Zhenya Ivakine

Dr. Evgueni (Zhenya) Ivakine is a scientist working to apply genome engineering tools and strategies to therapy development for genetic conditions, with a focus on childhood neurodegenerative and neurodevelopmental disorders. While his laboratory is a recent addition to the research institute, Dr. Ivakine has been leading cutting-edge genetics research at Sickkids in the laboratory of Dr. Ronald Cohn for nearly 7 years prior to starting his own laboratory. Originally from Russia, Dr. Ivakine has completed his B.Sc. there before coming to Canada for graduate and post-doctoral studies. Dr. Ivakine has wide-ranging scientific expertise and interests and is passionate about mentorship of trainees and students of all levels. Dr. Ivakine has co-authored over 40 peer-reviewed publications and is generously funded by a number of sources including CIHR, Niemann-Pick Canada and the Blu Genes Foundation.

Research

Dr. Ivakine seeks to understand disease pathogenesis and to develop next generation genetic medicines for the treatment of rare inherited disorders. To understand genotype-phenotype correlations, the Ivakine lab has recently developed saturation prime editing – a powerful technique that can be applied to predict disease risk at a single nucleotide resolution. In addition, the lab seeks to understand disease pathogenesis through generation of both cellular and animal models of disease. A main focus of the Ivakine group is on developing and testing treatments for genetic disease, with a particular focus on neurodevelopmental and neurodegenerative conditions including Niemann-Pick disease type C and Tay-Sachs disease, using a variety of genome engineering tools (i.e. CRISPR-Cas9, prime editing, base editing, CRISPR activation). Together, the Ivakine lab uses a multitude of complementary genetic, biochemical, molecular and genome engineering approaches to gain insight into how mutations lead to genetic disease and envision new ways of treating disease at the level of DNA.

Education and experience

• 2020–Present: Assistant Professor, University of Toronto
• 2019–Present: Scientist, Hospital for Sick Children
• 2014–2019: Senior Research Associate, Hospital for Sick Children
• 2012–2014: Research Associate, Hospital for Sick Children
• 2005–2011: Postdoctoral Fellow, Hospital for Sick Children
• 1999–2004: PhD, University of Toronto
• 1996–1998: MSc, University of Guelph
• 1989–1994: Undergraduate, Novosibirsk State University (Russia)

1. Erwood, S., Bily, T. M. I., Lequyer, J., Yan, J., Gulati, N., Brewer, R. A., Zhou, L., Pelletier, L., Ivakine, EA*, & Cohn, R. D. *Co-senior authors. (2022). Saturation variant interpretation using CRISPR prime editing. Nature Biotechnology. PMID: 35190686.Significance: Here we describe a saturation prime editing technique capable of making precise changes at the nucleotide level within the endogenous genomic regions, improving our ability to study functional roles of genetic variants at scale. This bypasses the often-inefficient homology-directed repair system to allow for more predictable and precise gene edits. We have applied this to the NPC1 gene underlying Niemann–Pick disease type C1 to characterize a series of NPC variants, increasing our understanding of their clinical significance and opening the doors for more individualized medical care. We further applied our approach to the BRCA2 gene, demonstrating that SPE is translatable to other genes with an appropriate cellular assay. 
2. Maino E, Wojtal D, Evagelou S, Farheen A, Wong TWY, Lindsay K, Scott O, Hyatt E, et al., Ivakine EA*, Cohn RD* *Co-senior authors. (2021). Targeted genome editing in-vivo corrects a Dmd duplication restoring wild-type dystrophin expression. EMBO Molecular Medicine. PMID: 33724658.
   Significance: This work describes generation, characterization, and in vivo correction of the first Duchenne Muscular Dystrophy mouse model with a duplication in the Dmd gene. This study creates a framework for targeted genome editing to correct duplication mutations representing ~10% of rare inherited disorders.
3. Kemaladewi DU , Bassi PS , Erwood S , Al-Basha D , Gawlik KI , Lindsay K , Hyatt E , Kember R , Place KM , Marks RM , Durbeej M , Prescott SA , Ivakine EA* , Cohn RD* *Co-senior authors. (2019). A mutation-independent approach for muscular dystrophy via upregulation of a modifier gene. Nature. PMID: 31341277.
   Significance: This is the very first demonstration of a therapeutic potential for CRISPR activation platform to upregulate expression of a compensatory gene in vivo. The work demonstrates potential of this strategy to prevent and rescue disease in a mouse model of muscular dystrophy.
4. Erwood S , Brewer RA , Bily TMI , Maino E , Zhou L , Cohn RD , Ivakine EA (2019). Modeling Niemann-Pick disease type C in a human haploid cell line allows for patient variant characterization and clinical interpretation. Genome research. PMID: 31754021.
   Significance: This work describes the very first model of Nieman Pick type C in haploid cells creating a framework for large-scale mutational scanning. Using base editing we rapidly generated and assigned pathogenicity to 20 previously characterized and uncharacterized mutations in NPC1.
5. Kemaladewi DU , Maino E , Hyatt E , Hou H , Ding M , Place KM , Zhu X , Bassi P, et al., Ivakine EA* , Cohn RD*. *Co-senior authors. (2017). Correction of a splicing defect in a mouse model of congenital muscular dystrophy type 1A using a homology-directed repair-independent mechanism. Nature medicine. PMID: 28714989
   Significance: First demonstration of correction for donor splice site mutations through targeted deletion of an intronic region and reconstitution of a novel splice site. When this genome editing strategy was initiated shortly after birth we completely prevented development of muscular dystrophy in mice.

See a full list of Dr. Ivakine's publications on PubMed.