Category Archives: Genetic medicine

Summary: Infiltrating gliomas are shaped by their genetic evolution and microenvironment, researchers report. The findings may help in the development of therapies to treat glioma brain tumors.

Source: University of Colorado

Researchers have discovered that infiltrating gliomas, a common brain and spinal cord tumor, are shaped by their genetic evolution and microenvironment, a finding that could lead to more targeted treatments.

We have identified epigenetic alterations at a recurrence that are not only prognostic in some cases, but may lead to different treatment options for the various subtypes that can improve long-term survival, said study co-author D. Ryan Ormond, MD, PhD, aUniversity of Colorado Cancer Centermember and associate professor of neurosurgery at the University of Colorado School of Medicine on the CU Anschutz Medical Campus.

Thestudywas published May 31 in the journalCell.

The researchers looked at how gliomas interact with the brain, change over time, develop treatment resistance and become more invasive.

They identified three distinct phenotypes or observable traits at glioma recurrence neuronal, mesenchymal and proliferative. Each of them converge with cellular, genetic and histological features that reveal themselves at recurrence. Some of these are associated with less favorable outcomes.

In this study, scientists used participant samples from the Glioma Longitudinal Analysis Consortium or GLASS cohort, a consortium created to identify the drivers of treatment resistance in glioma.

They analyzed RNA and/or DNA sequencing data from pairs of tumors from 304 adult patients with isocitrate dehydrogenase (IDH) wild type and IDH-mutant gliomas.

The tumors recurred in specific ways depending on the IDH mutation status. The changes they underwent during recurrence depended on how they interacted with the microenvironments they inhabited.

Researchers found that many IDH-wild type tumors were more invasive at recurrence. Their neoplastic cells showed increased neuronal signaling programs, suggesting a possible role for neuronal interactions in sparking the tumors progression.

They also discovered that hypermutation, often induced by treatment with drugs like temozolomide, along with deletion of the CDKN2A gene, which makes tumor-suppressing proteins, was associated with a proliferation of tumor cells at recurrence in both glioma subtypes.

In both IDH-wild type and IDH-mutant tumors, the hypermutation was associated with increased numbers of stem-like neoplastic cells. The growth of these cells reduced overall patient survival rates.

Collectively, these results indicate that genetic evolution at recurrence can alter neoplastic glioma cells toward a more proliferative phenotype that associates with poor prognosis, the study said.

Ormond said that therapy resistance remains a serious obstacle for patients with glioma and to improve quality of life and survival it needs to be overcome. These findings, he said, will enable physicians to better target the cancer with new therapies and treatments.

Author: David KellySource: University of ColoradoContact: David Kelly University of ColoradoImage: The image is in the public domain

Original Research: Closed access.Glioma progression is shaped by genetic evolution and microenvironment interactions by Ryan Ormond et al. Cell

Abstract

Glioma progression is shaped by genetic evolution and microenvironment interactions

The factors driving therapy resistance in diffuse glioma remain poorly understood. To identify treatment-associated cellular and genetic changes, we analyzed RNA and/or DNA sequencing data from the temporally separated tumor pairs of 304 adult patients with isocitrate dehydrogenase (IDH)-wild-type and IDH-mutant glioma.

Tumors recurred in distinct manners that were dependent on IDH mutation status and attributable to changes in histological feature composition, somatic alterations, and microenvironment interactions.

Hypermutation and acquiredCDKN2Adeletions were associated with an increase in proliferating neoplastic cells at recurrence in both glioma subtypes, reflecting active tumor growth.

IDH-wild-type tumors were more invasive at recurrence, and their neoplastic cells exhibited increased expression of neuronal signaling programs that reflected a possible role for neuronal interactions in promoting glioma progression.

Mesenchymal transition was associated with the presence of a myeloid cell state defined by specific ligand-receptor interactions with neoplastic cells.

Collectively, these recurrence-associated phenotypes represent potential targets to alter disease progression.

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Recurring Brain Tumors Shaped by Genetic Evolution and Microenvironment - Neuroscience News

Mrs Olufunmilayo Israel, a single mother of three, has sought the support of Nigerians to stop stigmatising children with rare medical conditions.

In an interview with the News Agency of Nigeria (NAN) in Ibadan on Monday, Mrs Israel, a vegetable seller and graduate of the University of Ibadan (UI), specifically sought an end to stigmatisation for her three children.

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She said, Taking care of the three children, diagnosed with achondroplasia and four other normal children have been extremely difficult, especially since my husband left us.

I am seeking social support for my children from well-meaning Nigerians and NGOs, because I want to take them back to hospital.

We were told by medical experts at the University College Hospital (UCH), Ibadan, that the childrens condition is genetic.

We did not know initially as the first child did not show any sign until she was a year old and contracted tuberculosis at a creche.

In the process of accessing care at UCH her genetic condition was discovered, her hands are not straight and she has bow legs.

After her, I gave birth to two other children with the same genetic disorder.

According to her, this condition led to the separation with her husband, having spent lots of money and incurring huge debts.

She said that the children, aged four, six and 12, were highly intelligent, but that the challenge in their physical growth had been a problem.

She further said that the stigmatisation as a result of the medical condition had led to suicidal thoughts by the eldest of the three children.

NAN reports that medical experts at UCH revealed that achondroplasia is the most common type of short-limbed dwarfism, a very rare condition with fewer than 10,000 cases per year in Nigeria.

The experts said that while the condition could sometimes be hereditary, most cases of dwarfism were caused by a genetic mutation.

Prof Adebola Orimadegun of the Institute of Child Health, College of Medicine, and Principal Investigator of Study on Stunting Reduction in Nigerian Children, however, said Mrs Israel and the children could not be classified as stunted but short-statued. (NAN)

Excerpt from:
Mum of 3 kids with rare health condition seeks end to stigmatisation - Daily Trust

Abbott Nutrition has resumed formula production in its Michigan plant to address the nationwide formula shortage; 2 distinct strains of monkeypox may indicate rapid, undetected spread nationwide; the overturn of Roe v Wade could have an effect on in vitro fertilization and genetic testing.

Abbott Nutrition resumed production of baby formula on Saturday in order to address the nationwide shortage after getting the green light from the FDA. Production of EleCare and other specialty and metabolic formulas will be the first to restart production, with a product release of June 20 as the target date, according to CNBC. Abbott Nutrition was initially closed in February due to contamination. The FDA has said in a statement that it is working diligently to ensure safe resumption of infant formula production. The FDA also said that it hopes that this measure will put more baby formula on the shelves nationwide.

A recent genetic analysis of monkeypox cases indicated that there are 2 distinct strains in the United States, which could mean that the virus has been circulating in the country for some time, according to AP News. There are many monkeypox cases with the same strain as the recent cases in Europe; however, the recent analysis showed a different strain as well and both strains were in the United States last year. More analysis will need to be done to determine how long monkeypox has been in the United States. These findings could mean that the virus will be difficult to contain in the future.

The overturning of Roe v Wade could have effects on reproductive medicine at large as state policies could determine how birth control is provided or in vitro fertilization (IVF), according to STAT News. In the states that are expected to ban or limit abortion, lab-made embryos would also have legal protections, which could make IVF more complicated. Preimplantation genetic testing could also come under scrutiny as embryos that arent implanted may not be able to be frozen if they are considered people with legal rights. Alabamas anti-abortion law only applies to embryos in the womb, which would allow IVF; however, experts are still figuring out whether Oklahomas anti-abortion law will also extend to IVF.

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What We're Reading: Abbott to Resume Formula Production; 2 Strains of Monkeypox; Impact of SCOTUS Decision on IVF, Embryo Genetic Testing - AJMC.com...

Introduction

Tuberculosis (TB) is an infectious disease, which remains a major public health problem globally. In the year 2020, the estimated number of people who died from tuberculosis is 1.3 million among HIV-negative people and 214,000 among HIV-positive.1 Current pharmacotherapy of tuberculosis involves a combination of at least four drugs. Rifamycins are key components of pharmacotherapy for both active and latent TB.

