PMID- 36909455
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240502
DP  - 2023 Nov 6
TI  - Disease modeling and pharmacological rescue of autosomal dominant Retinitis 
      Pigmentosa associated with RHO copy number variation.
LID - 2023.02.27.23286248 [pii]
LID - 10.1101/2023.02.27.23286248 [doi]
AB  - Retinitis pigmentosa (RP), a heterogenous group of inherited retinal disorder 
      causes slow progressive vision loss with no effective treatments available. 
      Mutations in the rhodopsin gene (RHO), account for ~25% cases of autosomal 
      dominant RP (adRP). In this study, we describe the disease characteristics of the 
      first ever reported mono-allelic copy number variation (CNV) in RHO as a novel 
      cause of adRP. We (1) show advanced retinal degeneration in a male patient (60-70 
      year old) harboring four transcriptionally active intact copies of rhodopsin, (2) 
      recapitulated the clinical phenotypes using retinal organoids, and (3) assessed 
      the utilization of a small molecule, Photoregulin3 (PR3), as a clinically viable 
      strategy to target and modify disease progression in RP patients associated with 
      RHO-CNV. Patient retinal organoids showed photoreceptors dysgenesis, with rod 
      photoreceptors displaying stunted outer segments with occasional elongated 
      cilia-like projections (microscopy); increased RHO mRNA expression (qRT-PCR and 
      bulk RNA-sequencing); and elevated levels and mislocalization of rhodopsin 
      protein (RHO) within the cell body of rod photoreceptors (western blotting and 
      immunohistochemistry) over the extended (300-days) culture time period when 
      compared against control organoids. Lastly, we utilized PR3 to target NR2E3, an 
      upstream regulator of RHO, to alter RHO expression and observed a partial rescue 
      of RHO protein localization from the cell body to the inner/outer segments of rod 
      photoreceptors in patient organoids. These results provide a proof-of-principle 
      for personalized medicine and suggest that RHO expression requires precise 
      control. Taken together, this study supports the clinical data indicating that 
      adRP due to RHO-CNV develops due protein overexpression overloading the 
      photoreceptor post-translational modification machinery.
FAU - Kandoi, Sangeetha
AU  - Kandoi S
AD  - Department of Ophthalmology, University of California San Francisco, CA, USA.
AD  - Eli and Edythe Broad Center of Regeneration Medicine & Stem Cell Research, 
      University of California San Francisco, CA, USA.
FAU - Martinez, Cassandra
AU  - Martinez C
AD  - Department of Ophthalmology, University of California San Francisco, CA, USA.
AD  - Eli and Edythe Broad Center of Regeneration Medicine & Stem Cell Research, 
      University of California San Francisco, CA, USA.
FAU - Chen, Kevin Xu
AU  - Chen KX
AD  - Eli and Edythe Broad Center of Regeneration Medicine & Stem Cell Research, 
      University of California San Francisco, CA, USA.
FAU - Reddy, L Vinod K
AU  - Reddy LVK
AD  - Department of Ophthalmology, University of California San Francisco, CA, USA.
AD  - Eli and Edythe Broad Center of Regeneration Medicine & Stem Cell Research, 
      University of California San Francisco, CA, USA.
FAU - Mehine, Miika
AU  - Mehine M
AD  - Blueprint Genetics, Helsinki, Finland.
FAU - Mansfield, Brian C
AU  - Mansfield BC
AD  - Section on Cellular Differentiation, Division of Translational Medicine, Eunice 
      Kennedy Shriver National Institute of Child Health and Human Development, 
      National Institutes of Health, Bethesda, MD USA.
FAU - Duncan, Jacque L
AU  - Duncan JL
AD  - Department of Ophthalmology, University of California San Francisco, CA, USA.
FAU - Lamba, Deepak A
AU  - Lamba DA
AD  - Department of Ophthalmology, University of California San Francisco, CA, USA.
AD  - Eli and Edythe Broad Center of Regeneration Medicine & Stem Cell Research, 
      University of California San Francisco, CA, USA.
LA  - eng
GR  - P30 EY002162/EY/NEI NIH HHS/United States
GR  - R01 EY032197/EY/NEI NIH HHS/United States
GR  - U24 EY029891/EY/NEI NIH HHS/United States
PT  - Preprint
DEP - 20231106
PL  - United States
TA  - medRxiv
JT  - medRxiv : the preprint server for health sciences
JID - 101767986
UIN - Elife. 2024 Apr 25;12:. PMID: 38661530
PMC - PMC10002783
COIS- Commercial relationships disclosures: Sangeetha Kandoi - None Cassandra Martinez 
      - None Kevin Xu Chen - None Miika Mehine - None L Vinod K. Reddy - None Brian C. 
      Mansfield - None Jacque L. Duncan - None Deepak A. Lamba - None
EDAT- 2023/03/14 06:00
MHDA- 2023/03/14 06:01
PMCR- 2023/11/13
CRDT- 2023/03/13 03:59
PHST- 2023/03/14 06:00 [pubmed]
PHST- 2023/03/14 06:01 [medline]
PHST- 2023/03/13 03:59 [entrez]
PHST- 2023/11/13 00:00 [pmc-release]
AID - 2023.02.27.23286248 [pii]
AID - 10.1101/2023.02.27.23286248 [doi]
PST - epublish
SO  - medRxiv [Preprint]. 2023 Nov 6:2023.02.27.23286248. doi: 
      10.1101/2023.02.27.23286248.