Need For Enzyme Replacement Therapy Research Articles

Phase I study of liver depot gene therapy in late-onset Pompe disease

Gene therapy with an adeno-associated virus serotype 8 (AAV8) vector (AAV8-LSPhGAA) could eliminate the need for enzyme replacement therapy (ERT) by creating a liver depot for acid α-glucosidase (GAA) production. We report initial safety and bioactivity of the first dose (1.6×1012 vector genomes/kg) cohort (n= 3) in a 52-week open-label, single-dose, dose-escalation study (NCT03533673) in patients with late-onset Pompe disease (LOPD). Subjects discontinued biweekly ERT after week 26 based on the detection of elevated serum GAA activity and the absence of clinically significant declines per protocol. Prednisone (60mg/day) was administered as immunoprophylaxis through week 4, followed by an 11-week taper. All subjects demonstrated sustained serum GAA activities from 101% to 235% of baseline trough activity 2weeks following the preceding ERT dose. There were no treatment-related serious adverse events. No subject had anti-capsid Tcell responses that decreased transgene expression. Muscle biopsy at week 24 revealed unchanged muscle glycogen content in two of three subjects. At week 52, muscle GAA activity for the cohort was significantly increased (p<0.05). Overall, these initial data support the safety and bioactivity of AAV8-LSPhGAA, the safety of withdrawing ERT, successful immunoprophylaxis, and justify continued clinical development of AAV8-LSPhGAA therapy in Pompe disease.

Gene Therapy for ADA-Deficient Severe Combined Immunodeficiency

Source: Reinhardt B, Habib O, Shaw KL, et al. Long-term outcomes after gene therapy for adenosine deaminase severe combined immune deficiency. Blood. 2021 Oct 14;138(15):1304-1316; doi:10.1182/blood.2020010260Investigators from multiple institutions conducted a study to evaluate long-term outcomes in children with severe combined immunodeficiency (SCID) caused by lack of adenosine deaminase activity (ADA) who were treated with autologous hematopoietic stem cell transplant (HSCT) of gene-corrected cells (gene therapy [GT]). Participants were children diagnosed with SCID with absence of ADA activity, an absolute lymphocyte count of <200 cells/mm3, and no suitable sibling donor for allogeneic HSCT who were being treated with ADA enzyme replacement therapy (ERT). These patients had CD34+ cells harvested by bone marrow aspirate that were transduced with a gamma-retroviral vector encoding for a functional human ADA cDNA sequence. The transduced cells were infused into the patient. Study patients were followed at annual visits at which interval histories were obtained along with blood specimens for multiple laboratory assays. Previously, short-term outcomes (up to 2 years post-GT treatment) were reported. For the current study, long-term outcomes, including occurrence of severe or unusual infections, leukoproliferative events or malignancies, ADA enzyme activity, need for ERT, lymphocyte counts, and immunoglobulin levels were assessed 8-11 years after treatment.Data were analyzed on 10 children with ADA SCID who received GT treatment between 2009 and 2012. At the time of treatment, the study patients ranged in age from 3 months to 15 years. At follow-up, no severe, persistent, or opportunistic infections, or leukoproliferative events or malignancies, occurred in any of the study patients. In 8 of the 10 study participants, peripheral blood mononuclear cell (PBMC) ADA activity was maintained in the normal range. In 1 child, with low PBMC ADA activity, ERT was resumed 6 months after GT; no other patient required ERT following treatment with GT. Patients who received GT at the youngest ages (3 months) had the highest PBMC ADA activity. Absolute lymphocyte counts remained relatively stable in study patients over the follow-up period, although levels were ≤ the 10th percentile for healthy children. Lymphocyte counts were higher in children receiving GT at 3 months of age and, overall, counts were highly correlated with ADA activity. Four patients had Immunoglobulin G (IgM) levels in the normal range. These children were taken off immunoglobulin replacement therapy, and 2 of these responded to vaccines. The other patients had IgM levels near or below the lower limit of normal.The authors conclude that in this group of children with ADA SCID, the long-term outcomes demonstrate enduring efficacy of GT.Dr Hogan has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.ADA deficiency results from an autosomal recessive inheritance of mutations in the ADA gene, accounting for up to 15% of severe combined immunodeficiency cases and affecting 1:200,000 to 1:1,000,000 live births worldwide.1 Lack of ADA results in buildup of adenosine, 2’-deoxyadenosine, and deoxyadenosine, which is toxic to lymphocytes, bone, brain, lungs, and other organs. Within 6-12 months of age, infants develop life-threatening sinopulmonary and gastrointestinal infections with failure to thrive.2Abnormal newborn screening with reduced T cell receptor excision circles should prompt immediate testing of serum T, B, and NK lymphocytes and immunoglobulins.1 Referral to pediatric immunology, genetics, and a pediatric HSCT center will help expedite confirmatory enzyme and genetic testing while providing prophylactic antimicrobials and intravenous immunoglobulin.2 When an ideal HLA-matched healthy sibling HSCT donor is not available, enzyme replacement therapy (ERT) with intramuscular injections of polyethylene glycol-conjugated ADA helps provide some lymphocyte recovery until a possible unrelated donor or GT of autologous CD34+ HSCT.3The current study’s strengths include a standard replicable therapy protocol with consistent long-term follow-up of clinical and microscopic characteristics.3 Since the initial treatment of these individuals, advances in GT include improvements in vectors, transduction, and cryopreservation.3 Thus far, more than 100 affected individuals have undergone GT on 11 different clinical trials worldwide with excellent immunocompetent results.4 However, randomized controlled trials comparing ideal sibling HSCT or variations in GT have not been done.4 Long-term safety monitoring for malignant transformation or loss of immunocompetence can be difficult due to the diversity of treatment sites, data collection, and patient retention.5Infusion of autologous hematopoietic stem cells transduced with ADA-gammaretroviral vector gene therapy has provided long-term immune reconstitution in children with ADA deficiency.