Rifamycins are a class of antibiotics isolated from Amycolatopsis in 1957. Four distinct semi-synthetic rifamycin analogs (rifampicin, rifabutin, rifapentine, and rifaximin) are approved for clinical use. Rifampicin, rifabutin, and rifapentine are used for the treatment of TB and chronic staphylococcal infections.2 Rifapentine given once weekly for 12 weeks with isoniazid is effective and well tolerated in the treatment of latent TB.3 Rifaximin is poorly absorbed from the gastrointestinal tract and is indicated for the treatment of travelers diarrhea, functional bloating, irritable bowel syndrome, and small bowel bacterial overgrowth.4

Variable exposure to anti-TB drugs may be associated with unfavorable treatment outcomes.5 Factors associated with drug exposure variability of anti-TB drugs, such as age, gender nutritional status, human immune-deficiency virus, diabetes, and genetic polymorphism, were described in various previous studies.69 There has been a notable development in recent years on how genetic variations in drug-metabolizing enzymes and transporters contribute to variation in exposure and response to the drugs.10,11 As the local and systemic concentrations of anti-TB drugs are affected by genetic variations in drug-metabolizing enzymes and transporters, pharmacokinetic and pharmacogenetic studies are increasingly performed to optimize TB treatments.12,13

Rifamycins are thought to be metabolized by microsomal hepatic carboxylesterases (CES), and serine esterase arylacetamide deacetylase (AADAC) to 25-deacetylrifamycins.14,15 The uptake, distribution, and excretion of rifampicin are mediated by membrane drug transporters. There are two transporters superfamilies; the solute carrier (SLC) transporters and the adenosine triphosphate (ATP)-binding cassette (ABC) transporters.16 SLC superfamily consists of more than 400 membrane-bound family proteins. Multiple studies revealed that the SLCO1B1 sinusoidal influx transporter influences rifampicin influx,17,18 and the SLCO1B1 *15 haplotype is associated with rifampin-induced liver injury.19 Most ABC transporters in eukaryotic cells mediate the efflux of the substrate from the cells. ABC transporters influence the hepatocellular concentration of rifampicin.2023 Rifamycins are substrates of P glycoprotein (P-gp), coded for by the polymorphic ABCB1 gene.24 Rifampicin also induces ABCB1 gene expression.25 Although SLCO1B1 and ABCB1 gene products have been reported to influence rifamycins pharmacokinetics, there is no candidate gene identified so far for therapeutic drug monitoring.

Recently, advances in technology and scientific discoveries in the medical arena have enabled the practitioner to individualize drug therapy. The keen interest to personalize TB treatment has been a point of discussion over the last decade.2629 The use of pharmacokinetics and pharmacogenetics of anti-tubercular drugs as tools for TB treatment optimization has been discussed previously.13,18 However, there is a scarcity of comprehensive data on the pharmacogenetics of rifamycins. This systematic review was, therefore, designed to evaluate the influence of genetic polymorphism in rifamycins metabolizing enzymes and transporters on their pharmacokinetics.

This systematic review was carried out following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statements (Table S1). The protocol has been registered at PROSPERO with registration number CRD42020206029.

Relevant studies were identified through a search of PubMed, Web of Science, Embase, and Scopus databases. The following combination of words was used: pharmacokinetics OR concentration OR drug concentration AND rifamycins OR rifampin OR rifampicin OR rifabutin OR rifapentine OR rifaximin AND SLCO1B1 OR ABCB1 OR carboxylesterase OR CES OR Arylacetamide deacetylase OR AADAC AND Genetic polymorphism OR pharmacogenetics OR pharmacogenomics OR single nucleotide polymorphisms OR SNP. Further, a hand-search was done from reference lists of studies included to identify eligible studies. There was no limitation on the dates of publication or publication status. Publications available only in the English language were included. The search was refined to studies of human participants.

The following were the eligibility criteria for the inclusion of studies: 1. Human participant studies; 2. Studies that reported on pharmacokinetic parameters of rifamycins; 3. Studies in which study participants were genotyped for rifamycins metabolizing enzyme or transporters gene; and 4. Studies that reported on the pharmacokinetic parameters of rifamycins and the effect of genetic variation on pharmacokinetics.

Validated tools exist for genetic association studies methodological quality assessment. We used the quality of genetic association studies (Q-Genie)30 tool to assess the quality of included studies. Using the checklist adopted (Table S2) from Q-Genie TS assessed the quality of selected studies.

Two (TS and GM) independently extracted data from all included publications using a pre-prepared data extraction format which included items as follows: first author, publication year, study drug, sample size, type of pharmacokinetic parameters assessed, a country in which the study was conducted, participant characteristics, genetic polymorphism investigated, pharmacokinetic parameter results and its association with genetic polymorphism. The disparity between the two reviewers during data extraction was resolved through discussion.

No contact with the authors was done for missing data and the data presented in this review were extracted from the articles.

A total of 115 articles related to genetic polymorphism of drug-metabolizing enzymes and drug transporters with the pharmacokinetics of rifamycins were retrieved from PubMed, Web of Science, Scopus, and Embase databases. Hand search identified two additional articles which were not obtained during the database search. As shown in the PRISMA flowchart (Figure 1) 51 duplicates were removed. The remaining 66 articles were screened by title and abstract for predefined criteria, and 47 were excluded. The reasons for exclusion of studies from titles and abstracts were (1) review articles (N=3); (2) studies focusing on drugs other than rifamycins (N=26); (3) studies that did not have information on the pharmacokinetics of rifamycins but only genetic information reported (N=8); and (4) studies in which only pharmacokinetics data were reported without genetic information (N=10). Furthermore, four articles were excluded after reading them fully. Of the four articles excluded; one article did not contain rifamycins data, one study was done on healthy participants and the other two articles did not contain pharmacokinetic parameters.

Figure 1 PRISMA flow diagram showing the literature search for studies that investigated the effect of genetic variations in drug metabolizing enzymes and drug transporters on the pharmacokinetics of rifamycins.

Notes: PRISMA figure adapted from Liberati A, Altman D, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Journal of clinical epidemiology. 2009;62(10). Creative Commons.

Of the 15 articles selected for qualitative data synthesis, most of the studies (N=14) focused on SLCO1B1 gene polymorphism association with the pharmacokinetics of rifamycins (Table S3). Specifically, seven studies evaluated the association of SLCO1B1 gene polymorphism and pharmacokinetics,3137 three studies SLCO1B1 and ABCB1 gene polymorphism with pharmacokinetics,3840 one study SLCO1B1 and AADAC gene polymorphism with pharmacokinetics,41 one study SLCO1B1, and CES gene polymorphism with pharmacokinetics,42 and two studies SLCO1B1, AADAC, and CES gene polymorphism with pharmacokinetics.43,44 Only one study investigated the association between CES gene polymorphism with pharmacokinetics.45 The most studied rifamycins are rifampicin (thirteen studies) and rifapentine (two studies). No study is available that reported the pharmacokinetic-pharmacogenetic association for rifabutin and rifaximin.

There was variation among studies in sample size, the type of study participants, and the pharmacokinetics parameter compared with gene polymorphism. The smallest sample size was 34,39 while the largest was 256.34 The study participants were TB patients from 13 different countries and races. The majority of the studies were done on adults, but one study data were obtained from children.42 In some studies, participants were TB-HIV co-infected patients. The pharmacokinetics parameters commonly compared with gene polymorphism were maximum concentration (Cmax), AUC (area under the curve), and clearance. However, methods for blood sample collection and pharmacokinetic parameter determination varied among studies.

SLCO1B1 gene encodes for an Organic Anion Transport Proteins 1B1 (OATP1B1). It is located on chromosome 12. OATP1B1 is a transmembrane protein involved in the uptake of various drugs including rifamycins from the blood into the hepatocyte.46 Currently, 191 clinical variants have been reported. SLCO1B1c.521T>C (rs4149056), where the valine amino acid changed to alanine at position 174, was reported to affect drug response.47 Eight studies assessed the effect of rs4149056 SNPs on rifamycin pharmacokinetic parameters. Among these studies, only Huerta-Garca et al reported increased AUC among heterozygous CT for SLCO1B1 521T>C than the other genotypes. However, the observed increase in AUC was not statistically significant.39 A summary of specific transporters influence on pharmacokinetics is presented in Table 1.

Table 1 Summary of the Studies Reported the Drug Transporter (SLCO11 and ABC1B) Gene Polymorphisms Association with Rifamycins Pharmacokinetics Variation

SLCO1B1 g.38664C>T (rs4149032) was reported in twelve studies. rs4149032 is an intronic SNP most common in the African population.48,49 Gengiah et al reported high frequency in the SLCO1B1 (rs4149032) gene polymorphism and its association with low median rifampicin C2.5hr in the heterozygous and homozygous variant carriers.32 Similarly, Chigutsa et al reported high allelic frequency of the SLCO1B1 rs4149032 polymorphism and 28% reductions in the bioavailability of rifampin for homozygous variants.40 No statistically significant increase in the rifampicin exposure for the homozygous TT of g.38664 C > T (rs4149032) was observed in the study of Kim et al.37 However, the large number of studies reviewed here did not report any observed significant effect of SLCO1B1 rs4149032 SNP polymorphism with rifamycin pharmacokinetic variation.

SLCO1B1 c.388A>G (rs2306283) is another SNP in the SLCO1B1 gene. This SNP causes a change of asparagine amino acid to aspartic at 130, but the effect of this change on the transporter function is not clear yet. Huerta-Garca et al reported the AG genotype derived from SNP SLCO1B1 c.388A>G was associated with lower rifampicin AUC024 h values compared to those with AA genotype.39 In post hoc analysis, Dompreh et al observed that the SLCO1B1 c.388AA genotype was associated with low rifampin concentrations compared to those with c.388GG.42 The five remaining studies did not report any association between rs2306283 SNP and rifamycin pharmacokinetics. The SNP SLCO1B1 c.463 C>A (rs11045819) is another variant allele of the SLCO1B1 gene reported to affect rifamycin pharmacokinetics. According to Weiner et al, patients with SLCO1B1c.463C>A variant allele had 42% lower rifampin exposure, 34% lower peak concentration levels, and 63% greater apparent oral clearance compared with SLCO1B1 c.463CC.36 However, the remaining five studies did not report any association between rs11045819 SNPs and rifamycin pharmacokinetics.

ABCB1 (ATP-binding cassette sub-family B member 1) genes encode for P-gp also known as multidrug resistance protein 1 (MDR1). P-gp is a transmembrane protein, which acts as an energy-dependent drug efflux pump. It decreases intracellular drug accumulation, thereby decreasing the effectiveness of many drugs.50 The ABCB1c.3435 C>T (rs1045642), ABCB1c.G2677T/A (rs2032582) and ABCB1c.1236C>T (rs1128503) SNPs are the most common nonsynonymous and synonymous SNPs studied.51 Rifamycins are a substrate and inducer of the ABCB1 gene.52 The decrease in rifampicin exposure with the time of treatment is partly explained by the induction of the ABCB1 gene. Three studies assessed the effect of four ABCB1, rs1045642 rs2032582, rs1128503, and rs3842 (ABCB1c.4036A>G) SNPs. Huerta-Garca et al demonstrated that the rs1045642 TT genotype is a predictor that explains 34.8% of the variability in rifampicin Cmax and 48.5% of the variability in AUC024 h.39 However, the other two studies did not replicate this observed result of Huerta-Garca et al.38,40

Rifamycins are metabolized by esterase enzymes. The esterase enzymes implicated in the metabolism of rifamycins are hepatic carboxylesterases (CES), and serine esterase arylacetamide deacetylase (AADAC). Two carboxylesterases, CES1 and CES2, are recognized to play major roles in drug metabolism. These enzymes metabolize rifamycins to their respective deacetylrifamycins.14,15,53 Polymorphism of the CES1 and CES2 genes have been shown to influence the metabolism of several drugs.54 However, few studies investigated the effect of CES1 and CES2 gene variants on rifamycin metabolism (Table 2).

Table 2 Summary of the Studies Reported the Drug-Metabolizing Enzyme (AADAC and CES) Gene Polymorphisms Association with Rifamycins Pharmacokinetics Variation

Sloan et al investigated CES1 rs12149368 SNP effect on rifampicin pharmacokinetics in Malawian tuberculosis patients. The rs12149368 variant does not affect the plasma rifampicin concentration43 (Table 2). Song et al identified 10 variations in CES2 in Korean TB patients. Among the ten variants three closely linked SNPs, c.-2263A>G (rs3759994, g.738A>G), c.269965A>G (rs4783745, g.4629A>G), and c.1612+136G>A (g.10748G>A), may alter the metabolism of rifampicin by affecting the efficiency of transcription of the gene. In particular, the CES2 c.-2263A>G variant, which is found in the promoter region is associated with increased plasma concentrations of rifampicin.45

Shimazu et al reported that microsomes from a liver sample genotyped as AADAC*3/AADAC*3 showed decreased enzyme activities, compared with others. However, the allelic frequency is low, 1.3% European American, and 2.0% African American. The AADAC*2 (rs1803155) allele, which has a higher frequency has also shown reduced enzyme activity. The recent report of Francis et al and Weiner et al revealed that rs1803155 SNP has a significant effect on rifapentine exposure in tuberculosis patients. The mean AUC-24 of rifapentine decreased by 10.2% in black tuberculosis patient carriers of AADAC rs1803155 G versus A allele.44 The odds increase for GG allele carriers. A similar result was reported by Francis et al. Patients carrying the AA variant of AADAC rs1803155 were found to have a 10.4% lower clearance of rifapentine.41 However, another study from Malawi showed that AADAC rs1803155 SNP did not affect rifampicin pharmacokinetics.43

This systematic review provides current updates on the impact of genetic polymorphisms of drug transporters and drug-metabolizing enzymes on the pharmacokinetics of rifamycins. The overall finding suggests that the polymorphism in the drug transporter SLCO1B1 rs4149032, rs2306283, rs11045819, and ABCB1 rs1045642 and metabolizing enzyme AADACrs1803155 and CES2 c.-22263A>G (g.738A>G) of rifamycins partly contributes to the variability of pharmacokinetic parameters in tuberculosis patients.

The SLCO1B1 gene is located on chromosome 12. Fifteen exons and many variants have been identified in the SLCO1B1 gene. The missense mutation of rs4149056 (c.521T>C) where the wild type T is substituted with variant C causes a change in amino acid of OATP1B1 protein from valine to alanine at 174 positions. This change has been implicated in reduced OATP1B1 protein function and is associated with an increased risk for statin-induced muscle toxicity.55 However, an increase in the exposure to rifamycins was not reported in seven studies, and the one study, which reported an increase in AUC for the heterogeneous variant is also statistically non-significant. Lower frequency of rs4149056 CC variant in African populations56 where the majority of studies were done and small sample size may contribute to no difference in the pharmacokinetics. rs2306283 (388A>G) SNP causes a change of asparagine amino acid to aspartic at 130 positions. The consequence of this change on the transporter function is not well elucidated. The patients who were homozygous wild type (AA)42 and heterozygous (AG)39 were reported to have lower rifampicin exposure. Similarly, no myopathy was observed with rs2306283 polymorphism which was observed in other SLCO1B1 genes in patients taking statins suggesting no effect or increased activity of the mutant variant.57

rs11045819, which is located on exon 4, is another missense variant known in SLCO1B1gene. Of the four studies that assessed the impact of rs11045819 SNPs on rifampicin pharmacokinetics, only Weiner et al reported lower rifampicin exposure, lower peak concentration levels and greater apparent oral clearance with the SLCO1B1 rs11045819 variant allele (CA) compared to the wild-type allele (CC).36 This is consistent with a previous report that rs11045819 polymorphism increases OATP1B1 transporter activity and decreases systemic exposure of the OATP1B1 substrate.58,59

