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Printable Handouts
Navigable Slide Index
- Introduction
- Programmable DNA targeting modules
- Effector domains: transcription modulators
- Fusions with effector domains
- Human disease and transcriptional dosage
- Haploinsufficiency
- Zygosity of pathogenic genes
- Around 15% of our genes could be haploinsufficient
- Treatments for haploinsufficient disease
- AAV vectors have a 4.7Kb limit on cargo
- Transcriptional modulation-dCas9-fusions
- Can CRISPRa correct haplinsufficiency?
- Haploinsufficiency of SIM1 leads to obesity
- SIM1 is downstream of the Leptin-Mc4r pathway
- CRISPRa targeting to rescue Sim1 obesity
- CRISPRa upregulates Sim1 in vitro
- Sim1 CRISPRa upregulation strategy: in vivo
- Sim1 promoter CRISPRa rescues obesity
- Sim1 enhancer CRISPRa rescues obesity
- Sim1 CRISPRa targeting can define tissue specificity
- CRISPRa-AAV upregulates Sim1 in the hypothalamus
- Postnatal rescue of neuroendocrine obesity
- Sim1-CRISPRa-AAVs have long lasting effect
- Can CRISPRa strategy work for other HI genes?
- Leptin-Mc4r pathway
- CRISPRa-AAV rescues Mc4r haploinsufficiency
- Overcoming size limitation of AAV gene therapy
- Summary
- Loss of function of Lama2-MDC1A
- CRISPRa targeting alternative/redundant gene
- FABP4 expression is linked to many diseases
- CRISPRi to downregulate the biomarker genes
- Autosomal dominant: Huntington's Disease
- ZF-KRAB to downregulate the pathogenic gene
- DNA methylation modulation
- DNA looping modulation
- Advantages and disadvantages
- Acknowledgements
Topics Covered
- Programmable DNA targeting modules
- Effector domain functions and possibilities
- Haploinsufficiency and its role in disease
- CRISPRa targeting strategy to rescue Sim1 obesity
- CRISPRa targeting strategy to treat Mc4r haploinsufficiency
Links
Series:
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Talk Citation
Matharu, N. (2021, December 13). Modulating gene expression to treat diseases [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved December 3, 2024, from https://doi.org/10.69645/BOTL2560.Export Citation (RIS)
Publication History
Financial Disclosures
- Dr. Navneet Matharu has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.
Other Talks in the Series: Periodic Reports: Advances in Clinical Interventions and Research Platforms
Transcript
Please wait while the transcript is being prepared...
0:00
Hi, everybody. This is Navneet Matharu; I'm an Assistant Professor
in the Department of Bioengineering and Therapeutic Sciences at UCSF.
The topic of my talk today is
future gene therapy strategies for modulating gene expression.
It's my pleasure to discuss with you today some of the recent advances in research that
highlight the use of non-editing versions of gene editors to treat genetic disorders.
0:28
Broadly, there are three versions of gene editors that are
explored in the last couple of decades first-generation:
zinc-finger nucleases, second-generation: TALENs,
and third-generation: the CRISPR system.
All of these have programmable DNA recognition or targeting modules.
Zinc finger nucleases have C2H2 zinc-finger domains for DNA recognition.
TALENs have TAL effector DNA recognition and binding domains and CRISPR is
a ribonuclease complex where DNA target recognition is guided by the guide, RNA.
Zinc fingers or TALs can be made into nucleases by fusing
the FOK1 restriction enzyme that creates a single-strand DNA break.
It takes two zinc-finger FOK when fusion molecules to make a double-strand DNA break.
CRISPR-Cas9 mind hazard to new peers domains that can make double-stranded DNA break.
These editors can be programmed into nuclease deficient versions, for example,
if you don't fuse a FOK1 to zinc-finger or TAL
these molecules are nucleus deficient on their own.
To make nuclease deficient CRISPR Cas9 we can mutate
these two catalytically active nucleus domains such that it loses
its DNA editing ability and we can make a dead Cas9 version out of it.
Now, these DNA targeting modules can be fused to any effective domains that
can perform a variety of biochemical functions at the target locus.
These effector domains that can modulate
the target gene expression are mostly transcription activators or repressors.