OC 30.5 - Expression and Activity of Human Factor VIII (hFVIII) Following Single and Repeat Administration of an Integrating Non-viral Gene Therapy in Multiple Mouse Models of Severe Hemophilia A

Monday, June 26, 2023

11:45 – 12:00 ET

Room: 517

Session Available As: Live-Stream and On-Demand

Co-Author(s)

Brian Truong, PhD (he/him/his)

Senior Scientist
Poseida Therapeutics
San Diego, California, United States

Co-Author(s)

KH

Khal Hajj

Scientist
Poseida Therapeutics
San Diego, California, United States
GN

Giang Nguyen

Scientist
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States
JS

Johannes Schwerk

Scientist
Poseida Therapeutics
San Diego, California, United States
JT

Jonnatan Tamayo

Research Associate
Poseida Therapeutics
San Diego, California, United States
DS

Daniel Smith

Scientist
Poseida Therapeutics
San Diego, California, United States
MG

Manjunath Goolyam

Scientist
Takeda Pharmaceutical Company
Boston, Massachusetts, United States
DA

Daniel Abernathy

Scientist
Takeda Pharmaceutical Company
Boston, Massachusetts, United States
FL

Fernando Lopez Espinoza

Research Associate
Poseida Therapeutics
San Diego, California, United States
MB

Michelle Burrascano

Scientist
Poseida Therapeutics
San Diego, California, United States
JY

James Yen

Scientist
Poseida Therapeutics
San Diego, California, United States
KB

Kevin Briseno

Research Associate
Poseida Therapeutics
San Diego, California, United States
JL

Joseph Lucas

Associate Director
Poseida Therapeutics
San Diego, California, United States
PB

Pavan Battiprolu

Executive Director
Poseida Therapeutics
San Diego, California, United States
MB

Mike Bennett

Senior Director
Poseida Therapeutics
San Diego, California, United States
BM

Blair Madison

Vice President, Genetic Engineering
Poseida Therapeutics
San Diego, California, United States

Presenting Author(s)

Denise E. Sabatino, PhD (she/her/hers)

Research Associate Professor of Pediatrics
The Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States

Co-Author(s)

BW

Brent Warner

President, Gene Therapy
Poseida Therapeutics
San Diego, California, United States
EO

Eric Ostertag

Chairman
Poseida Therapeutics
San Diego, California, United States
JR

Joshua Rychak

VP, Gene Therapy
Poseida Therapeutics, Inc
San Diego, California, United States

Background:

Background: The current first-line treatment for Hemophilia A patients is factor replacement and/or bi-specific antibodies; however, these require continuous, lifelong infusions and yet, patients continue to have breakthrough bleeds, representing a high unmet need for safe and effective curative therapies.

Aims:

Aims: We evaluated the potential of a liver-directed non-viral in vivo gene insertion approach using the Super piggyBac (SPB) transposition platform to produce stable hFVIII expression in mice. The non-viral SPB platform enables delivery of large transgenes (beyond 4.7 kb), the ability to stably integrate the therapeutic transgene, and potential for re-dosing to titrate target FVIII activity. These attributes may enable a significant improvement in the treatment of severe hemophilias.

Methods: Methods/

Results: Juvenile Hemophilia A mice (F8−/−/CD4−/−) were dosed intravenously with two individual LNP formulations, each optimized for either the delivery of the SPB transposase mRNA or the therapeutic hFVIII transposon DNA cassette.

Results: We observed dose-dependent FVIII activity (30-150% of normal) sustained over the duration of the six-month study. To further support the concept of re-dosing, we dosed adult WT mice up to 4 times and observed a dose-proportionate increase in hFVIII antigen levels after each administration.
We subsequently developed a co-encapsulated strategy, where both the SPB mRNA and transposon DNA were encapsulated in the same nanoparticle. To validate the co-encapsulated nanoparticle approach, we performed a three-month efficacy study in a mouse model of severe hemophilia A (FVIII knock-out) tolerized to prevent immune response against human FVIII. Following a single dose in adult mice, we observed substantial (~30% of normal) hFVIII expression sustained over the duration of the study.

Conclusion(s):

Conclusion: Our results demonstrate the capabilities of Poseida’s SPB® platform and non-viral approach in providing stable FVIII transgene expression through genomic integration, along with the potential for redosing. Our data provide proof-of-principle toward developing a potential functional cure for hemophilia A.

Learning Objectives:

Describe the advantages of an integrating non-viral gene therapy using the piggyBac® DNA delivery system over traditional gene therapy modalities for treatment of Hemophilia A.
Observe the effectiveness of an integrating non-viral gene therapy in a preclinical mouse model of Hemophilia A.
Understand the importance and benefits of the ability to re-dose genetic medicines for Hemophilia A.