The well-studied SLCO1B1 gene SNPs believed to affect rifamycin pharmacokinetics is rs4149032. The rs4149032 is an intron-located SNP and is reported to have a high allelic frequency. The effect of SLCO1B1 rs4149032 on gene expression and OATP1B1 protein transporter function is not clear yet. Nevertheless, SLCO1B1 rs4149032 polymorphism was found to be associated with lower rifampicin exposures. Emmanuel et al and Gengiah et al reported that patients who are homozygous mutant and heterozygous for rs4149032 polymorphism have lower bioavailability and Cmax respectively of rifampicin.32,40 In addition, Kim et al observed lower oral clearance and higher rifampicin exposure for rs4149032 homozygous wild type (TT).37

Rifampicin significantly increases gene expression, protein levels, and efflux activity of ABCB1.25,60 It is also a substrate for P-glycoprotein.61 Huerta-Garca et al demonstrated that the rs1045642 SNPs, which is a silent mutation, is associated with rifampicin pharmacokinetics. Patients with CC or CT genotypes showed lower values of Cmax and AUC 24 compared to those with a TT genotype.39 Although the rs1045642 SNPs is a silent mutation, previous studies have shown that rs1045642 affects the P-gp protein either by being in linkage disequilibrium with other functional SNPs or by allele-specific differences in the codon usage affecting the protein folding and function.62,63 The observed change in the rifampicin pharmacokinetics with rs1045642 SNPs may be attributed to the above explanation.

Rifamycins are metabolized by the esterase enzyme family; microsomal hepatic carboxylesterases (CES), and serine esterase arylacetamide deacetylase (AADAC) to 25-deacetylrifamycins.14 Three esterase enzymes AADAC, CES1, and CES2 have been reported as enzymes responsible for rifamycin deacetylation. Several genetic polymorphisms of the CES1 and CES2 genes have been shown to affect drug metabolism. For example, variations of the CES1 gene have been reported to affect the metabolism of dabigatran oseltamivir, imidapril, and clopidogrel. Similarly, CES2 gene polymorphisms have been found to affect aspirin and irinotecan.54 Few studies are available that report the association of CES1 and CES2 variants and rifamycin pharmacokinetics. Song et al evaluated 10 SNPs of CES2 and found increased plasma rifampicin concentrations with the CES2 c.-22263A>G (g.738A>G) variants.45 Although Dompreh et al did not report similar results,42 the higher frequency of this variant allele warrants further investigation.

AADAC is primarily expressed in the liver and metabolizes clinically important drugs including rifamycins. Three, namely, AADAC*1 (wild-type), AADAC*2, and AADAC*3, where the latter two have decreased enzymatic activity, were reported so far.14,15 Recently, Francis et al and Weiner et al reported AADAC rs1803155 SNPs to have a significant effect on rifapentine metabolism. Shortly, a mutant variant of rs1803155 (AA) has decreased activity and decreased clearance of rifapentine. On the other hand, patients who have the wild type (GG) have shown decreased rifapentine exposure.41,44 Furthermore, Gabriele et al discovered the presence and inter-individual variation of AADAC in the human lung.64 These findings suggest the important role of AADAC pharmacogenetics in tuberculosis drug therapy.

Exposure to rifamycins in particular rifampicin is a crucial variable for successful tuberculosis treatment outcomes. The high inter-individual variability in rifamycins pharmacokinetics have been associated with various factors such as diabetes mellitus65 and partly HIV co-infection.66,67 The majority of studies included in this review included patients with co-morbid conditions. The sample size is also inadequate for some studies.

In conclusion, the genetic polymorphism of drug transporters and drug-metabolizing enzymes has an impact on rifamycin pharmacokinetics. However, based on the available data, it is difficult to identify candidate SNPs in the drug transporters SLCO1B1 and ABCB1 for therapeutic drug monitoring. On the other hand, the effect of drug-metabolizing enzyme SNPs on the rifamycin pharmacokinetics is promising but needs more studies. In general, further controlled clinical studies with adequate sample size are required to characterize the genetic variation influence on the pharmacokinetics of rifamycins for tuberculosis chemotherapy optimization.

A study reported in this publication was supported by the Fogarty International Center and National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number D43 TW009127 and by the Center for Innovative Drug Development and Therapeutic Trials for Africa (CDT-Africa), Addis Ababa University. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or CDT-Africa, Addis Ababa University.

The authors declare no conflicts of interest.

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9. Mtabho CM, Semvua HH, van den Boogaard J, et al. Effect of diabetes mellitus on TB drug concentrations in Tanzanian patients. J Antimicrob Chemother. 2019;74(12):35373545. doi:10.1093/jac/dkz368

10. Afsar NA, Bruckmueller H, Werk AN, Nisar MK, Ahmad HR, Cascorbi I. Implications of genetic variation of common drug metabolizing enzymes and ABC transporters among the Pakistani population. Sci Rep. 2019;9(1):7323. doi:10.1038/s41598-019-43736-z

11. Ahmed S, Zhou Z, Zhou J, Chen S-Q. Pharmacogenomics of drug metabolizing enzymes and transporters: relevance to precision medicine. Genom Proteom Bioinform. 2016;14(5):298313. doi:10.1016/j.gpb.2016.03.008

12. Choi R, Jeong BH, Koh WJ, Lee SY. Recommendations for optimizing tuberculosis treatment: therapeutic drug monitoring, pharmacogenetics, and nutritional status considerations. Ann Lab Med. 2017;37(2):97107. doi:10.3343/alm.2017.37.2.97

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14. Nakajima A, Fukami T, Kobayashi Y, Watanabe A, Nakajima M, Yokoi T. Human arylacetamide deacetylase is responsible for deacetylation of rifamycins: rifampicin, rifabutin, and rifapentine. Biochem Pharmacol. 2011;82(11):17471756. doi:10.1016/j.bcp.2011.08.003

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33. Jeremiah K, Denti P, Chigutsa E, et al.. Nutritional supplementation increases rifampin exposure among tuberculosis patients coinfected with HIV. Antimicrob Agents Chemother. 2014;58(6):34683474. doi:10.1128/AAC.02307-13

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38. Medellin-Garibay SE, Huerta-Garcia AP, Rodriguez-Baez AS, et al. A population approach of rifampicin pharmacogenetics and pharmacokinetics in Mexican patients with tuberculosis. Tuberculosis. 2020;124:101982.

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40. Chigutsa E, Visser ME, Swart EC. The SLCO1B1 rs4149032 polymorphism is highly prevalent in South Africans and is associated with reduced rifampin concentrations: dosing implications. Antimicrob Agents Chemother. 2011;55(9):41224127. doi:10.1128/AAC.01833-10

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Effect of Genetic Variations on Rifamycins | PGPM - Dove Medical Press

CAMBRIDGE, Mass., June 02, 2022 (GLOBE NEWSWIRE) -- Sarepta Therapeutics, Inc. (NASDAQ: SRPT), the leader in precision genetic medicine for rare diseases, today announced the appointments of Michael Chambers and Kathryn Boor, Ph.D., to its Board of Directors. Both Mr. Chambers and Dr. Boor bring distinct and invaluable experience to the Sarepta board that will help guide the company on its mission to change the course of life-threatening rare diseases.

Were pleased to welcome two new board members whose participation will contribute to the realization of Sareptas strategic vision to create transformative therapies for patients with rare diseases, said M. Kathleen Behrens, Ph.D., Chairperson of Sareptas Board of Directors.

