Designed Zinc Finger Protein Transcription Factors for Single-Gene Regulation Throughout the Central Nervous System Bryan J Zeitler 1 *, Sarah L DeVos 2 *, Susanne K Wegmann 2 *, Kimberly Marlen 1 , Qi Yu 1 , Hoang-Oanh Nguyen 1 , Annemarie Ledeboer 1 , David S. Ojala 1 , Lei Zhang 1 , David A. Shivak 1 , Jeffrey C Miller 1 , Edward J Rebar 1 , Brigit E Riley 1 , Bradley T Hyman 2 , Michael C Holmes 1 1 Sangamo Therapeutics 2 Mass General * These authors contributed equally to this work.
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Designed Zinc Finger Protein Transcription Factors for Single ......Designed Zinc Finger Protein Transcription Factors for Single-Gene Regulation Throughout the Central Nervous System
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Designed Zinc Finger Protein Transcription Factors for Single-Gene Regulation Throughout the Central Nervous System
Bryan J Zeitler1*, Sarah L DeVos2*, Susanne K Wegmann2*, Kimberly Marlen1, Qi Yu1, Hoang-Oanh Nguyen1, Annemarie Ledeboer1, David S. Ojala1, Lei Zhang1, David A. Shivak1, Jeffrey C Miller1, Edward J Rebar1, Brigit E Riley1, Bradley T Hyman2, Michael C Holmes1
1 Sangamo Therapeutics
2 Mass General
* These authors contributed equally to this work.
Disclosure
2
I am an employee of Sangamo Therapeutics
Single-administration AAV ZFP to lower all tau forms at the DNA level
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Administration options:
Intracranial, Intrathecal
or Intravenous
ZFP-TFs reduce
tau at the DNA levelPackaging into AAV
AAV Vector
Zinc Finger Protein Transcription
Factor (ZFP-TF)
Stable repression of
Tau/MAPT gene
Non-integrating
CNS Disease
Gene Regulation
1. ZFP-TF technology
2. Targeting tau for the treatment of tauopathies
3. Repression of mouse and human tau in vitro
Outline
CNS Disease
Gene Regulation
1. ZFP-TF technology
2. Targeting tau for the treatment of tauopathies
3. Repression of mouse and human tau in vitro
Outline
Zinc Fingers can be engineered to recognize specific DNA sequences
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• Most abundant DNA
binding domain in the
human genome
• 28 amino acid peptide
• Binds 3-4 bp of DNA
• Specificity and affinity
can be engineered
5’ 3’
ZFP-TFs can be engineered to regulate any gene
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ZFP-TFs can be engineered to regulate any gene
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• Fully human-derived sequence
• 3 ZFPs can fit in 1 rAAV genome
• High potency – 2 targets per cell
CNS Disease
Gene Regulation
1. ZFP-TF technology
2. Targeting tau for the treatment of tauopathies
3. Repression of mouse and human tau in vitro
Outline
10Xia C … Dickerson BC. Association of In Vivo [18F]AV-1451 Tau PET Imaging Results With Cortical
Atrophy and Symptoms in Typical and Atypical Alzheimer Disease. JAMA Neurol. February 20, 2017
tau PETCortical loss Amyloid PET
tau “tangles”Intracellular
Amyloid b “plaques”Extracellular
Tau defects causes many other “tauopathy” diseases: