Gene Therapy for Adenosine Deaminase Deficiency: A Comprehensive Evaluation of Short- and Medium-Term Safety

Abstract

Loss of adenosine deaminase activity leads to severe combined immunodeficiency (ADA-SCID); production and function of T, B, and natural killer (NK) cells are impaired. Gene therapy (GT) with an autologous CD34-enriched cell fraction that contains CD34 cells transduced with a retroviral vector encoding the human ADA cDNA sequence leads to immune reconstitution in most patients. Here, we report short- and medium-term safety analyses from 18 patients enrolled as part of single-arm, open-label studies or compassionate use programs. Survival was 100% with a median of 6.9 years follow-up (range, 2.3 to 13.4 years). Adverse events were mostly grade 1 or grade 2 and were reported by all 18 patients following GT. Thirty-nine serious adverse events (SAEs) were reported by 15 of 18 patients; no SAEs were considered related to GT. The most common adverse events reported post-GT include upper respiratory tract infection, gastroenteritis, rhinitis, bronchitis, oral candidiasis, cough, neutropenia, diarrhea, and pyrexia. Incidence rates for all of these events were highest during pre-treatment, treatment, and/or 3-month follow-up and then declined over medium-term follow-up. GT did not impact the incidence of neurologic/hearing impairments. No event indicative of leukemic transformation was reported.

Indications for haematopoietic stem cell transplantation for haematological diseases, solid tumours and immune disorders: current practice in Europe, 2019

“…Factors such as the type of SCID (B-lymphocyte+ vs B-lymphocyte−), patient age and status at the time of diagnosis, in particular the presence of viral respiratory infections, and the type of donor and degree of HLA histocompatibility determine the need for conditioning regimen, the recovery of B lymphocyte function and overall outcomes after HSCT [224]. Gene therapy may represent a valid alternative to allogeneic HSCT for selected well-characterised genetic subgroups of SCID, such as adenosine deaminase-deficient SCID [225,226], although the experience in this field remains limited and requires further follow-up.…”

How will the field of gene therapy survive its success?

“…In this case, the evidence for the efficacy of the treatment and the magnitude of the benefit is overwhelming. One dose of the therapy provides what is essentially a cure for the disease—there was a survival rate of 100% of the 18 children involved in the clinical trials of the treatment . The therapy was priced at 594,000 Euros in 2016, with GSK also providing a “money‐back guarantee.” Nevertheless, as of 2017, only two patients had received the treatment with two others “in queue” to receive the therapy, and GSK was seeking a buyer for Strimvelis…”

Genome-Editing and Biomedical Cell Products: Current State, Safety and Efficacy

“…Из 18 пациентов, включенных в КИ, 15 ранее получали лечение аденозиндезаминазой, конъюгированной с ПЭГ, четверым была проведена неудачная ТГСК. Всем пациентам в течение двух дней перед применением Strimvelis проводили кондиционирование бусульфаном, обладающим цитостатическим действием на миелоидные клетки, после которого они получали однократную внутривенную инфузию в диапазоне доз (0,9-18,2)•10 6 CD34 + клеток на 1 кг массы тела [28,31,32].…”

“…Средняя продолжительность наблюдения составила 6,9 года (от 2,3 до 13,4 года), в течение которого выжили 100 % пациентов. Применение Strimvelis приводило к восстановлению иммунитета: уменьшалась степень инфицирования, увеличивалась продукция иммуноглобулинов, 58 % испытуемых прекращали внутривенное введение иммуноглобулина, появлялся гуморальный ответ на вакцинацию, нормализовались популяция Т-клеток (CD3 + , CD4 + и CD8 + клеток) и тимопоэз с устойчивой способностью к пролиферации Т-клеток [32].…”

“…Считается, что часть выявленных побочных реакций связана с восстановлением иммунитета в силу их характера и сроков. Также за все время наблюдений не зарегистрированы случаи онкологических заболеваний [28,32].…”