The latest gene therapy for chronic granuloma: restoring immunity to patients for up to 1 year

Orchard Therapeutics is a UK gene therapy start-up dedicated to changing the lives of patients with severe and life-threatening rare diseases through innovative gene therapy. Recently, the company presented clinical proof-of-concept evidence for gene therapy OTL-102 to treat X-series chronic granuloma (X-CGD) at the annual meeting of the American Society of Hematology (ASH2018).
these clinical proof-of-concept data came from 7 patients (aged 2-27 years) who were severely affected by X-CGD in a single dose of OTL-102, an introviral virus gene therapy developed using a self-inactivated virus vector (G1XCGD). Of the seven assessable patients, 6 sustained functional neutral granulocytes (an average of 30.2%) for 12 months or more after treatment. Previously disclosed data show that this is above the minimum threshold of 10% that is necessary to show potential clinical benefits and to restore both biodetic factors and immunity. Two other patients were treated but died within three months of treatment, and the researchers believe the two deaths were related to pre-existing complications of the disease associated with the progression of the disease. These results are the first to demonstrate that introphy hematopoietic stem cell gene therapy has the potential to produce corrected neutral granulocyte function for 12 months or more in patients severely affected by X-CGD.
, a life-threatening disease that can lead to significant reductions in the quality of life and longevity of patients," commented Dr. Kohn, a professor of pediatric hematology/oncology at the University of California, California, who presented the report. Current treatment options, including preventive antibiotics, antifygal drugs and hematopoietic stem cell transplantation, have significant associated risks and limitations. By proving for the first time that self-hematopoietic stem cell gene therapy can achieve long-term clinical benefits from consistent levels of functional nexual granulocytes, we hope that OTL-102 will provide x-CGD patients with a new treatment option that improves the quality and length of life and avoids chronic disease-related infections and inflammation.
Professor Adrian Thrasher, of the Institute of Child Health at University College London, commented: "These clinical proof-of-concept data confirm for the first time that the recovery of immune function in X-CGD patients treated with inosotroviral gene therapy lasted 12 months or more. In 6 of the 7 assessable patients, persistent functional neutral granulocyte levels were observed at more than 10%, and previously disclosed data showed that this level was sufficient to demonstrate potential clinical benefits. This important milestone, together with improved clinical results and a new safety profile with no signs of genotoxicity, suggests that OTL-102 could lead to a revolutionary therapy for X-CGD patients. Orchard
to meet with regulators in 2019 to discuss the clinical development path of the OTL-102 treatment X-CGD project.
X-CGD is a rare, life-threatening primary immunodeficiency caused by a mutation in the CYBB gene that encodes the gp91phox protein, an important component of the NADPH oxidase complex that produces superoxides. and respiratory bursts that effectively kill ingested microorganisms (respiratory bursts, the process by which neitrocytes are activated, oxygen consumption increases significantly, and most of the oxygen consumed is produced by NADPH and NADH oxidase in cells. Because of the CYBB gene mutation, specific white blood cells, including neutral granulocytes, are not effective at removing bacteria and fungi.
X-CGD patients are vulnerable to severe chronic bacterial and fungal infections. In addition, X-CGD can cause inflammation, characterized by granuloma formation and potentially life-threatening organs including the gastrointestinal tract and lungs. Recurrent infections and inflammation can seriously reduce the quality of life expectancy of patients. Preventive antibiotics and antifive drugs do not stop the disease from progressing, and the only cure possible at present, isogen hematopoietic stem cell transplantation, may be related to the toxicity associated with anti-host disease of the graft and the chemotherapy conditions required for heterogeneous cell transplantation.
In addition to OTL-102, Orchard's portfolio of in-body gene therapies includes a listed product, Strimvelis, which was acquired from GlaxoSmithKline in April and is the first autologic gene therapy approved by the European Medicines Agency (EMA) to treat adenosine deaminase severe combined immunodeficiency (ADA-SCID). In addition, Orchard has several clinical programs in its pipeline to treat primary immunodeficiency (OTL-101: treatment of ADA-SCID; OTL-103: treatment of Wiscott-Aldridge syndrome (WAS), neuro metabolic disease (OTL-200: treatment of hetero-cerebral whiteness malnutrition; OTL-201:201: Treatment of Type A San Felipe syndrome (MPS-IIIA); OTL-202: Treatment of Type B San Felipe syndrome (MPS-IIIB),hemoglobin disease (OTL-300: treatment of transfusion dependence β Thylamphidemia (TDBT),) and preclinical projects in several studies are under study. (Bio Valley)