GABA and Combined GABA with GAD65-Alum Treatment Alters Th1 Cytokine Responses of PBMCs from Children with Recent-Onset Type 1 Diabetes.

Type 1 diabetes (T1D) is an autoimmune disease culminating in the destruction of insulin-producing pancreatic cells. There is a need for the development of novel antigen-specific strategies to delay cell destruction, including combinatorial strategies that do not elicit systemic immunosuppression. Gamma-aminobutyric acid (GABA) is expressed by immune cells, ß-cells, and gut bacteria and is immunomodulatory. Glutamic-acid decarboxylase 65 (GAD65), which catalyzes GABA from glutamate, is a T1D autoantigen. To test the efficacy of combinatorial GABA treatment with or without GAD65-immunization to dampen autoimmune responses, we enrolled recent-onset children with T1D in a one-year clinical trial (ClinicalTrials.gov NCT02002130) and examined T cell responses. We isolated peripheral blood mononuclear cells and evaluated cytokine responses following polyclonal activation and GAD65 rechallenge. Both GABA alone and GABA/GAD65-alum treatment inhibited Th1 cytokine responses over the 12-month study with both polyclonal and GAD65 restimulation. We also investigated whether patients with HLA-DR3-DQ2 and HLA-DR4-DQ8, the two highest-risk human leukocyte antigen (HLA) haplotypes in T1D, exhibited differences in response to GABA alone and GABA/GAD65-alum. HLA-DR4-DQ8 patients possessed a Th1-skewed response compared to HLA-DR3-DQ2 patients. We show that GABA and GABA/GAD65-alum present an attractive immunomodulatory treatment for children with T1D and that HLA haplotypes should be considered.

Interval delivery of 5HT2A agonists using multilayered polymer films.

There is an urgent unmet medical need to develop therapeutic options for the ~50% of depression patients suffering from treatment-resistant depression, which is difficult to treat with existing psycho- and pharmaco-therapeutic options. Classical psychedelics, such as the 5HT2A agonists, have re-emerged as a treatment paradigm for depression. Recent clinical trials highlight the potential effectiveness of 5HT2A agonists to improve mood and psychotherapeutic growth in treatment-resistant depression patients, even in those who have failed a median of four previous medications in their lifetime. Moreover, microdosing could be a promising way to achieve long-term alleviation of depression symptoms without a hallucinogenic experience. However, there are a gamut of practical barriers that stymie further investigation of microdosing 5HT2A agonists, including: low compliance with the complicated dosing regimen, high risk of diversion of controlled substances, and difficulty and cost administering the long-term treatment regimens in controlled settings. Here, we developed a drug delivery system composed of multilayered cellulose acetate phthalate (CAP)/Pluronic F-127 (P) films for the encapsulation and interval delivery of 5HT2A agonists from a fully biodegradable and biocompatible implant. CAPP film composition, thickness, and layering strategies were optimized, and we demonstrated three distinct pulses from the multilayered CAPP films in vitro. Additionally, the pharmacokinetics and biodistribution of the 5HT2A agonist 2,5-Dimethoxy-4-iodoamphetamine (DOI) were quantified following the subcutaneous implantation of DOI-loaded single and multilayered CAPP films. Our results demonstrate, for the first time, the interval delivery of psychedelics from an implantable drug delivery system and open the door to future studies into the therapeutic potential of psychedelic delivery.

Effect of gamma aminobutyric acid (GABA) or GABA with glutamic acid decarboxylase (GAD) on the progression of type 1 diabetes mellitus in children: Trial design and methodology.

BACKGROUND: Evidence suggests that GABA may reduce pancreatic inflammation, protect ß-cells from autoimmune destruction, and potentiate the regeneration of new ß-cells in the setting of type 1 diabetes mellitus (T1DM). The enzyme GAD, also expressed in human pancreatic ß-cells, is an antigenic target of reactive T cells. We hypothesized that treatment of children with recent onset T1DM with GABA or combination GABA with GAD will preserve ß-cell function and ameliorate autoimmune dysregulation. METHODS: This is a one-year, prospective, randomized, double-blind, placebo-controlled trial. Ninety-nine patients aged 4-18 years with newly diagnosed T1DM are randomized into three treatment groups: 1) oral GABA twice daily in addition to two injections of recombinant GAD enzyme, 2) oral GABA plus placebo GAD injections, or 3) placebo GABA and placebo GAD. Patients are evaluated at baseline and months 1, 5, 8 and 12. Mixed meal tolerance testing is performed at all but the 8-month visit. Laboratory studies will assess indices of beta and alpha cell function, glycemic control, immunophenotyping, and diabetes-related autoantibodies. RESULTS: The primary outcome is the effect on pancreatic ß-cell function as measured by meal-stimulated c-peptide secretion compared between the treatment groups before and after one year of treatment. Secondary outcomes include: 1) fasting and meal stimulated glucagon and proinsulin levels, 2) response in insulin usage by participants, 3) indices of immune cell function, and 4) effect on autoantibodies GAD65, ICA512, and ZnT8. CONCLUSIONS: This trial will determine the safety and efficacy of GABA and combination GABA/GAD therapy to delay T1DM progression in children.