A reagent for improved purity and yield of biofluid-derived extracellular vesicles (EVs)

A reagent for improved purity and yield of biofluid-derived extracellular vesicles (EVs)

Key features:

  • Simple and effective method for improved removal of lipoproteins, major contaminants in biofluid-derived EVs.
  • Improved EV yield while preserving EV morphology.
  • Compatible with industry standard purification methods including TFF and SEC

Background

Extracellular vesicles (EVs) are nanosized biomolecular packages involved in intercellular communication. EVs are released by all cell types, making them broadly applicable in therapeutic and diagnostic applications. EVs are a promising next generation cell-free therapy and drug delivery platform and have potential as biomarkers for diseases diagnosis.

Sample purity is critical to maximise performance and correctly attribute observed therapeutic or diagnostic effects to EVs rather than other biological particles. Lipoprotein contaminants represent a major challenge for obtaining pure samples of biofluid-derived EVs.


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Fluorescent bioassay to quantify the potency of human growth hormone and other hormones and cytokines

Background
Human growth hormone (hGH) is used as a prescription biologic pharmaceutical to treat children’s growth disorders and adult growth hormone deficiency. Bioassays used in the manufacture and characterisation of growth hormone traditionally are expensive, laborious and require the sacrificing of rodents.

Cell-based assays have the potential to improve analytical release testing for hGH drug products and be used as research tools. Cell-based assays are usually measured via colourimetric endpoints (eg. using MTT or MTS) that can be tedious to carry out, requiring additional labour and time. In addition, endpoint assays do not allow for quantification over multiple time points.

University of Queensland (UQ) researchers have developed a fluorescent in vitro receptor-based bioassay capable of continuously detecting the potency of hGH using high content imaging.

The technology
The assay consists of a murine pro-B cell line (BaF/B03) that has been modified to express green fluorescent protein (GFP) and the hGH receptor on the cell surface. The cell line is designated Ba/F3-hGHR-GFP, and proliferation occurs in a dose dependent manner according to the concentration of hGH.

The UQ team has proof of concept data that demonstrates the bioassay can detect hGH at concentrations as low as 0.05 ng/mL when using the Ba/F3-hGHR-GFP cell line

Key features

  • Highly sensitive detection of hGH (0.05 ng/mL)
  • Compatible with high throughput screening (384-well plates)
  • Cell culture can be continued after analysis to allow for time course assays
  • Assay adaptable to receptors for other hormones or cytokines.


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Transgenic plants for recombinant manufacture of cyclotides and other cyclic peptides

Increased rigidity and stability are some of the numerous benefits of cyclic peptides. Cyclotides are a class of cyclic peptides that contain three disulfide bonds arranged in a cystine knot motif, which confers exceptional stability.  Cyclotides have exhibited a range of bioactivities, from agricultural pests to human pathogens and diseases. The stable cyclotide framework can also be used as a pharmaceutical scaffold for the grafting of peptide sequences conferring bioactivity. Despite their attractive properties, efficient manufacture of cyclotides is a significant obstacle to their commercial development.

Using Agrobacterium-mediated transformation, University of Queensland (UQ) researchers have developed transgenic plants capable of producing cyclic peptides. The UQ team has demonstrated that the cyclotide precursor (Oak1) can be effectively cyclised using OaAEP1b in three plant species.

Key features

  • Production of difficult to manufacture cyclic peptides in a plant-based expression system
  • Improved yields over synthetic or in vitro production
  • Compatible with existing molecular pharming methods (including Agrobacterium-mediated transformation)
  • Peptide products with exceptional stability for therapeutic and/or agricultural applications
  • Ongoing development of optimised enzyme variants and expression systems.


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Focused ultrasound for treatment of neurodegenerative disease

Neurological disorders present an increasing challenge for an ageing population.  The global incidence of dementia is predicted to reach 82 million by 2030 with up to 80% of those individuals having Alzheimer’s disease (AD).

Researchers at The University of Queensland (UQ) have developed a novel ultrasound technology that can be used in conjunction with microbubbles, which they have shown effectively removes AD pathology and restores memory in animal models.

Unlike drug-based monotherapy, therapeutic ultrasound is not restricted to a single target, resulting in a unique mechanism of action. The UQ team further showed that their prototype technology is a tool for non-invasive intracerebral delivery of therapeutic antibodies.  The technology has the potential to address the unmet need in neurodegenerative disease treatment, in addition to being an attractive solution for improving the delivery and effectiveness of pipeline neurological therapeutics.

Key features

  • Non-invasive technology for treatment of brain diseases including Alzheimer’s disease
  • Investigational Use Only clinical research platform, ready for 2022 first-in-human study
  • Functional data in small and large animal models showing restoration of memory
  • Transient blood-brain barrier (BBB) opening resulting in >10-fold increased uptake of therapeutic antibodies
  • Improved cognitive function in healthy aged animals post-treatment without the need for BBB opening.