Delphi consensus on the current clinical and therapeutic knowledge on Anderson–Fabry disease

BackgroundManagement of Anderson–Fabry disease (AFD) is contentious, particularly regarding enzyme replacement therapy (ERT). We report results of a Delphi consensus panel on AFD management. MethodsA survey to gauge consensus among AFD experts was distributed online and responses were analysed. Statements on: 1) diagnosis; 2) when starting ERT; 3) management of ERT infusion and adverse reactions; and 4) follow-up/monitoring response to therapy and progression of disease were included. Responses without consensus were discussed with an enlarged panel and modified to reach consensus. Results15 experts responded to the survey. After plenary discussion among the enlarged panel, consensus was reached on most statements. Key points were the use of a target organ biopsy to show Gb3 deposits in symptomatic women with negative molecular analysis, the need for ERT in symptomatic women and in all patients with persistent signs and symptoms±organ damage. It was agreed to assess vital signs before ERT administration and use a 0.2μL filter on infusion to reduce the risk of adverse reactions, that serum should be drawn prior to the first infusion for anti-agalsidase antibody analysis to have a baseline value if a subsequent adverse reaction appears, and that pre-medication is required in those with prior infusion reactions. Holter ECG monitoring, cardiac and brain MRI, renal parameters, and abdominal ultrasound were considered important for the assessment of disease progression and response at ERT. ConclusionsThis consensus supplies guidance to healthcare providers on best practice in the management of patients with AFD and indicates a need for more guidance.

Utilizing interactive web mapping technology to map unmet medical need for enzyme replacement therapy (ERT) for Fabry, Gaucher and MPS II

Utilizing interactive web mapping technology to map unmet medical need for enzyme replacement therapy (ERT) for Fabry, Gaucher and MPS II

Proteinase-activated receptor (PAR1) polymorphic variant correlates with thrombocytopenia in Gaucher disease

Background Enzyme replacement therapy (ERT) for Gaucher disease is safe and effectively corrects hepatosplenomegaly and hypersplenism; however, thrombocytopenia, may not normalize. Platelet proteinase-activated receptors (PARs) are signaling effectors in response to inflammation; PAR1 expression is down-regulated during inflammation and may be associated with thrombocytopenia. Accumulation of undegraded lipids in macrophages in Gaucher disease induces a chronic state of inflammation. The purpose of this study was to describe PAR1 polymorphic genotypes in patients with Gaucher disease and ascertain whether these are correlated with platelet counts. Methods Helsinki Committee approval was received for this study. Blood samples were taken from 80 patients with non-neuronopathic disease, some on ERT, and from 44 healthy Jewish controls. PAR1 polymorphisms IVS[−14(A/T)], and [−506(I/D)] and [−1426(C/T)] were analyzed. Patient data were collected from the files. Associations between PAR1 and categorical variables were analyzed by chi-square and Fisher's exact tests; assessment of associations with quantitative variables used ANOVA and Scheffe post-hoc for multiple pair-wise comparisons. Non-parametric Kruskal–Wallis ANOVA was used when one category was small. All tests were 2-tailed; p values ≤ 0.05 were considered statistically significant. Results There was a statistically significant difference ( p = 0.015) between patients and controls for [−1426(C/T)] TT genotype. There was no significant correlation for [−1426(C/T)] with disease severity, need for ERT, splenectomy, or presence of bone disease; rather, there was a significant correlation between lower platelet counts ( p = 0.0003) and the [−1426(C/T)] TT genotype and a trend for correlation with inflammation markers ( p = 0.079). There was a statistically significant correlation for [−506(I/D)] II genotype with femoral neck bone density ( p = 0.034). All patients carried the wild type for IVS[−14(A/T)]. Conclusion The [−1426(C/T)] polymorphic variant of PAR1 is associated with thrombocytopenia in Gaucher disease.

