Optimizing regulatory frameworks for gene therapies in rare diseases: Challenges and solutions.

The advent of genetic medicines and advanced diagnostics has revolutionized the treatment landscape for rare diseases and, with over 10,000 identified conditions affecting millions globally, has the potential to improve many lives. Despite this progress, only 5% of rare diseases have FDA-approved therapies, highlighting a significant unmet need. This article examines the critical need for optimizing the regulatory environment to support the development and approval of gene therapies for rare and ultrarare diseases, which often face unique challenges due to their complexity in the midst of a rapidly evolving field.

Medicaid coverage practices for approved gene and cell therapies: Existing barriers and proposed policy solutions.

The current Medicaid system is ill equipped to handle the anticipated approvals of new gene and cell therapy products. These advanced therapies tend to be single-dose, potentially durable options for a variety of indications spanning oncology, rare disease, and more. The up-front cost of these therapies contrasts with chronic care treatment, which may incur cost over the life of a patient.

Evaluation of a temperature-restricted, mucosal tuberculosis vaccine in guinea pigs.

Tuberculosis (TB) is currently the leading cause of death in humans by a single infectious agent, Mycobacterium tuberculosis. The Bacillus Calmette-Guérin (BCG) vaccine prevents pulmonary TB with variable efficacy, but can cause life-threatening systemic infection in HIV-infected infants. In this study, TBvac85, a derivative of Mycobacterium shottsii expressing M.

PrimaTB STAT-PAK assay, a novel, rapid lateral-flow test for tuberculosis in nonhuman primates.

Tuberculosis (TB) is the most important zoonotic bacterial disease in nonhuman primates (NHP). The current diagnostic method, the intradermal palpebral tuberculin test, has serious shortcomings. We characterized antibody responses in NHP against Mycobacterium tuberculosis to identify immunodominant antigens and develop a rapid serodiagnostic test for TB.

The effects of microwaves on airborne microorganisms.

This paper reports preliminary results of simple experiments carried out to study the effects of microwave irradiation at 2.45 GHz on fungi, yeast and bacteria of the type encountered in food processing plants or in enclosures containing individuals infected with tuberculosis mycobacterium (TB). The results are sufficiently encouraging to justify further multivariable experiments particularly with air circulation schemes in which the air can be sterilized in a circular cylindrical microwave cavity operating at a higher order mode.

Potential of the monoglyceride and triglyceride of DL-3-hydroxybutyrate for parenteral nutrition: synthesis and preliminary biological testing in the rat.

Esters of short-chain organic acids have shown some promise as potential nutrients for parenteral feeding. Most glycerols are water insoluble but those of the ketone bodies have some water solubility. Of interest is that the triacylglycerol of 3-hydroxybutyrate has water solubility while the triacylglycerol of acetoacetate does not.

An autosomal screen for genes that predispose to celiac disease in the western counties of Ireland.

Celiac disease is a strongly heritable gastrointestinal illness that is an especially important model of the genetically complex multifactorial immune mediated diseases. The HLA component of celiac disease (a specific HLA-DQ heterodimer)is largely established and is relatively uncomplicated, and the environmental component (gluten and related grain storage proteins in the diet) is remarkably well understood. Previous family studies of celiac disease suggested that there is at least one important non-HLA locus.

HLA-DR, DQ genotypes of celiac disease patients and healthy subjects from the West of Ireland.

Celiac disease (CD) has one of the strongest class II HLA associations of any human illness. We used DNA-RFLP typing to study the class II HLA genotypes of celiac disease patients from the West of Ireland, the geographic area with the highest rate of celiac disease in the world. We confirmed the high frequency of HLA-DR3 in this population, and we were also able to demonstrate the additional risk of developing celiac disease imparted by HLA-DR7.

T cell receptor gamma gene polymorphisms and class II human lymphocyte antigen genotypes in patients with celiac disease from the west of Ireland.

Although celiac disease has one of the strongest human lymphocyte antigen (HLA) class II associations of any human illness, it is clear that at least one gene that is not linked to the HLA region also is required for its pathogenesis. The occurrence of large numbers of gamma delta T cells in the bowel mucosa of patients and the recent description of T cell receptor (TCR) gamma chain polymorphic variants identified by restriction fragment length polymorphism analysis led the authors to examine TCR gamma genotypes in relation to HLA-DR, DQ genotypes in 89 patients with celiac disease and 55 control subjects from the West of Ireland. The overall frequency of TCR gamma genotypes in patients and control subjects was comparable.

Celiac disease: clinical features and pathogenesis.

Celiac disease is a fascinating illness, from both a clinical and research perspective. Most clinicians consider a diagnosis of celiac disease when a young patient has classic signs and symptoms of steatorrhea and severe malabsorption. However, the typical gastrointestinal symptoms often are absent.

Evidence for an ongoing role of class I histocompatibility molecules for the production of interleukin-2 in response to suboptimal concentrations of phytohaemagglutinin.

To examine the role of cellular interactions involving class I histocompatibility antigens in the response to low concentrations of phytohaemagglutinin, we studied the effect of antibodies to components of these antigens on proliferative responses, interleukin-1 and interleukin-2 production, and IL-2 receptor expression. Antibody to human beta 2-microglobulin (beta 2m) had an inhibitory effect both on IL-2 accumulation at 48 h of culture and on the proliferative response 24 h later. Exogenous IL-2 completely reconstituted the inhibited proliferative responses, and also restored the modest decrease in IL-2 receptor expression that was induced by anti-beta 2m.