Mr. Chambers appointment brings tremendous bioscience and entrepreneurial leadership, along with deep expertise in areas of fundamental importance to genetic medicine innovators. Dr. Boor, in addition to her scientific and academic credentials, is an expert in environment, sustainability and governance, a topic of significant importance to Sarepta, said Doug Ingram, Sareptas president and chief executive officer. These new appointments add to the diversity of experience and perspective on our Board, providing outstanding leadership as we work with the greatest urgency to bring innovative genetic medicines to patients.

Mr. Chambers co-founded Aldevron, based in Fargo, N.D., in 1998, and served as its chief executive officer for more than 20 years before serving as Executive Chairman of the Board until 2021 when Aldevron was acquired for $9.6 billion. As founder, Chambers oversaw the growth of Aldevron into a world-class service organization, specializing in nucleic acid and protein production, antibody development, and custom services with operations in the United States and Europe. Chambers currently serves on the Board of Directors at Calviri, Inc.

In 2018, Chambers was named one of the 100 Most Intriguing Entrepreneurs by Goldman Sachs. He earned his bachelors degree in biotechnology, microbiology, and chemistry from North Dakota State University.

Dr. Boor is the Dean of the Graduate School and Vice Provost for Graduate Education at Cornell University. Previously, Dr. Boor served as the Ronald P. Lynch Dean of the College of Agriculture and Life Sciences (CALS) at Cornell.She earned a bachelors degree in food science from Cornell University, a masters degree in food science from the University of Wisconsin and a Ph.D. in microbiology from the University of California, Davis. She joined the Cornell Food Science department as assistant professor in 1994, became its first tenured female faculty member in 2000, and led as department chair from 2007-2010.

Dr. Boor serves on the Board of Directors for Seneca Foods Corporation, International Flavors and Fragrances, the United States-Israel Binational Agricultural Research and Development (BARD) Fund, and the Foundation for Food and Agriculture Research (FFAR).She serves on the Science Board for the US Food and Drug Administration and on the New York State Southern Tier Regional Economic Development Council.

About Sarepta TherapeuticsSarepta is on an urgent mission: engineer precision genetic medicine for rare diseases that devastate lives and cut futures short. We hold leadership positions in Duchenne muscular dystrophy (DMD) and limb-girdle muscular dystrophies (LGMDs), and we currently have more than 40 programs in various stages of development. Our vast pipeline is driven by our multi-platform Precision Genetic Medicine Engine in gene therapy, RNA and gene editing. For more information, please visitwww.sarepta.com or follow us on Twitter, LinkedIn, Instagram and Facebook.

Internet Posting of InformationWe routinely post information that may be important to investors in the 'For Investors' section of our website atwww.sarepta.com. We encourage investors and potential investors to consult our website regularly for important information about us.

Forward-Looking StatementsThis press release contains forward-looking statements. Any statements contained in this press release that are not statements of historical fact may be deemed to be forward-looking statements. Words such as "believes," "anticipates," "plans," "expects," "will," "intends," "potential," "possible" and similar expressions are intended to identify forward-looking statements. These forward-looking statements include statements related to Sareptas mission to change the course of life-threatening rare diseases and the potential benefits of the additions of Dr. Boor and Michael Chambers to Sareptas Board.

These forward-looking statements involve risks and uncertainties, many of which are beyond Sareptas control. Known risk factors include, among others: Sarepta may not be able to execute on its business plans, including meeting its expected or planned regulatory milestones and timelines, clinical development plans, and bringing its products to U.S. and ex-U.S. markets for various reasons including possible limitations of Company financial and other resources, manufacturing limitations that may not be anticipated or resolved for in a timely manner, and regulatory, court or agency decisions, such as decisions by the United States Patent and Trademark Office with respect to patents that cover Sareptas product candidates; and those risks identified under the heading Risk Factors in Sareptas most recent Annual Report on Form 10-K for the year ended December 31, 2021, and most recent Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) as well as other SEC filings made by the Company which you are encouraged to review.

Any of the foregoing risks could materially and adversely affect the Companys business, results of operations and the trading price of Sareptas common stock. For a detailed description of risks and uncertainties Sarepta faces, you are encouraged to review the SEC filings made by Sarepta. We caution investors not to place considerable reliance on the forward-looking statements contained in this press release. Sarepta does not undertake any obligation to publicly update its forward-looking statements based on events or circumstances after the date hereof, except as required by law.

Source: Sarepta Therapeutics, Inc.

Investor Contact: Ian Estepan, 617-274-4052iestepan@sarepta.com

Media Contact: Tracy Sorrentino, 617-301-8566tsorrentino@sarepta.com

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Sarepta Therapeutics Appoints Michael Chambers and Kathryn Boor, Ph.D., to Its Board of Directors - GlobeNewswire

A new preclinical study conducted on rat models and published on May 31, 2022, reports the discovery of a new class of drugs that could prove effective in treating patients infected with drug-resistant strains of Mycobacterium tuberculosis.

Senior author of the study, Ho-Yeon Song, PhD, of Soonchunhyang University in South Korea said, The new class of PP derivatives is aMycobacterium tuberculosis-targeted antimicrobial with microbiome-safe properties.

The findings were published in an article titled Discovery of Mycobacterium tuberculosisTargeted antimicrobial PP derivatives, in the journal PLOS Biology.

While further testing will be required, the low effective dose and high level of safety in these early tests indicate that these new drugs are likely to be important alternatives to the current regimen for treatment of tuberculosis, Song said.

As part of the study, the scientists screened a variety of natural products derived from plant extracts for potent antibacterial activity against M. tuberculosis. This led them to isolate and purify deoxypergularinine (DPG) from the roots ofCynanchum atratum,a flowering plant used in traditional Chinese medicine.

In earlier studies, the team showed that this compound inhibited not only normal M. tuberculosis but also drug-resistant strains of the bacterium. They had also shown, combining this active ingredient with the first line of standard drugs used to treat tuberculosis, significantly reduced the minimum doses (minimum inhibitory concentrations, MICs) of these drugs needed to inhibit a strain of the bacterium (H37Ra).

In the current study, the team developed and tested multiple analogues of DPG for their ability to inhibitM. tuberculosis without harming the infected cells. They identified a class of PP-derivatives, characterized by the presence of phenanthrene and pyrrolidine groups in their structures, that could inhibit M. tuberculosis effectively with negligible effects on the cells infected, indicating their low toxicity.

The team found several PP derivatives were effective at concentrations lower that that used for current first-line tuberculosis drugs in cells infected with drug-resistant strains of the bacterium in culture, indicating higher antibacterial potency of these derivatives.

The authors notes, PPs demonstrated antitubercular activities in macrophage and tuberculosis mouse models, showing no detectable toxicity in all assays tested.

The team treated infected rats with three PP derivatives (PP1S, PP2S and PP3S) separately for 4 weeks and found this reduced the burden of tuberculosis infection compared to untreated mice. Moreover, the treatments produced no adverse effects in the rats upon two weeks of high-dose treatment and four weeks of intermediate-dose treatment.

The authors also tested the effects of the PP derivative on the intestinal microbiome in mice, since antibiotic treatments are generally associated with off-target killing of beneficial or harmless bacteria that colonize the human gut.

The authors noted, PPs specifically inhibited M. tuberculosis without significantly changing the intestinal microbiome in mice. Whereas standard drugs compromised the mouse gut microbiome, treatment with PP2S for a week showed no significant reduction in gut bacteria.

The team also conducted in vitro studies to identify the drug target. They found a gene called PE-PGRS57, that is found only in the genomes of the M. tuberculosis complex, to be the genetic target of the drug. This explains the high selectivity and safety potency of these new class of compounds.

Mycobacterium tuberculosisinfects and kills nearly 1.5 million people each year globally. Current standard care for drug-susceptible tuberculosis includes a four-month regimen of rifapentine-moxifloxacin or a six-to-nine-month regimen of rifampin, isoniazid, pyrazinamide, and ethambutol (RIPE), according to the US Centers for Disease Control and Prevention (CDC).