Are symptoms of peripheral neuropathy more prevalent in patients with Gaucher disease?

A previous epidemiological survey from an American referral clinic noted a high incidence of neurological symptoms among patients with type I (non-neuronopathic) Gaucher disease all of whom were treated with specific enzyme replacement. The current study replicates the above in a larger cohort of Ashkenazi Jewish patients with at least one N370S mutation which has been assumed to be protective of neurological involvement. About half the patients had mild disease and were untreated. Methods - Self-reporting questionnaires were sent to patients and their significant others as socio-economically matched controls. There was no significant difference between groups in incidence of concomitant diseases and medications, except patients who reported a significantly higher incidence of vitamin B(12) deficiency and gammopathies. Patients reported significantly higher incidence of virtually all symptoms and signs of peripheral neuropathy and a significantly higher number of symptoms than controls (mean 4.4 vs 2.4). The conclusion of this study, as of the seminal study, is that the high incidence of neurological complaints in patients with the non-neuronopathic form of Gaucher disease should be viewed in the context of concomitant illnesses, specifically, vitamin B(12) deficiency and gammopathies, regardless of the need for enzyme replacement therapy.

Improving the specificity of the [13C]mixed triacylglycerol breath test by estimating carbon dioxide production from heart rate

The [13C]mixed triacylglycerol (MTG) breath test is a non-invasive measure of fat digestion and can be used to assess the need for enzyme replacement therapy in children with cystic fibrosis (CF). However, it lacks specificity. Quantitation of cumulative percent dose recovered (cPDR) requires knowledge of carbon dioxide production rate (VCO2). A resting value is assumed, but children are unlikely to remain at rest during the test. To improve the specificity and therefore the positive predictive value (PPV) of the MTG breath test using calibrated heart rate monitors to estimate non-resting VCO2. Proof of concept study. Six children with CF, 10 healthy children and eight healthy adults performed [13C]MTG breath tests. Heart rate monitors were worn throughout the test. Non-resting VCO2 was estimated continuously from heart rate. Percentage dose recovered was calculated using predicted resting VCO2, measured resting VCO2 and non-resting VCO2 estimated from heart rate. Physical activity level (PAL) was taken as cPDR calculated using non-resting VCO2 divided by cPDR calculated using measured resting VCO2. The cutoff point was determined using two graph-receiver operator characteristics. Use of calibrated heart rate monitors to estimate non-resting VCO2 improved the specificity of the test. The PPV increased from 0.67 to 0.99. PAL was 1.3 in adults and children who performed the test in hospital, and 1.7 in children who performed the test at home. Individually calibrated heart rate monitors are useful tools to estimate non-resting VCO2 during the [13C]MTG breath test.

Intraduodenal Lipase Activity in Celiac Disease Assessed by Means of 13C Mixed-Triglyceride Breath Test

In patients with celiac disease, the occurrence of exocrine pancreatic insufficiency has been related to an impairment of the gut-mediated stimulatory effect of the meal on the pancreas. The purpose of this study was to assess the intraduodenal lipase activity in patients with celiac disease by means of the 13C mixed-triglyceride breath test and to monitor pancreatic function after the institution of a gluten-free diet. Seventeen untreated patients with celiac disease (mean age, 17.4 +/- 10.5 years) were studied. After an overnight fast, patients were given a standard test meal consisting of 100 g of white bread and 0.25 g of butter per kilogram of body weight, to which 16 mg di-stearyl-13C-octanoyl-glyceride (mixed triglyceride) had been added. Breath samples were taken twice at baseline and at 30-minute intervals for 6 hours after the meal. 13C enrichment in breath was determined by means of Isotope Ratio Mass Spectrometer (IRMS) (ANCA-NT; Europa Scientific, Crewe, UK). Results were expressed as the maximum percentage of 13C recovery per hour at any time, the time to reach peak excretion of 13C, and the percentage of 13C cumulative dose over 6 hours. Mixed-triglyceride breath test results were pathologic in three patients and at the lower limit of the normal range in another patient. In the remaining 13 patients, the results were within normal values. At the 6- and 12-month follow-ups, all patients showed normal intraduodenal lipase activity. In approximately 24% of patients with celiac disease, the intraduodenal pancreatic lipolytic activity is impaired. The mixed-triglyceride breath test could be used to assess fat maldigestion and to monitor the need for enzyme replacement therapy in such patients.