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Introduction: Adenosine deaminase (ADA) deficiency is an ultrarare inherited purine metabolism disorder characterized by severe combined immunodeficiency. Elapegademase‐lvlr is a new pegylated recombinant bovine ADA used in enzyme‐replacement therapy (ERT) for ADA deficiency. Therefore, replacement with the new drug may eliminate the infectious risks associated with the currently used bovine intestinal‐derived product, pegademase. Methods: We conducted a multicenter, single‐arm, open‐label, phase 3, and postmarketing clinical study of elapegademase for patients with ADA deficiency. The following biochemical markers were monitored to determine an appropriate dose of elapegademase: the trough deoxyadenosine nucleotide (dAXP) level ≤0.02 μmol/mL in erythrocytes or whole blood and the trough serum ADA activity ≥1100 U/L (equivalent to plasma levels ≥15 μmol/h/mL) indicated sufficient enzyme activity and detoxification as efficacy endpoints and monitored adverse events during the study as safety endpoints. Results: A total of four patients (aged 0–25 years) were enrolled. One infant patient died of pneumonia caused by cytomegalovirus infection whereas the other three completed the study and have been observed in the study period over 3 years. The infant patient had received elapegademase at 0.4 mg/kg/week until decease and the others received elapegademase at maximum doses of 0.3 mg/kg/week for 164–169 weeks. As a result, all four patients achieved undetectable levels of dAXPs together with sufficient enzyme activity, increased T and B cell numbers, and slightly elevated and maintained IgM and IgA immunoglobulin levels. Serious adverse events occurred in three patients, all of which were assessed as unrelated to elapegademase. Conclusions: This study showed that elapegademase had comparable safety and efficacy to pegademase as ERT for ADA deficiency by demonstrating stable maintenance of sufficient ADA activity and lowering dAXP to undetectable levels, while no drug‐related adverse events were reported (Trial registration: JapicCTI‐163204). [ABSTRACT FROM AUTHOR]

The Sendai virus vector has received a lot of attention due to its broad tropism for mammalian cells. As a result of efforts for genetic studies based on a mutant virus, we can now express more than 10 genes of up to 13.5 kilo nucleotides in a single vector with high protein expression efficiency. To prove this benefit, we examined the efficacy of the novel ribonucleic acid (RNA) virus vector harboring the human iduronate‐2‐sulfatase (IDS) gene with 1,653 base pairs, a causative gene for mucopolysaccharidosis type II, also known as a disorder of lysosomal storage disorders. As expected, this novel RNA vector with the human IDS gene exhibited its marked expression as determined by the expression of enhanced green fluorescent protein and IDS enzyme activity. While these cells exhibited a normal growth rate, the BHK‐21 transformant cells stably expressing the human IDS gene persistently generated an active human IDS enzyme extracellularly. The human IDS protein produced failed to be incorporated into the lysosome when cells were pretreated with mannose‐6‐phosphate, demonstrating that this human IDS enzyme has potential for therapeutic use by cross‐correction. These results suggest that our novel RNA vector may be applicable for further clinical settings. [ABSTRACT FROM AUTHOR]

Background Patients with chronic granulomatous disease (CGD) develop severe infections, including Bacillus Calmette-Guérin (BCG). Although the autosomal recessive CGD (AR-CGD) patients should hypothetically develop relatively fewer infections compared to the X-linked CGD (X-CGD) patients due to more residual reactive oxygen intermediates, the impacts of BCG vaccination on AR-CGD and X-CGD patients are unclear. Herein, we demonstrated the clinical features of BCG infections, treatments, and genetic factors in CGD patients after BCG vaccination under the Japanese immunization program. Methods We collected data retrospectively from 43 patients with CGD and assessed their history of initial infection, age at diagnosis of CGD, BCG vaccination history, clinical course, treatment for BCG infections, and genetic mutations associated with CGD. Results Fourteen CGD patients avoided BCG vaccination because of other preceding infections and family history. Of 29 patients with CGD who received BCG vaccination, 20 patients developed BCG infections. Although the age at onset of initial infection in X-CGD patients was significantly younger than that in AR-CGD patients (P  < .01), the onset and frequency of BCG infections were similar in X-CGD and AR-CGD patients. In X-CGD patients, BCG infections equally developed in the patients carrying missense, insertion, deletion, nonsense, and splice mutations of CYBB. All CGD patients with BCG infections were successfully treated with anti-tuberculous drugs. Conclusions Although X-CGD patients develop severe infections at a younger age than AR-CGD patients, our data suggested that BCG infections develop at high frequency in both AR-CGD and X-CGD patients, regardless of genotype and mutant forms. [ABSTRACT FROM AUTHOR]

Purpose: Newborn screening using dried blood spot (DBS) samples for the targeted measurement of metabolites and nucleic acids has made a substantial contribution to public healthcare by facilitating the detection of neonates with genetic disorders. Here, we investigated the applicability of non-targeted quantitative proteomics analysis to newborn screening for inborn errors of immunity (IEIs)., Methods: DBS samples from 40 healthy newborns and eight healthy adults were subjected to non-targeted proteomics analysis using liquid chromatography-mass spectrometry after removal of the hydrophilic fraction. Subsequently, DBS samples from 43 IEI patients were analyzed to determine whether patients can be identified by reduced expression of disease-associated proteins., Results: DBS protein profiling allowed monitoring of levels of proteins encoded by 2912 genes, including 1110 listed in the Online Mendelian Inheritance in Man database, in healthy newborn samples, and was useful in identifying patients with IEIs by detecting reduced levels of disease causative proteins and their interacting proteins, as well as cell-phenotypical alterations., Conclusion: Our results indicate that non-targeted quantitative protein profiling of DBS samples can be used to identify patients with IEIs and develop a novel newborn screening platform for genetic disorders., (© 2024. The Author(s).)

Regulators and industry are actively seeking improvements and alternatives to current models and approaches to evaluate potential carcinogenicity of gene therapies (GTs). A meeting of invited experts was organized by NC3Rs/UKEMS (London, March 2023) to discuss this topic. This article describes the consensus reached among delegates on the definition of vector genotoxicity, sources of uncertainty, suitable toxicological endpoints for genotoxic assessment of GTs, and future research needs. The collected recommendations should inform the further development of regulatory guidelines for the nonclinical toxicological assessment of GT products.

Two patients with adenosine deaminase (ADA)-deficient severe combined immunodeficiency (ADA-SCID) received stem cell-based gene therapy (SCGT) using GCsapM-ADA retroviral vectors without preconditioning in 2003 and 2004. The first patient (Pt1) was treated at 4.7 years old, and the second patient (Pt2), who had previously received T cell gene therapy (TCGT), was treated at 13 years old. More than 10 years after SCGT, T cells showed a higher vector copy number (VCN) than other lineages. Moreover, the VCN increased with differentiation toward memory T and B cells. The distribution of vector-marked cells reflected variable levels of ADA requirements in hematopoietic subpopulations. Although neither patient developed leukemia, clonal expansion of SCGT-derived clones was observed in both patients. The use of retroviral vectors yielded clonal dominance of vector-marked clones, irrespective of the lack of leukemic changes. Vector integration sites common to all hematopoietic lineages suggested the engraftment of gene-marked progenitors in Pt1, who showed severe osteoblast (OB) insufficiency compared to Pt2, which might cause a reduction in the stem/progenitor cells in the bone marrow (BM). The impaired BM microenvironment due to metabolic abnormalities may create space for the engraftment of vector-marked cells in ADA-SCID, despite the lack of preconditioning., Competing Interests: The authors declare no competing interests., (© 2021 The Authors.)