Factor VIII Expression From a Novel F8 Transgene Through a Lentiviral Vector Transduced CD34+ Autologous Hematopoietic Stem Cells for Gene Therapy of Severe Hemophilia Α

Highlights From the 66th ASH Annual Meeting and Exposition

Factor VIII Expression From a Novel F8 Transgene Through a Lentiviral Vector Transduced CD34+ Autologous Hematopoietic Stem Cells for Gene Therapy of Severe Hemophilia Α: Final Results From a Phase 1 Clinical Trial

Presenting Author: Alok Srivastava, MD, FRACP, FRCPA, FRCP

Alok Srivastava, MD, FRACP, FRCPA, FRCP^1,2; Aby Abraham, MD, DM^1*; Fouzia N Aboobacker, DNB, DM^3*; Gurbind Singh, PhD^4*; Tulasi Geevar, MD^5*; Uday Kulkarni, MD, DM¹; Sushil Selvarajan, MD, DM^6*; Anu Korula, MD, DM, MRCP^7*; Rutvi Gautam Dave, MD^8*; Mohanashankar A M, MSc^9*; Abraham Sunder Singh, RN^10*; Anbu Jeba, RN^6*; Navien Kumaar, MSc^6*; Christopher Benjamin, B Pharm, Dip Clin Pharm^6*; Kavitha M Lakshmi, MSc^6*; Shaji R Velayudhan, PhD^6,11*; Sukesh C Nair, MD^12*; Gabriela Denning, PhD^13*; Pete Lollar, MD¹⁴; Christopher B Doering, PhD¹⁵; and H. Trent Spencer, PhD^15*

Department of Haematology, Christian Medical College Ranipet Campus, Ranipet, India
Unit of inStem Bengaluru, Centre for Stem Cell Research, Vellore, India
Department of Haematology, Christian Medical College Vellore, Vellore, India
Centre for Stem Cell Research (a Unit of inStem, Bengaluru), Vellore, India
Christian Medical College, Vellore, Vellore, Tamil Nadu, India
Department of Haematology, Christian Medical College, Vellore, India
Department of Haematology, Christian Medical College & Hospital, Vellore, India
Christian Medical College, Vellore, Vellore, IND
Centre for Stem Cell Research (a unit of inStem, Bengaluru), Vellore, India
Department of Haematology, Christian Medical College Vellore, Ranipet Campus, Ranipet, Tamil Nadu, India
Centre for Stem Cell Research (a unit of inStem, Bengaluru), Vellore, Tamil Nadu, India
Department of Transfusion Medicine and Immunohematology, Christian Medical College, Vellore, India
Expression Therapeutics, Inc., Tucker, GA
Emory University, Children's Center, Atlanta, GA
Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Emory University and Children's Healthcare of Atlanta, Atlanta, GA

Data Points

Clinical Trials

Figure 1: Serial Factor VIII Activity (One-Stage Assay) After Gene Therapy

A Phase 1 clinical trial tested a third-generation lentiviral vector for gene therapy in patients with severe hemophilia A. Five male participants (ages 22-41) received autologous hematopoietic stem cell transplantation (HSCT) with transduced CD34+ cells. The trial had two groups: G1 (two participants) and G2 (three participants, with an enhanced protocol).

The therapy was well tolerated with no significant toxicity, and neutrophil and platelet engraftment occurred within 10-15 days. FVIII levels ranged from 4-7.9% in G1 and 14.2-36.6% in G2 by day 60. Over 77 months, no bleeding episodes occurred (annualized bleeding rate = 0). Vector copy numbers were higher in G2, correlating with FVIII levels. FVIII mRNA expression was highest in CD14+ cells, supporting targeted expression.

This therapy demonstrated sustained FVIII expression with no major safety issues, but further trials are required for long-term evaluation.