Clinical Trials for Blindness and Hemophilia Gene Transfer Underway


The Center for Cellular and Molecular Therapeutics at Children's Hospital is testing two cutting-edge gene transfer approaches to treatment in Phase 1 clinical trials. Focused on hemophilia and a form of blindness, the trials are both evaluating the safety and tolerability of the approaches.

One of only a few such programs based at a pediatric institution, the center targets new gene, stem cell and tissue engineering findings that have the greatest potential impact to translate into medical innovations. Howard Hughes Medical Institute Investigator Katherine High, M.D., Division of Hematology, leads the center.

One study focuses on treatment of Leber congenital amaurosis (LCA), a rare but severe form of retinal degeneration that is present at birth. Mutations in any one of at least ten different genes can give rise to the disease, which leads to the death of the photoreceptor cells in the eye. There is currently no treatment for LCA, and all children with the disease eventually become completely blind.

Approximately 20 percent of LCA cases are caused by mutations in the gene encoding RPE65, a protein that is necessary for vision. The gene transfer approach under investigation, which was developed by University of Pennsylvania investigator Jean Bennett, M.D., Ph.D., uses adeno-associated viral (AAV) vector to deliver the gene for RPE65 into the eye. The vector is injected under the retina during a surgical procedure and participants are evaluated for any safety concerns in both the long- and short-term.

This study, led by principal investigator Albert Maguire, M.D., focuses on nine young adults and children with LCA ages 8 to 27. Participants in this age group represent good candidates for the trial, because the pathways carrying visual signals have not yet atrophied, but they are less likely than younger children to experience problems like amblyopia, commonly known as lazy eye. If results in this open label, dose escalation trial are favorable, future trials will focus on younger age groups.

"This investigation is particularly noteworthy because it is the first pediatric gene transfer trial to be conducted for a non-life threatening condition," says Dr. High. "In addition, it is the first trial to try to restore the function of an organ that is no longer functioning."

Catherine Manno, M.D., Division of Hematology, leads the center's second gene transfer clinical trial. This trial focuses on hemophilia B, a bleeding disorder that results from a deficiency of blood coagulation factor IX. The current treatment options for hemophilia have a number of limitations that make it difficult for physicians to provide comprehensive, accessible treatment to all hemophilia patients. The treatment under investigation would potentially provide a viable alternative for disease management.

Investigators are studying an AAV vector that delivers the gene for factor IX. They have already conducted a Phase 1 clinical trial that delivered the treatment into the hepatic artery. The results indicated that treatment was safe and could achieve therapeutic levels of factor IX. However, a decline in Factor IX expression was associated with an immune cell response, which may have been responsible for eliminating the liver cells that had incorporated the gene for factor IX from the AAV vector. Now investigators want to study doses that can achieve long-lasting, sustained expression.

The current trial is designed to continue to evaluate the safety of the gene transfer, and to deliver it in conjunction with sirolimus and mycophenolate mofetil (MMF), two immunomodulating agents. The study, supported by key scientific advisor, Valder Arruda, M.D., Ph.D., Division of Hematology, focuses on eight to nine participants with severe hemophilia B who express 1 percent or less of the normal level of Factor IX. The open label, dose ranging study involves a single administration of vector that is injected into the hepatic artery. As safety is established in one group of participants, the next group receives a higher dose. In addition to the vector, all patients receive sirolimus and MMF according to a specified regimen and individual patient immune responses.

"The implications that this gene transfer approach may have for hemophilias alone are considerable," says Dr. High. "But this investigation also serves as a platform study that may eventually enable other types of liver applications. Since so many diseases could potentially be addressed by liver-directed gene transfer, this work has ramifications that extend far beyond hemophilia."

The Center for Cellular and Molecular Therapeutics is currently recruiting participants for both of these studies and hope to enroll the first participants in the next few weeks. Based on preclinical data in the LCA trial and previous results in the hemophilia B trial, investigators are confident that the trials will yield valuable information that can lay the groundwork for future progress.

The center is one of six Centers of Emphasis at Children's Hospital, part of the Hospital's significant investment in translational research. The centers target areas of research that have the greatest potential to translate basic findings to medical innovations.

Resources that Children's Hospital provides through the Centers for Emphasis have enabled these gene transfer trials to be possible. One such resource is the newly established Clinical Vector Core, a current Good Manufacturing Processes facility that produces clinical-grade vectors in accordance with FDA regulations. The core has already established a track record of consistency, high vector production capacity and world-class expertise.