Several factors including incomplete treatment course, and wrong dosage or period of treatment, has led to the emergence of multi-drug resistant (MDR), pre-extensively drug-resistant (pre-XDR), extensively drug-resistant (XDR) and totally drug-resistant (TDR) strains of Mycobacterium tuberculosis. If successfully tested in clinical trials, the new class of deoxypergularinine derivates would represent a major advance in treating tuberculosis.

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Drug Resistant Tuberculosis Could be Treated with Derivative of Tropical Plant - Genetic Engineering & Biotechnology News

PITTSBURGH and CAMBRIDGE, Mass., June 01, 2022 (GLOBE NEWSWIRE) -- NeuBase Therapeutics, Inc.NBSE ("NeuBase" or the "Company"), a biotechnology platform company Drugging the Genome to address disease at the base level using a new class of precision genetic medicines, announced today that company management will present a corporate overview at the Jefferies Healthcare Conference being held in New York on June 8 10, 2022.

A replay of the webcast will be available following the presentation for 90 days. To access the webcast, please click here. Please contact your representative at Jefferies to schedule a one-on-one meeting with NeuBase management during the conference.

About NeuBase TherapeuticsNeuBase is accelerating the genetic revolution by developing a new class of precision genetic medicines that Drug the Genome. The Company's therapies are built on a proprietary platform called PATrOL that encompasses a novel peptide-nucleic acid antisense oligonucleobase technology combined with a novel delivery shuttle that overcome many of the hurdles to selective mutation engagement, repeat dosing, and systemic delivery of genetic medicines. With an initial focus on silencing disease-causing mutations in debilitating neurological, neuromuscular, and oncologic disorders, NeuBase is committed to redefining medicine for the millions of patients with both common and rare conditions, who currently have limited to no treatment options. To learn more, visitwww.neubasetherapeutics.com.

NeuBase Investor Contact:Daniel FerryManaging DirectorLifeSci Advisors, LLCdaniel@lifesciadvisors.com OP: (617) 430-7576

NeuBase Media Contact:Jessica Yingling, Ph.D.PresidentLittle Dog Communications Inc.jessica@litldog.comOP: (858) 344-8091

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NeuBase to Participate at the Jefferies Healthcare Conference - Benzinga - Benzinga

PITTSBURGH and CAMBRIDGE, Mass., May 12, 2022 (GLOBE NEWSWIRE) -- NeuBase Therapeutics, Inc. (Nasdaq: NBSE) (NeuBase or the Company), a biotechnology platform company Drugging the Genome to address disease at the base level using a new class of precision genetic medicines, today reported its financial results for the three-month period ended March 31, 2022, and other recent developments.

We are pleased with the progress being made across our development pipeline of therapeutic programs to treat DM1, HD, and KRAS-driven cancers. The new data weve announced to date this year have further validated the use of our PATrOLplatform to design novel genetic medicines that target and rescue gene dysfunctions, with the potential for clinically impactful outcomes in both rare and common diseases, said Dietrich A. Stephan, Ph.D., Founder, Chief Executive Officer, and Chairman of NeuBase. We continue to execute the development strategy for our DM1 program, which includes a series of IND-enabling studies scheduled to report data throughout CY2022. Last quarter, we presented pharmacodynamic data that illustrated a single intravenous (IV) dose or multiple subcutaneous (SC) doses of our DM1 development candidate resolves the genetic defect and myotonia in skeletal muscle of the gold-standard mouse model of the disease. Building off these results, we plan on announcing at ASGCT additional pharmacokinetic (PK) data, which will illustrate the exposure levels of our development candidate when administered via systemic administration in skeletal muscles, heart, and brain, tissues that are affected in DM1. We expect these data to support further advancement of our lead candidate for DM1 and validate a differentiated whole-body solution for this disease. Considering this progress, we believe the submission of an IND application to the FDA is on track for the fourth quarter of CY2022.

Second Quarter of Fiscal Year 2022 and Recent Operating Highlights

Financial Results for the Second Fiscal Quarter Ended March 31, 2022

Financial Results for the Six-Month Period Ended March 31, 2022

About NeuBase TherapeuticsNeuBase is accelerating the genetic revolution by developing a new class of precision genetic medicines that Drug the Genome. The Companys therapies are built on a proprietary platform called PATrOL that encompasses a novel peptide-nucleic acid antisense oligonucleobase technology combined with a novel delivery shuttle that overcome many of the hurdles to selective mutation engagement, repeat dosing, and systemic delivery of genetic medicines. With an initial focus on silencing disease-causing mutations in debilitating neurological, neuromuscular, and oncologic disorders, NeuBase is committed to redefining medicine for the millions of patients with both common and rare conditions, who currently have limited to no treatment options. To learn more, visit http://www.neubasetherapeutics.com.

Use of Forward-Looking StatementsThis press release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act. These forward-looking statements are distinguished by use of words such as "will," "would," "anticipate," "expect," "believe," "designed," "plan," or "intend," the negative of these terms, and similar references to future periods. These forward-looking statements include, among others, those related to the plan to provide updates on the Company's development pipeline, in particular the DM1 program, at the ASGCT 25th Annual Meeting, the potential and prospects of the Companys proprietary PATrOL platform and DM1 program, the Companys expectation that it will submit an IND application for the DM1 program to the U.S. Food and Drug Administration in the fourth quarter of CY2022, our expectations to initiate scale-up and toxicology activities for development of a systemically administered allele-selective NT-0100 program to treat HD in CY2022, the potential of our therapeutic program for HD and the potential for our PATrOL-enabled compounds to silence activating KRAS point mutations in vivo to inhibit protein production. These views involve risks and uncertainties that are difficult to predict and, accordingly, our actual results may differ materially from the results discussed in our forward-looking statements. Our forward-looking statements contained herein speak only as of the date of this press release. Factors or events that we cannot predict, including those risk factors contained in our filings with the U.S. Securities and Exchange Commission, may cause our actual results to differ from those expressed in forward-looking statements. The Company may not actually achieve the plans, carry out the intentions or meet the expectations or projections disclosed in the forward-looking statements, and you should not place undue reliance on these forward-looking statements. Because such statements deal with future events and are based on the Company's current expectations, they are subject to various risks and uncertainties, and actual results, performance or achievements of the Company could differ materially from those described in or implied by the statements in this press release, including: the Company's plans to develop and commercialize its product candidates; the timing of initiation of the Company's planned clinical trials; the risks that prior data will not be replicated in future studies; the timing of any planned investigational new drug application or new drug application; the Company's plans to research, develop and commercialize its current and future product candidates; the clinical utility, potential benefits and market acceptance of the Company's product candidates; the Company's commercialization, marketing and manufacturing capabilities and strategy; global health conditions, including the impact of COVID-19; the Company's ability to protect its intellectual property position; and the requirement for additional capital to continue to advance these product candidates, which may not be available on favorable terms or at all, as well as those risk factors contained in our filings with the U.S. Securities and Exchange Commission. Except as otherwise required by law, the Company disclaims any intention or obligation to update or revise any forward-looking statements, which speak only as of the date hereof, whether as a result of new information, future events or circumstances or otherwise.

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NeuBase Therapeutics Reports Business Update and Financial Results for the Second Quarter of Fiscal Year 2022 - GlobeNewswire

This discovery validates siderophore secretion as a drug target in tuberculosis and reveals a new mechanism for putative drugs. Many tuberculosis bacteria are highly resistant to multiple antibiotics.

Michael Niederweis, left, and Lei ZhangLei Zhang, Ph.D., and Michael Niederweis, Ph.D., of the University of Alabama at Birmingham have made what they call a major step in understanding how Mycobacterium tuberculosis acquires iron from its human host a process essential for the pathogenesis of this bacterium. Tuberculosis kills more than 1 million people each year, but without iron, M. tuberculosis cannot grow.

