Advancing Gene-Targeted Therapies for Central Nervous System Disorders Proceedings of a Workshop (2019) / Chapter Skim
Currently Skimming:
3 Gene-Targeted Therapy Approaches for Central Nervous System Disorders: Opportunities and Challenges
3 Gene-Targeted Therapy Approaches for Central Nervous System Disorders: Opportunities and Challenges
Pages 17-26
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
From page 17... ...
. • The safety of chronic expression versus redosing or regulated expression is an important consideration when targeting RNA (Davidson)
|
From page 18... ...
Whether targeting the genome or RNA with sustained delivery, Davidson noted the importance of considering immune responses. Genome editing raises additional safety considerations, including consideration of what happens at the editing site.
|
From page 19... ...
Ronald Crystal, professor and chair of the department of genetic medicine at the Weill Medical College of Cornell University, said more work and better models are needed to determine whether immunosuppression is necessary, when to immunosuppress, and with what drugs. ASO Therapies DeVos demonstrated in mouse models expressing mutant human tau that repressing tau expression with antisense oligonucleotides (ASOs)
|
From page 20... ...
Anastasia Khvorova, professor in the RNA Therapeutics Institute at the University of Massachusetts Medical School, said that for oligonucleotide therapeutics, safe delivery to the CNS can also be achieved by defining the chemical and structural architecture of the oligonucleotide to have the desired pharmacokinetic properties, that is, absorption, distribution, metabolism, and excretion. Once this structural backbone has been defined, the oligonucleotide can be easily reprogrammed with different sequences to silence genes on demand.
|
From page 21... ...
mouse model, ICV injection of a siRNA directed against the mutant huntingtin gene (HTT) demonstrated significant protein silencing for up to 6 months, said hvorova.
|
From page 22... ...
Most importantly, a single ICV injection of siRNA efficiently silenced huntingtin protein expression in the cortex and deep brain structures of non-human primates, said Khvorova. Vaishnaw and colleagues are developing another approach, which they call a conjugate-based approach, to target siRNAs to the CNS.
|
From page 23... ...
In their efforts to develop therapies that would repress production of tau, DeVos and colleagues are developing a longer lasting central gene therapy approach by packaging into an AAV capsid a zinc finger protein fused to a transcription factor that recognizes and represses tau. She said they hope to couple this with an AAV variant called AAV-PHP.B.
|
From page 24... ...
Several different gene therapy approaches have been developed for G aucher disease, said Abeliovich. A lentiviral vector used to transduce hematopoietic stem cells with the GBA gene was shown to prevent Gaucher disease progression in mouse models (Dahl et al., 2015)
|
From page 25... ...
An investigator in her laboratory, Alex Monteys, answered the question of how to intervene, said Davidson. He devised a CRISPR strategy that took advantage of single nucleotide polymorphisms linked to the mutant allele, but not present on the normal allele so that he could selectively edit out only the HTT gene that contained the mutation, leaving the non-mutated HTT gene intact to carry out its normal functions (Monteys et al., 2017)
|
From page 26... ...
26 ADVANCING GENE-TARGETED THERAPIES FOR CNS DISORDERS models. Davidson's lab has also demonstrated the ability to silence the locus using a novel approach called CRISPR interference.
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.