Hemophilia gene therapy: ushering in a new treatment paradigm?

Abstract

After 3 decades of clinical trials, repeated proof-of-concept success has now been demonstrated in hemophilia A and B gene therapy. Current clinical hemophilia gene therapy efforts are largely focused on the use of systemically administered recombinant adeno-associated viral (rAAV) vectors for F8 or F9 gene addition. With multiple ongoing trials, including licensing studies in hemophilia A and B, many are cautiously optimistic that the first AAV vectors will obtain regulatory approval within approximately 1 year. While supported optimism suggests that the goal of gene therapy to alter the paradigm of hemophilia care may soon be realized, a number of outstanding questions have emerged from clinical trial that are in need of answers to harness the full potential of gene therapy for hemophilia patients. This article reviews the use of AAV vector gene addition approaches for hemophilia A and B, focusing specifically on information to review in the process of obtaining informed consent for hemophilia patients prior to clinical trial enrollment or administering a licensed AAV vector.

Graphical abstract

Figure 1.

Biochemical characterization of FIX-Padua (FIX-R338L). Data support that FIX-R338L requires factor VIIIa (FVIIIa) cofactor function for enzymatic activity to generate factor Xa (FXa) from FX and is similarly activated for factor XIa (FIXa) and inactivated by antithrombin (AT). Modified with permission from Samelson- Jones et al.

Figure 2.

Aggregated reported annualized bleeding rate data for hemophilia A and B clinical trials before (blue) and after (maroon) receiving the described recombinant AAV vectors. The dotted line denotes an annualized bleeding rate of 1.AAV8-wt-FIX, also known as scAAV2/8-LP1-hFIXco. Data from Nathwani et al. AMT-060 data from Miesbach et al. AMT-061, now etranocogene dezaparvovec, data from Pipe et al. SPK-9001, now fidancogene elaparvovec, data from George et al. BMN270, now valoctocogene roxaparvovec, data from Pasi et al. SPK-8011 data from George et al.

Figure 3.

FVIII activity 1 and 2 years post vector infusion in trial participants who received a therapeutic vector dose (6 × 10¹³ vg/kg of AAV5-hFVIII vs 5 × 10¹¹ to 2 × 10¹² vg/kg of SPK 8011) that maintained expression and were followed >2 years post vector. FVIII activity is reported by 1-stage assay for SPK-8011 participants and CSA in participants who received AAV5-hFVIII. Data for AAV5-hFVIII are from Pasi et al and data for SPK-8011 are from George et al.

Figure 4.

Summary of known and unknown variables for recombinant AAV gene edition clinical efforts for in hemophilia A and B.