In general, bacteria acquire iron in a well-understood manner. They produce molecules called siderophores, which is Greek for iron carrier, and they use molecular pumps to excrete the siderophores out through the inner and outer membranes. The siderophores have the ability to bind iron very tightly. Then these iron-clutching siderophores are transported back into the bacteria. Inside, the iron is released for use in essential enzymes.

However, the Mycobacteriaceae family which includes the microbial pathogens for tuberculosis and leprosy differ greatly from bacteria like E. coli, where the machinery involved in siderophore transport has been heavily studied.

Over the past decade, researchers in the Niederweis lab at UAB have advanced siderophore knowledge for M. tuberculosis, or Mtb. In 2013, they described two small membrane proteins that are required for siderophore secretion by Mtb, through their association with known efflux pumps to comprise a siderophore export system at the inner membrane.

In 2014, they described how a double mutant of those two small proteins left the Mtb exquisitely sensitive to tiny concentrations of the Mtb siderophore mycobactin, a toxicity phenomenon they named siderophore poisoning.

In 2020, they described how mutation of another Mtb gene, rv0455c, showed the same phenotype as deletion of the two small proteins siderophore poisoning in the presence of mycobactin. Furthermore, the rv0455c gene is located close to the gene location for the two small proteins that are essential for siderophore efflux. Therefore, the UAB researchers hypothesized that rv0455c also would function in siderophore secretion.

That was correct, as they report in the Nature Communications study, A periplasmic cinched protein is required for siderophore secretion and virulence of Mycobacterium tuberculosis.

Using a variety of genetic and biochemical approaches, they showed that the rv0455c gene is essential for Mtb to grow in low-iron medium, and that the secretion of the two Mtb siderophores mycobactin and carboxymycobactin is drastically reduced in the rv0455c deletion mutant.

Although quantities of the Rv0455c protein are found outside of growing Mtb cells, Zhang and Niederweis found that a genetically engineered Rv0455c variant designed to anchor in the Mtb inner membrane was functional in siderophore secretion, supporting an intracellular role for Rv0455c. Deletion of Rv0455c from a virulent strain of Mtb severely impaired replication of M. tuberculosis in mice, demonstrating the importance of Rv0455c and siderophore secretion during disease.

The rv0455c gene in Mtb has no sequence homology with genes in bacteria like E. coli, but it is one of the core genes found in Mycobacteria, with a high degree of homology among the various homologs. Prior to the current study, Rv0455c had been annotated as a protein of unknown function.

The researchers found that genes homologous to rv0455c from M. smegmatis, M. leprae and M. haemophilium were fully functional in Mtb, restoring its growth in the presence of mycobactin. The crystal structure of the homologous protein from M. smegmatis showed a disulfide bond in the protein, producing a cinched structure, and the protein presents two surface patches of amino acids that are evolutionarily conserved among the Mycobacteria.

The mechanistic function of Rv0455c is still unknown, and the protein does not show the deep cleft commonly found in siderophore-binding proteins. However, Rv0455c may play an important structural role in the siderophore secretion system of Mtb, researchers say, possibly by acting as an essential accessory protein or by connecting the inner-membrane siderophore exporters with a putative outer membrane channel.

This study presents a major step forward in understanding the Mtb siderophore secretion system, whose proteins have no similarities to other bacterial siderophore secretion systems, Niederweis said. Furthermore, we identify siderophore poisoning as an important mechanism of the large virulence loss of the Mtb mutant lacking the rv0455c gene, validating siderophore secretion as a drug target and revealing a new mechanism for putative tuberculosis drugs.

At UAB, Niederweis is a professor and Zhang is a researcher v in the Department of Microbiology in the Marnix E. Heersink School of Medicine.

Co-authors with Niederweis and Zhang are James E. Kent, Alexander E. Aleshin and Francesca M. Marassi, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California; Meredith Whitaker and Sabine Ehrt, Weill Cornell Medical College, New York, New York; David C. Young and D. Branch Moody, Harvard Medical School, Boston, Massachusetts; Dominik Herrmann and Jamil S. Saad, UAB Department of Microbiology; and Ying-Hui Ko and Gino Cingolani, Thomas Jefferson University, Philadelphia, Pennsylvania.

Support came from National Institutes of Health grants AI049313 and AI151239.

At UAB, Niederweis holds the Triton Endowed Professorship in Bacteriology.

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A gene in tuberculosis bacteria is found essential for siderophore secretion and virulence - University of Alabama at Birmingham

The following discussion should be read in conjunction with the unauditedConsolidated Financial Statements and the notes thereto included in thisQuarterly Report on Form 10-Q and the audited Consolidated Financial Statementsand the notes thereto included in our Annual Report on Form 10-K for the fiscalyear ended December 31, 2021. Some of the statements we make in this section areforward-looking statements within the meaning of the federal securities laws.Some of the statements we make in this section are forward-looking statementswithin the meaning of the federal securities laws. For a complete discussion offorward-looking statements, see the section in this Quarterly Report on Form10-Q entitled "Special Note Regarding Forward-Looking Statements". Certain riskfactors may cause actual results, performance or achievements to differmaterially from those expressed or implied by the following discussion. For adiscussion of such risk factors, see the section in our Annual Report on Form10-K for the fiscal year ended December 31, 2021 entitled "Risk Factors".

Overview

We are a global, patient-dedicated biotechnology company focused on discovering,developing, and delivering novel medicines for rare diseases. We have aportfolio of product opportunities including the first, oral monotherapy forFabry disease that has achieved widespread global approval and a differentiatedbiologic for Pompe disease that is under review with the U.S. Food and DrugAdministration ("FDA") as well as the European Medicines Agency ("EMA"). We arecommitted to discovering and developing next generation therapies in Fabry andPompe diseases.

The cornerstone of our portfolio is Galafold (also referred to as"migalastat"), the first and only approved oral precision medicine for peopleliving with Fabry disease who have amenable genetic variants. Migalastat iscurrently approved under the trade name Galafold in the United States ("U.S."),European Union ("E.U."), United Kingdom ("U.K."), and Japan, with multipleadditional approvals granted and applications pending in several geographiesaround the world.

The lead biologics program of our pipeline is Amicus Therapeutics GAA ("AT-GAA",also known as ATB200/AT2221, or cipaglucosidase alfa/miglustat), a novel,two-component, potential best-in-class treatment for Pompe disease. In February2019, the FDA granted Breakthrough Therapy designation ("BTD") to AT-GAA for thetreatment of late onset Pompe disease. In September 2021, the FDA set thePrescription Drug User Fee Act ("PDUFA") target action date of May 29, 2022 forthe New Drug Application ("NDA") for miglustat and July 29, 2022 for theBiologics License Application ("BLA") for cipaglucosidase alfa. The EMAvalidated the Marketing Authorization Application ("MAA") in the fourth quarterof 2021. On May 9, 2022, the FDA extended the review period for the NDA formiglustat and the BLA for cipaglucosidase alfa resulting in revised PDUFA actiondates of August 29, 2022 and October 29, 2022, respectively.

Our Strategy

Our strategy is to create, manufacture, test, and deliver the highest qualitymedicines for people living with rare diseases through internally developed,jointly developed, acquired, or in-licensed products and product candidates thathave the potential to obsolete current treatments, provide significant benefitsto patients, and be first- or best-in-class. We are leveraging our globalcapabilities to develop and broaden our lead franchises in Fabry and Pompedisease, with focused discovery work on next generation therapies and novelplatform technologies.

Our operations have not been significantly impacted by the novel coronavirus("COVID-19") pandemic thus far. The Company continued to observe increased lagtimes between patient identification and Galafold initiation due to theresurgence of COVID-19 in certain markets. We have maintained operations in allgeographies, secured our global supply chain for our commercial and clinicalproducts, as well as maintained the operational integrity of our clinicaltrials, with minimum disruptions. Our ability to continue to operate without anysignificant disruptions will depend on the continued health of our employees,the ongoing demand for Galafold and the continued operation of our globalsupply chain. We have continued to provide uninterrupted access to medicines forthose in need of treatment, while prioritizing the health and safety of ourglobal workforce. However, our results of operations in future periods may benegatively impacted by unknown future impacts from the COVID-19 pandemic.

