AAV-MEDIATED GENE THERAPY FOR HEMOPHILIA B-EXPRESSION AT THERAPEUTIC LEVELS WITH LOW VECTOR DOSES
Author(s): ,
Katherine A High
Affiliations:
Spark Therapeutics,Philadelphia,United States
,
Lindsey George
Affiliations:
Pediatrics,Children's Hospital of Philadelphia,Philadelphia,United States
,
Spencer Sullivan
Affiliations:
University of Mississippi Medical Center,Jackson,United States
,
Alvin Luk
Affiliations:
Spark Therapeutics,Philadelphia,United States
,
Teresa Urich
Affiliations:
Spark Therapeutics,Philadelphia,United States
,
Jerome Teitel
Affiliations:
St. Michael's Hospital,Toronto,United States
,
Adam Cuker
Affiliations:
Perelman School of Medicine of the University of Pennsylvania,Philadelphia,United States
,
Fraser Wright
Affiliations:
Spark Therapeutics,Philadelphia,United States
,
Yifeng Chen
Affiliations:
Spark Therapeutics,Philadelphia,United States
,
Daniel Hui
Affiliations:
Spark Therapeutics,Philadelphia,United States
,
Katie Wachtel
Affiliations:
Spark Therapeutics,Philadelphia,United States
,
Aline Galvao
Affiliations:
The Children's Hospital of Philadelphia,Philadelphia,United States
,
Linnea E McMillan
Affiliations:
The University of Mississippi Medical Center,Jackson,United States
,
Daniel Takefman
Affiliations:
Spark Therapeutics,Philadelphia,United States
,
Marcus E Carr
Affiliations:
Pfizer,Philadelphia,United States
,
Linda Couto
Affiliations:
Spark Therapeutics,Philadelphia,United States
Xavier Anguela
Affiliations:
Spark Therapeutics,Philadelphia,United States
EHA Learning Center. Sullivan S. Jun 11, 2016; 135342
Dr. Spencer Sullivan
Dr. Spencer Sullivan
Login now to access Regular content available to all registered users.

Access to EHA Members only content is an EHA membership benefit.
Click here to join EHA or renew your membership here.


Abstract
Discussion Forum (0)
Rate & Comment (0)
Abstract: LB771

Type: Poster Presentation

Presentation during EHA21: On Saturday, June 11, 2016 from 17:30 - 19:00

Location: Poster area (Hall H)

Background
Published data from Nathwani et al. (NEJM 2014) demonstrated long-term expression of Factor IX in men with hemophilia B infused with an AAV8 vector expressing wild-type Factor IX. However, levels of expression ranged from 1.4%>2.2% normal at the lowest dose (2 x 1011 vector genomes [vg]/kg body weight) to 2.9-7.2% normal at the highest dose (2 x 1012 vg/kg). Moreover, 4/6 subjects infused at the highest dose required a course of prednisolone to reduce rising transaminases associated with the highest dose (but not observed at the lower doses of 2 x 1011 or 6 x 1011 vg/kg). Data from a natural history study of patients with hemophilia by den Uijl et al. suggest that circulating levels of ~12% are required to eliminate spontaneous joint bleeds (Haemophilia 2011). 

Aims
We sought to develop a high specific activity vector that would drive therapeutic levels of FIX activity at doses low enough to avoid the need for immunomodulation with steroids.

Methods
We developed a vector containing: 1) a novel bioengineered AAV capsid with tropism for liver; and 2) a Factor IX expression cassette that carries a strong liver-specific promoter driving the expression of FIX Padua (R338L). The Padua variant shows an ~8-fold increase in specific activity compared to wild-type FIX (Simioni et al., NEJM 2009). Based on studies in non-human primates, we predicted that therapeutic FIX activity levels, >10%, would be attained at doses as low as 5 x 1011 vg/kg. We further predicted that the ability to observe therapeutic levels of FIX activity at lower doses of vector would limit potential need for a course of immunomodulation with steroids. 

Results
Here we report data on the first three subjects with severe hemophilia B infused with this novel vector. The first two subjects, ages 23 and 18 respectively, had no prior history of liver disease, while the third, age 47, had a history of HCV infection but had cleared spontaneously. These subjects had been screened for neutralizing antibodies to the novel AAV capsid and found to be negative. Subjects were infused intravenously with SPK-FIX at a dose of 5 x 1011 vg/kg over a period of ~1 hour.  FIX activity levels (shown in figure) in the first two subjects have plateaued at 28% and 30% respectively at 18 and 7 weeks post infusion, while subject #3 is currently at 16% 3 weeks after infusion. Subject #3 treated himself with an extended half-life product for a suspected ankle bleed 2 days after vector infusion; other than this there have been no other factor infusions and no bleeds in the 28 cumulative weeks of observation. There have been no transaminase elevations higher than 1.5 times upper limit of normal, and steroids have not been administered to any subjects thus far. ELISPOTs were used to monitor T cell responses to AAV and to FIX in all subjects and have shown no or very low responses. Of note, the time course of rise in Factor IX levels to a plateau level has been remarkably consistent among the three subjects to date.

Conclusion
Conclusion/Summary: We report the first clinical results using a novel bioengineered AAV capsid expressing a high specific activity FIX transgene. This has led to plateau FIX activity levels of 28% and 30% in the first two subjects infused, with no factor use since vector infusion. The development of a vector that can direct high level clotting factor expression at low doses, so that immunosuppression is not required, represents an important goal for liver-directed gene therapy. 



Session topic: Bleeding disorders (Poster)

Keyword(s): AAV, Gene therapy, Hemophilia B
Code of conduct/disclaimer available in General Terms & Conditions
Anonymous User Privacy Preferences

Strictly Necessary Cookies (Always Active)

MULTILEARNING platforms and tools hereinafter referred as “MLG SOFTWARE” are provided to you as pure educational platforms/services requiring cookies to operate. In the case of the MLG SOFTWARE, cookies are essential for the Platform to function properly for the provision of education. If these cookies are disabled, a large subset of the functionality provided by the Platform will either be unavailable or cease to work as expected. The MLG SOFTWARE do not capture non-essential activities such as menu items and listings you click on or pages viewed.


Performance Cookies

Performance cookies are used to analyse how visitors use a website in order to provide a better user experience.



Google Analytics is used for user behavior tracking/reporting. Google Analytics works in parallel and independently from MLG’s features. Google Analytics relies on cookies and these cookies can be used by Google to track users across different platforms/services.


Save Settings