Pathobiology and Treatment of Lysosomal Disorders of Brain

Training in Comparative Medicine and Neuroscience provided the basis for my career interests in neurogenetic disease, particularly those disorders impacting neuronal homeostatic mechanisms and resulting in intellectual disability and related neurobehavioral abnormalities. My lab has published extensively in the area of pathogenic cascade analysis in lysosomal disease, defining key changes in neuronal structure and function as a consequence of lysosomal compromise. Current studies include: (i) the causes and consequences of ectopic dendritogenesis and neuroaxonal dystrophy, (ii) altered synaptic function underlying intellectual compromise, (iii) involvement of mTOR and TFEB/TFE3 in homeostatic dysregulation following lysosomal compromise and its impact on endosomal and autophagasomal function, and (iv) the importance of metabolite salvage in lysosomal processing.

Diseases of current focus include the lysosomal diseases Niemann-Pick types A and C, mucolipidosis IV, GM1 and GM2 gangliosidosis, Sanfilippo type A (MPS IIIA), Batten disorders (CLN2 and CLN3) and Free Sialic Acid Storage Disorders like Salla disease.

My lab is also significantly involved in therapy development for genetic brain disease. We were the first to show essentially complete correction of CNS disease in the lysosomal disorder known as alpha-mannosidosis through the use of bone marrow transplantation and this treatment approach is now the standard of care for children diagnosed with this rare disorder. We have also actively pursued treatments for Niemann-Pick type C (NPC), a fatal cholesterol-glycosphingolipid lysosomal storage disorder of children. Based on our studies of glycosphingolipid processing abnormalities in NPC disease we developed the first and presently only approved (by EMEA) therapy for this disorder. This is the imino sugar known as N-butyldeoxynojirimycin, or miglustat, which is a partial inhibitor of glycosphingolipid synthesis.

More recently we discovered that the FDA-approved excipient known as hydroxypropyl beta-cyclodextrin is efficacious in limiting intraneuronal accumulation of both unesterified cholesterol and glycosphingolipids, and dramatically extends the lifespan in animal models of NPC disease. Research and clinical trial development was subsequently pursued through a unique scientist/clinician/parent consortium known as SOAR (Support Of Accelerated Research) for NPC disease (SOAR-NPC) and through collaboration with TRND (Therapeutics for Rare and Neglected Diseases) and NCATS (National Center for Advancing Translational Sciences) at NIH. We remain hopeful that the successful preclinical studies for NPC disease will lead to FDA and EMA approval for this cyclodextrin compound now known as adrabetadex.

https://www.youtube.com/watch?v=EE9kh6OTTSY&feature=youtu.be&app=desktop

Walkley SU.  Rethinking lysosomes and lysosomal disease.  Neurosci Lett. 2021 Sep 25;762:136155. doi: 10.1016/j.neulet.2021.136155. Epub 2021 Aug 4.  PMID: 34358625

Huizing M, Hackbarth ME, Adams DR, Wasserstein M, Patterson MC, Walkley SU, Gahl WA; FSASD Consortium.  Free sialic acid storage disorder: Progress and promise. Neurosci Lett. 2021 Jun 11;755:135896. doi: 10.1016/j.neulet.2021.135896. Epub 2021 Apr 20.  PMID: 33862140

Walkley SU, Abbeduto L, Batshaw ML, Bhattacharyya A, Bookheimer SY, Christian BT, Constantino JN, de Vellis J, Doherty DA, Nelson DL, Piven J, Poduri A, Pomeroy SL, Samaco RC, Zoghbi HY, Guralnick MJ; Intellectual and Developmental Disabilities Research Centers Directors Committee. Intellectual and developmental disabilities research centers: Fifty years of scientific accomplishments.  Ann Neurol. 2019 Sep;86(3):332-343. doi: 10.1002/ana.25531. Epub 2019 Jul 27.  PMID: 31206741

Davidson J, Molitor E, Moores S, Gale SE, Subramanian K, Jiang X, Sidhu R, Kell P, Zhang J, Fujiwara H, Davidson C, Helquist P, Melancon BJ, Grigalunas M, Liu G, Salahi F, Wiest O, Xu X, Porter FD, Pipalia NH, Cruz DL, Holson EB, Schaffer JE, Walkley SU, Maxfield FR, Ory DS. 2-Hydroxypropyl-β-cyclodextrin is the active component in a triple combination formulation for treatment of Niemann-Pick C1 disease.  Biochim Biophys Acta Mol Cell Biol Lipids. 2019 Oct;1864(10):1545-1561. doi: 10.1016/j.bbalip.2019.04.011. Epub 2019 Apr 30.  PMID: 31051283

