PMID- 35347645
OWN - NLM
STAT- MEDLINE
DCOM- 20220721
LR  - 20240204
IS  - 1878-7479 (Electronic)
IS  - 1933-7213 (Print)
IS  - 1878-7479 (Linking)
VI  - 19
IP  - 3
DP  - 2022 Apr
TI  - AAV-Mediated Artificial miRNA Reduces Pathogenic Polyglucosan Bodies and 
      Neuroinflammation in Adult Polyglucosan Body and Lafora Disease Mouse Models.
PG  - 982-993
LID - 10.1007/s13311-022-01218-7 [doi]
AB  - Adult polyglucosan body disease (APBD) and Lafora disease (LD) are autosomal 
      recessive glycogen storage neurological disorders. APBD is caused by mutations in 
      the glycogen branching enzyme (GBE1) gene and is characterized by progressive 
      upper and lower motor neuron dysfunction and premature death. LD is a fatal 
      progressive myoclonus epilepsy caused by loss of function mutations in the EPM2A 
      or EPM2B gene. These clinically distinct neurogenetic diseases share a common 
      pathology. This consists of time-dependent formation, precipitation, and 
      accumulation of an abnormal form of glycogen (polyglucosan) into gradually 
      enlarging inclusions, polyglucosan bodies (PBs) in ever-increasing numbers of 
      neurons and astrocytes. The growth and spread of PBs are followed by 
      astrogliosis, microgliosis, and neurodegeneration. The key defect in 
      polyglucosans is that their glucan branches are longer than those of normal 
      glycogen, which prevents them from remaining in solution. Since the lengths of 
      glycogen branches are determined by the enzyme glycogen synthase, we hypothesized 
      that downregulating this enzyme could prevent or hinder the generation of the 
      pathogenic PBs. Here, we pursued an adeno-associated virus vector (AAV) mediated 
      RNA-interference (RNAi) strategy. This approach resulted in approximately 15% 
      reduction of glycogen synthase mRNA and an approximately 40% reduction of PBs 
      across the brain in the APBD and both LD mouse models. This was accompanied by 
      improvements in early neuroinflammatory markers of disease. This work represents 
      proof of principle toward developing a single lifetime dose therapy for two fatal 
      neurological diseases: APBD and LD. The approach is likely applicable to other 
      severe and common diseases of glycogen storage.
CI  - (c) 2022. The Author(s).
FAU - Gumusgoz, Emrah
AU  - Gumusgoz E
AD  - Division of Neurology, Department of Pediatrics, University of Texas Southwestern 
      Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA.
FAU - Kasiri, Sahba
AU  - Kasiri S
AD  - Division of Neurology, Department of Pediatrics, University of Texas Southwestern 
      Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA.
FAU - Guisso, Dikran R
AU  - Guisso DR
AD  - Division of Neurology, Department of Pediatrics, University of Texas Southwestern 
      Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA.
FAU - Wu, Jun
AU  - Wu J
AD  - Division of Neurology, Department of Pediatrics, University of Texas Southwestern 
      Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA.
FAU - Dear, Matthew
AU  - Dear M
AD  - Division of Neurology, Department of Pediatrics, University of Texas Southwestern 
      Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA.
FAU - Verhalen, Brandy
AU  - Verhalen B
AD  - Division of Neurology, Department of Pediatrics, University of Texas Southwestern 
      Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA.
AD  - Present affiliation: Corteva Agriscience, Johnston, IA, 50131, USA.
FAU - Minassian, Berge A
AU  - Minassian BA
AD  - Division of Neurology, Department of Pediatrics, University of Texas Southwestern 
      Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA. 
      berge.minassian@utsouthwestern.edu.
LA  - eng
GR  - P01 NS097197/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20220328
PL  - United States
TA  - Neurotherapeutics
JT  - Neurotherapeutics : the journal of the American Society for Experimental 
      NeuroTherapeutics
JID - 101290381
RN  - 0 (Glucans)
RN  - 0 (MicroRNAs)
RN  - 9005-79-2 (Glycogen)
RN  - 9012-72-0 (polyglucosan)
RN  - EC 2.4.1.11 (Glycogen Synthase)
RN  - Polyglucosan Body Disease, Adult Form
SB  - IM
CIN - Neurotherapeutics. 2022 Apr;19(3):977-981. PMID: 35460010
MH  - Animals
MH  - Disease Models, Animal
MH  - Glucans
MH  - Glycogen
MH  - Glycogen Storage Disease
MH  - Glycogen Synthase/genetics
MH  - *Lafora Disease/genetics/pathology/therapy
MH  - Mice
MH  - *MicroRNAs
MH  - Nervous System Diseases
MH  - Neuroinflammatory Diseases
PMC - PMC9294094
OTO - NOTNLM
OT  - AAV9
OT  - APBD
OT  - EPM2A
OT  - EPM2B
OT  - GBE1
OT  - GYS1
OT  - RNAi
OT  - miRNA
EDAT- 2022/03/30 06:00
MHDA- 2022/07/22 06:00
PMCR- 2022/03/28
CRDT- 2022/03/29 05:48
PHST- 2022/03/07 00:00 [accepted]
PHST- 2022/03/30 06:00 [pubmed]
PHST- 2022/07/22 06:00 [medline]
PHST- 2022/03/29 05:48 [entrez]
PHST- 2022/03/28 00:00 [pmc-release]
AID - S1878-7479(23)01117-0 [pii]
AID - 1218 [pii]
AID - 10.1007/s13311-022-01218-7 [doi]
PST - ppublish
SO  - Neurotherapeutics. 2022 Apr;19(3):982-993. doi: 10.1007/s13311-022-01218-7. Epub 
      2022 Mar 28.