Highlights of our progress include:

Commercial and regulatory success in Fabry disease. For the three months endedMarch 31, 2022, Galafold revenue totaled $78.7 million, an increase of $12.3million compared to the same period in the prior year. We continue to see strongcommercial momentum and expansion into additional geographies. In countrieswhere we have been operating the longest, we see an increasing proportion ofpreviously untreated patients come onto Galafold. In the U.S., we

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continue to see a significant increase in patients from a growing and very wideprescriber base. Across all markets, we see a high rate of compliance andadherence to this oral treatment option.

Pompe disease clinical program milestones. In February 2021, we reportedtopline results from the Phase 3 study of AT-GAA (ATB200-03, also known as"PROPEL"). In June 2021, the MHRA granted AT-GAA a positive scientific opinionthrough the Early Access to Medicines Scheme ("EAMS") which permits eligibleadults living with late-onset Pompe disease ("LOPD") who have receivedalglucosidase alfa for at least 2 years to switch to AT-GAA prior to marketingauthorization in the U.K. We completed the submission of the rolling BLA and NDAto the FDA, which was accepted for review in September 2021, and in the fourthquarter of 2021, the MAA was submitted and validated by the EMA. In March 2022,we announced positive long-term data from our ongoing phase 1/2 clinical study.Study participants treated with AT-GAA for up to 36 months demonstratedpersistent and durable effects on six-minute walk test distance and measures ofmotor function and muscle strength, stability, or increase in forced vitalcapacity, and reductions in biomarkers of muscle damage and disease substrate.

Pipeline advancement and growth. We are leveraging our global capabilities todevelop and broaden our lead franchises in Fabry and Pompe disease, with focuseddiscovery work on next generation therapies and novel platform technologies.

Manufacturing. We have managed our clinical and commercial supply chains duringthe COVID-19 pandemic such that as of the date hereof we have not experiencedsupply impacts. We have been able to continue to meet required commercial demandfor Galafold as well as supply our ongoing Pompe disease clinical studies andaccess programs including EAMS without interruption. We have secured supply forour continued needs for the Pompe disease program through a long-term supplyagreement with Wuxi Biologics. The agreement allows for the continuousmanufacture of our biologic to support future clinical needs and our anticipatedcommercial requirements should we garner regulatory approvals as planned. Wehave contracts in place to supply miglustat, our small molecule component ofAT-GAA, to support both clinical and future commercial requirements.

Financial strength. Total cash, cash equivalents, and marketable securities asof March 31, 2022 was $411.2 million. Based on the current operating model, webelieve that the current cash position, which includes expected revenues, issufficient to fund our operations and ongoing research programs to achieveself-sustainability. Potential impacts of the COVID-19 pandemic, businessdevelopment collaborations, pipeline expansion, and investment in manufacturingcapabilities could impact our future capital requirements.

Our Commercial Product and Product Candidates

Galafold (Migalastat HCl) for Fabry Disease

Our oral precision medicine Galafold was granted accelerated approval by theFDA in August 2018 under the brand name Galafold for the treatment of adultswith a confirmed diagnosis of Fabry disease and an amenable galactosidase alphagene ("GLA") variant based on in vitro assay data. The FDA has approvedGalafold for 350 amenable GLA variants. Galafold was approved in the E.U. andU.K. in May 2016 as a first-line therapy for long-term treatment of adults andadolescents, aged 16 years and older, with a confirmed diagnosis of Fabrydisease and who have an amenable mutation (variant). The approved E.U. and U.K.labels include 1,384 mutations amenable to Galafold treatment, which representup to half of all patients with Fabry disease. In countries where mutations areprovided only on the amenability website, these 1,384 amenable mutations are nowavailable. Marketing authorization approvals have been granted in over 40countries around the world, including the U.S., E.U., U.K., Japan, and others.In July 2021, Galafold was approved in the E.U. for adolescents aged 12 yearsand older weighing 45 kg or more. We plan to continue to launch Galafold inadditional countries during 2022, including for adolescents aged 12 years andolder.

As an orally administered monotherapy, Galafold is designed to bind to andstabilize an endogenous alpha-galactosidase A ("alpha-Gal A") enzyme in thosepatients with genetic variants identified as amenable in a GLP cell-basedamenability assay. Galafold is an oral precision medicine intended to treatFabry disease in patients who have amenable genetic variants, and at this time,it is not intended for concomitant use with ERT.

In early 2022, we announced the issuance of six additional patents, includingthe new U.S. Composition of Matter patent, for the Galafold intellectualproperty. Galafold now has 35 issued patents, 18 of which provide protectionthrough 2038.

Next Generation for Fabry Disease

We are committed to continued innovation for all people living with Fabrydisease. Our pipeline includes a Fabry gene therapy.

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Novel ERT for Pompe Disease

We are leveraging our biologics capabilities to develop AT-GAA, a noveltreatment paradigm for Pompe disease. AT-GAA consists of a uniquely engineeredrhGAA enzyme, ATB200, or cipaglucosidase alfa, with an optimized carbohydratestructure to enhance lysosomal uptake, administered in combination with AT2221,or miglustat, that functions as an enzyme stabilizer. Miglustat binds to andstabilizes ATB200, or cipaglucosidase alfa, preventing inactivation of rhGAA incirculation to improve the uptake of active enzyme in key disease-relevanttissues, resulting in increased clearance of accumulated substrate, glycogen.Miglustat is not an active ingredient that contributes directly to substratereduction ("glycogen").

In February 2021, we reported topline results from the Phase 3 PROPEL study. Ofthe Pompe disease patients enrolled, 77% were being treated with alglucosidasealfa (n=95) immediately prior to enrollment ("Switch") and 23% had never beentreated with any ERT (n=28) ("Nave"). Nearly all patients from the PROPEL studycontinue to be treated with AT-GAA in the extension clinical study. The clinicaldata from the PROPEL study, the extension study as well as the Phase 1/2 studywere included in the AT-GAA submissions to the FDA and the EMA.

In March 2022, we announced positive long-term data from our ongoing phase 1/2clinical study. Study participants treated with AT-GAA for up to 36 monthsdemonstrated persistent and durable effects on six-minute walk test distance andmeasures of motor function and muscle strength, stability, or increase in forcedvital capacity, and reductions in biomarkers of muscle damage and diseasesubstrate.

In addition, we are conducting ongoing clinical studies in pediatric patientsfor both LOPD and infantile-onset Pompe disease ("IOPD") populations.

Next Generation for Pompe Disease

As part of our long-term commitment to provide multiple solutions to address thesignificant unmet needs of the Pompe disease community, we are also continuingdiscovery for next-generation genetic medicines for Pompe disease.

CDKL5 Deficiency Disorder

We are researching a potential first-in-class genetic medicine for CDKL5deficiency disorder consisting of a CDKL5 protein engineered for crosscorrection, delivered as either a protein replacement or as a gene therapythrough our collaboration with Penn. We are collaborating with the LouLouFoundation to assess the natural history of the disease to identify endpointsfor potential use in future studies.

Additional Next Generation Programs

We have a number of additional gene therapies in clinical and preclinicaldevelopment, including potential gene therapies in multiple forms of Battendisease.

Strategic Alliances and Arrangements

We will continue to evaluate business development opportunities as appropriateto build stockholder value and provide us with access to the financial,technical, clinical, and commercial resources necessary to develop and markettechnologies or products with a focus on rare and orphan diseases. We areexploring potential collaborations, alliances, and other business developmentopportunities on a regular basis. These opportunities may include businesscombinations, partnerships, the strategic out-licensing of certain assets, orthe acquisition of preclinical-stage, clinical-stage, or marketed products orplatform technologies consistent with our strategic plan to develop and providetherapies to patients living with rare and orphan diseases.

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