Boudewyn LC, Walkley SU.  Current concepts in the neuropathogenesis of mucolipidosis type IV. J Neurochem. 2019 Mar;148(5):669-689. doi: 10.1111/jnc.14462. Epub 2018 Aug 30.  PMID: 29770442

Ory DS, Ottinger EA, Farhat NY, King KA, Jiang X, Weissfeld L, Berry-Kravis E, Davidson CD, Bianconi S, Keener LA, Rao R, Soldatos A, Sidhu R, Walters KA, Xu X, Thurm A, Solomon B, Pavan WJ, Machielse BN, Kao M, Silber SA, McKew JC, Brewer CC, Vite CH, Walkley SU, Austin CP, Porter FD. Intrathecal 2-hydroxypropyl-β-cyclodextrin decreases neurological disease progression in Niemann-Pick disease, type C1: a non-randomised, open-label, phase 1-2 trial.  Lancet. 2017 Oct 14;390(10104):1758-1768. doi: 10.1016/S0140-6736(17)31465-4. Epub 2017 Aug 10. PMID: 28803710

Boudewyn LC, Sikora J, Kuchar L, Ledvinova J, Grishchuk Y, Wang SL, Dobrenis K, Walkley SU.  N-butyldeoxynojirimycin delays motor deficits, cerebellar microgliosis, and Purkinje cell loss in a mouse model of mucolipidosis type IV. Neurobiol Dis. 2017 Sep;105:257-270. doi: 10.1016/j.nbd.2017.06.003. Epub 2017 Jun 10.PMID: 28610891

Sikora J, Dworski S, Jones EE, Kamani MA, Micsenyi MC, Sawada T, Le Faouder P, Bertrand-Michel J, Dupuy A, Dunn CK, Xuan ICY, Casas J, Fabrias G, Hampson DR, Levade T, Drake RR, Medin JA, Walkley SU. Acid Ceramidase Deficiency in Mice Results in a Broad Range of Central Nervous System Abnormalities Am J Pathol. 2017 Apr;187(4):864-883. doi: 10.1016/j.ajpath.2016.12.005.  PMID: 28342444

Walkley SU, Davidson CD, Jacoby J, Marella PD, Ottinger EA, Austin CP, Porter FD, Vite CH, Ory DS. Fostering collaborative research for rare genetic disease: the example of niemann-pick type C disease. Orphanet J Rare Dis. 2016 Dec 1;11(1):161. doi: 10.1186/s13023-016-0540-x. PMID: 27903269

Davidson CD, Fishman YI, Puskás I, Szemán J, Sohajda T, McCauliff LA, Sikora J, Storch J, Vanier MT, Szente L, Walkley SU, Dobrenis K. Efficacy and ototoxicity of different cyclodextrins in Niemann-Pick C disease.  Ann Clin Transl Neurol. 2016 Apr 20;3(5):366-80. doi: 10.1002/acn3.306. eCollection 2016 May. PMID: 27231706

Sikora J, Leddy J, Gulinello M, Walkley SU.  X-linked Christianson syndrome: heterozygous female Slc9a6 knockout mice develop mosaic neuropathological changes and related behavioral abnormalities. Dis Model Mech. 2016 Jan;9(1):13-23. doi: 10.1242/dmm.022780. Epub 2015 Oct 29. PMID: 26515654

Herbert AS, Davidson C, Kuehne AI, Bakken R, Braigen SZ, Gunn KE, Whelan SP, Brummelkamp TR, Twenhafel NA, Chandran K, Walkley SU, Dye JM. Niemann-pick C1 is essential for ebolavirus replication and pathogenesis in vivo. mBio. 2015 May 26;6(3):e00565-15. doi: 10.1128/mBio.00565-15. PMID: 26015498

Vite CH, Bagel JH, Swain GP, Prociuk M, Sikora TU, Stein VM, O'Donnell P, Ruane T, Ward S, Crooks A, Li S, Mauldin E, Stellar S, De Meulder M, Kao ML, Ory DS, Davidson C, Vanier MT, Walkley SU. Intracisternal cyclodextrin prevents cerebellar dysfunction and Purkinje cell death in feline Niemann-Pick type C1 disease.  Sci Transl Med. 2015 Feb 25;7(276):276ra26. doi: 10.1126/scitranslmed.3010101. PMID: 25717099