Mechanism of calcium ionophore and phorbol ester-induced T-cell activation. Accessory cell requirement for T-cell activation.

We examined the role of monocytes in T-cell activation induced by phorbol myristate acetate (PMA) and calcium ionophore ionomycin. Depletion of monocytes from peripheral blood mononuclear cells (PBMC) was associated with the loss of interleukin-2 (IL-2) production, IL-2 receptor (IL-2R) expression and proliferation, in response to either PMA or ionomycin. Addition of monocytes to highly purified T cells resulted in the complete reconstitution of IL-2 production, IL-2R expression and proliferation by PMA-stimulated lymphocytes.

Evidence for a dominant gene mechanism underlying coeliac disease in the west of Ireland.

Although coeliac disease (CD) is strongly associated with the HLA alleles B8 and DR3, the genetic basis of this illness remains obscure. Recent studies show that at least two unlinked loci are involved. Most studies agree on recessivity at the HLA-unlinked locus but differ with respect to dominance or recessivity at the HLA-linked disease susceptibility locus.

Inhibition of polyamine synthesis suppresses human lymphocyte proliferation without decreasing cytokine production or interleukin 2 receptor expression.

Difluoromethylornithine (DFMO) irreversibly inhibits ornithine decarboxylase (ODC), a crucial enzyme in polyamine synthesis, and impairs mitogen-induced lymphocyte proliferation. To examine the mechanism of action of DFMO, we studied the effect of this ODC inhibitor on lymphokine production and interleukin 2 (IL 2) receptor expression. DFMO decreased thymidine uptake of peripheral blood mononuclear cells stimulated by the mitogens phytohemagglutinin, concanavalin A, phorbol myristate acetate and ionomycin 60-70% compared with untreated cells, and the inhibition could be completely reversed by 10 mM spermidine.

Mechanism of a lymphocyte abnormality associated with HLA-B8/DR3: role of interleukin-1.

Lymphocytes from normal individuals with the histocompatibility antigens HLA-B8 and DR3 have impaired proliferative responses when stimulated with suboptimal concentrations of mitogens. We have previously shown that an important factor in the impaired response is a failure to produce normal quantities of interleukin-2 (IL-2). To examine the mechanism of decreased responsiveness further, we measured interleukin-1 (IL-1) production of low responder subjects compared with controls.

Antibodies to beta 2-microglobulin, the light-chain component of class I histocompatibility molecules, provide an activation signal to human lymphocytes.

Antibodies to beta 2-microglobulin (beta 2m), the light-chain component of class I histocompatibility antigens, provide a strong co-stimulatory signal to human lymphocytes in the presence of phorbol ester. This activation signal requires a high concentration of antibody, whereas the effect on responses to a mitogenic lectin is exclusively inhibitory over a broad dose range. A rabbit polyclonal and a mouse monoclonal antibody to beta 2m were similarly co-stimulatory.

Mechanism of a lymphocyte abnormality associated with HLA-B8/DR3 in clinically healthy individuals.

An important unanswered question in clinical immunology is why the histocompatibility antigens HLA-B8/DR3 should be associated with at least nine quite different immune-mediated diseases. The purpose of this study was to examine the mechanism of an immunologic abnormality, commonly found in healthy individuals with HLA-DR3, that may reflect an immune defect predisposing to autoimmunity. Fourteen healthy subjects with HLA-DR3 had a proliferative response to a suboptimal concentration of PHA nearly eight-fold lower than that observed in 10 individuals without this HLA antigen.

Alpha 1-antitrypsin phenotypes, including M subtypes, in pulmonary disease associated with rheumatoid arthritis and systemic sclerosis.

Alpha 1-antitrypsin is a glycoprotein that functions as the major protease inhibitor in human serum. Many genetic variants of alpha 1-antitrypsin can be detected by electrophoretic techniques. We used isoelectric focusing on ultrathin gels to determine the common M subtypes as well as other variants of alpha 1-antitrypsin in 62 white patients with rheumatoid arthritis (RA) and 51 white patients with systemic sclerosis (SSc).

Immune abnormalities associated with HLA-B8: lymphocyte subsets and functional correlates.

Mononuclear cell populations were enumerated in healthy young adults with or without the histocompatibility antigen HLA-B8. Mononuclear cell counts were lower in subjects with HLA-B8, as was reflected in lower absolute numbers of the cell subsets. When cell populations were compared as percentages of total mononuclear cells, subjects with HLA-B8 had significantly more B lymphocytes bearing IgM than did subjects without HLA-B8.

A modified double antibody sandwich enzyme-linked immunosorbent assay for measurement of alpha-1-antitrypsin in biologic fluids.

Alpha-1-antitrypsin (alpha 1AT) is the major protease inhibitor in human serum, and plays an important role protecting tissues from potentially harmful enzymes released during inflammatory reactions. Proteolytic enzymes such as leukocyte elastase are usually released and inactivated locally at the site of inflammation, so there has been much recent interest in measuring local alpha 1AT concentrations in biologic fluids. In this study, we developed a modified double antibody sandwich enzyme-linked immunosorbent assay (ELISA) and used it to measure alpha 1AT concentrations in several biologic fluids.