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Method for stable integration of genes that boosts product expression in yeast

Yeast-based expression systems are commonly used to produce both recombinant proteins and small molecules. Overexpression of a gene by increasing its copy number is generally desirable, but that copy number (and therefore yield) is often traded for other important factors such as growth efficiency and/or unstable modifications.

Researchers at The University of Queensland (UQ) have developed a technology for targeted and stable integration of a gene of interest in a manner that affords control of copy number and – when tested on a range of target genes in S. cerevisiae – increased protein expression compared to standard yeast systems.

Key potential benefits

  • Increase expression yields of small molecules and recombinant proteins by amplifying gene copy number
  • Targeted and stable genomic integration of construct(s) without harsh selection conditions
  • Compatibility with many synbio circuits for auto-induction of protein expression
  • Proof-of-concept data in yeast, but potential application in other cell-based expression systems.

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Modulators of Class IIa HDACs

Histone deacetylases (HDACs) are enzymes that mediate the removal of acetyl groups from numerous acetylated proteins (including histones) and some are associated with the cell cycle, inflammation, apoptosis and cancer. HDACs have been found to be involved in a wide range of diseases and conditions and represent promising drug targets.  There are eleven zinc-binding mammalian HDACs including 4 class I, 4 class IIa and 2 class IIb proteins.

The Fairlie Research Group at The University of Queensland (UQ) has exploited structural differences between Class I and IIa HDACs to develop two generations of new compounds that are potent and selective inhibitors of class IIa HDACs.

Inhibitors of Class IIa HDACs have the potential to treat many inflammation-related pathologies.

Key features

  • New potent and selective inhibitors of class IIa HDAC enzymes
  • No induction of cellular histone H4 acetylation, unlike most inhibitors of HDACs
  • Potential for modulating class IIa HDAC functions in vivo with fewer cytotoxic side effects than other HDAC inhibitors.


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Clec9a targeted vaccination for virus-mediated autoimmune disease

Growing evidence is now associating the development of auto-immune disease with poor chronic viral control, including:

  • Rheumatoid arthritis: associated with increased EBV viral load and expanded viral-specific T cells;
  • Multiple sclerosis: high prevalence of EBV at disease onset, cross-reactive pathogenic antibodies identified;
  • Sjogren’s syndrome: high EBV and CMV viral load, viral-specific T cells.

Vaccination against viruses such as EBV and CMV in the early stages of disease could intercept progression of, or potentially cure, a range of autoimmune diseases.  Eliciting an appropriate immune response is key, with the goal to manage viral control as opposed to viral elimination.

Researchers at The University of Queensland (UQ) have developed a technology: liposome nanoparticle targeted to human CD141+ DC-1 cross-presenting dendritic cells that selectively express clec9a through a novel clec9a-targeting peptide.  Targeted liposomes effectively deliver tailorable payloads and induce specific cytotoxic T-lymphocytes without requiring adjuvant.

Proof of concept

Data for clec9a-targeted delivery with prototype nanoparticles (nanoemulsions) demonstrates successful delivery of payloads to human CD141+ DC1 populations.

Key features

  • Novel approach to deliver bespoke, tailorable payloads to dendritic cells
  • Self-adjuvanting liposomes generate robust CD4+ and CD8+ responses to payloads
  • Proposed to prevent progression of viral-associated autoimmune diseases.


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IBD therapeutic derived from gut microbial metabolites

Inflammatory bowel disease (IBD) is a chronic and incurable disease characterised by episodic and disabling inflammation of the gut.  Current therapeutic strategies aim to decrease the frequency and severity of inflammatory episodes to prevent progression of bowel damage and avoid disabling disease with need for surgery.  However, these therapeutic options suffer from poor compliance, toxicity or cost.

There is an urgent need for better therapeutics.  With clear evidence that intestinal immunity is regulated through microbiome-immune crosstalk, the microbiome has now emerged as a valuable potential source for immune-modifying IBD therapeutics.

Researchers at The University of Queensland (UQ) have isolated gut bacteria that secreted soluble suppressors of the pro-inflammatory NF-κβ pathway, and identified a novel class of NF-κβ inhibitory bioactives.  Based on the bioactives, a lead compound with potent NF-κβ activity (IC50 = 1 nM) was synthesised.

Preliminary pharmacokinetic profiling in mice shows that the lead compound is detectable at active concentrations throughout the ileum and colon less than 1 hour following oral administration and remains at concentrations >100×IC50 for >6 hours.

Key features

  • Leverage benefits of microbiome to treat IBD
  • Novel molecules potently inhibit NF-κβ pathway throughout the colon
  • Comparable reduction in disease severity to biologic therapies
  • Orally active, with >6 hours gut stability and favourable PK profile.


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