻohaʻahaʻa ʻana i nā hōʻailona neuroinflammatory, hōʻemi i ka make cell cortical, a me ka hoʻomaikaʻi ʻana i ka autophagy flux. Ma hope o ka mālama ʻana iā NALL, ua hoʻihoʻi ʻia ka hana kaʻa a me ka cognitive o nā ʻiole i ʻeha a ua hoʻemi ʻia ka nui o ka lesion.

ʻO ka pane inflammatory o ka ʻōnaehana nerve waena ka hōʻailona o ka hapa nui o nā maʻi mālama mālama lysosomal neurodegenerative. Inā hiki ke hoʻemi ʻia ka neuroinflammation me ka mālama ʻana i ka NALL, hiki ke hoʻomaikaʻi ʻia nā hōʻailona lapaʻau o ka nui, inā ʻaʻole nā ​​​​mea āpau, neurodegenerative lysosomal storage disorders. E like me ka hōʻike ʻana o kēia haʻawina, manaʻo ʻia ʻo NALL e hui pū me nā lāʻau lapaʻau ʻē aʻe no ka maʻi mālama lysosomal.

Nui nā maʻi mālama lysosomal i pili pū me ka cerebellar ataxia. Wahi a kahi noiʻi honua e pili ana i nā keiki a me nā pākeke me nā maʻi mālama mālama ganglioside GM2 (maʻi Tay-Sachs a me Sandhoff maʻi), ua hoʻemi ʻia ka ataxia a ua hoʻomaikaʻi ʻia ka hoʻonohonoho ʻana o nā kaʻa ma hope o ka mālama ʻana iā NALL. Eia naʻe, ua hōʻike ʻia kahi hoʻokolohua nui, multicenter, double-blind, randomized, placebo-controlled trial i ka n-acetyl-DL-leucine ʻaʻole maikaʻi i ka maʻi maʻi me ka cerebellar ataxia hui pū ʻia (hoʻoilina, hoʻoilina ʻole, a wehewehe ʻole ʻia). Hōʻike kēia ʻike e ʻike ʻia ka hopena i nā hoʻokolohua e pili ana i nā poʻe maʻi me ka cerebellar ataxia hoʻoilina a me nā ʻano hana pili i kālai ʻia. Eia kekahi, no ka mea e hōʻemi ana ʻo NALL i ka neuroinflammation, hiki ke alakaʻi i ka hōʻeha ʻeha o ka lolo, hiki ke noʻonoʻo ʻia nā hoʻokolohua o NALL no ka mālama ʻana i ka ʻeha lolo.