injections

Novel Drug Delivery Method Could Replace Injections with Pills

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Scientists at the Baylor College of Medicine and collaborators say they have been exploring a better way of delivering medications that does not require injections but could be as easy as swallowing a pill. Their study “A bioengineered probiotic for the oral delivery of a peptide Kv1.3 channel blocker to treat rheumatoid arthritis” appears in PNAS.

“People don’t like to have injections for the rest of their lives,” said co-corresponding author Christine Beeton, PhD, professor of integrative physiology at Baylor. “In the current work, we explored the possibility of using the probiotic bacteria Lactobacillus reuteri as a novel oral drug delivery platform to treat rheumatoid arthritis in an animal model.”

Previous work from the Beeton lab had shown that a peptide derived from sea anemone toxin effectively and safely reduces disease severity in rat models of rheumatoid arthritis and patients with plaque psoriasis. “However, peptide treatment requires repeated injections, reducing patient compliance, and direct oral delivery of the peptide has low efficacy,” noted Beeton.

She began working with Robert A. Britton, PhD, professor of molecular virology and microbiology and member of the Dan L Duncan Comprehensive Cancer Center at Baylor. The Britton lab has genetically modified probiotic bacteria to produce and release compounds. In the current study, the team bioengineered the probiotic L. reuteri to secrete peptide ShK-235 derived from sea anemone toxin.

The bacteria are indigenous to human and other animal guts

They chose L. reuteri because these bacteria are indigenous to human and other animal guts. It is one of the lactic acid bacteria groups that has long been used as a cell factory in the food industry and is recognized as safe by the FDA L. reuteri has an excellent safety profile in infants, children, adults and even in an immunosuppressed population, according to Beeton.

“Engineered microbes for the delivery of biologics are a promising avenue for the treatment of various conditions such as chronic inflammatory disorders and metabolic disease. In this study, we developed a genetically engineered probiotic delivery system that delivers a peptide to the intestinal tract with high efficacy,” write the investigators.

“We constructed an inducible system in the probiotic Lactobacillus reuteri to secrete the Kv1.3 potassium blocker ShK-235 (LrS235). We show that LrS235 culture supernatants block Kv1.3 currents and preferentially inhibit human T effector memory (TEM) lymphocyte proliferation in vitro. A single oral gavage of healthy rats with LrS235 resulted in sufficient functional ShK-235 in the circulation to reduce inflammation in a delayed-type hypersensitivity model of atopic dermatitis mediated by TEM cells.

“Furthermore, the daily oral gavage of LrS235 dramatically reduced clinical signs of disease and joint inflammation in rats with a model of rheumatoid arthritis without eliciting immunogenicity against ShK-235.

“This work demonstrates the efficacy of using the probiotic L. reuteri as a novel oral delivery platform for the peptide ShK-235 and provides an efficacious strategy to deliver other biologics with great translational potential.”

“The results are encouraging,” Beeton said. “Daily delivery of these peptide-secreting bacteria, called LrS235, dramatically reduced clinical signs of disease, including joint inflammation, cartilage destruction and bone damage in an animal model of rheumatoid arthritis.”

The researchers followed bacteria LrS235 and the peptide ShK-235 it secretes inside the animal model. They found that after feeding rats live LrS235 that release ShK-235, they could detect ShK-235 into the blood circulation.

“Another reason we chose L. reuteri is that these bacteria do not remain in the gut permanently. They are removed as the gut regularly renews its inner surface layer to which the bacteria attach,” explained Beeton. “This opens the possibility for regulating treatment administration.”

More research is needed to bring this novel drug delivery system into the clinic, but the researchers anticipate that it could make treatment easier for patients in the future.

“These bacteria could be stored in capsules that can be kept on the kitchen counter,” pointed out Beeton. “A patient could take the capsules when on vacation without the need of refrigeration or carrying needles and continue treatment without the inconvenience of daily injections.”

The findings provide an alternative delivery strategy for peptide-based drugs and suggest that such techniques and principles can be applied to a broader range of drugs and the treatment of chronic inflammatory diseases.

Intralymphatic Injections Safe for Grass Pollen Allergy

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Intralymphatic injections of standard grass-pollen extract are well tolerated and could offer a new and convenient option for treating grass-pollen allergy, new research suggests.

The therapy involves ultrasound-guided injection into the right inguinal lymph node, and requires only three preseasonal doses, given 1 month apart, explained investigator Amber Patterson, MD, from Nationwide Children’s Hospital in Columbus, Ohio.

Intralymphatic immunotherapy is similar to subcutaneous immunotherapy “in that you do your course of treatment, but then you’re done,” without the monthly injections for 3 to 5 years, she explained.

In several European trials, it has been demonstrated that intralymphatic injections are effective against grass, birch, and cat.

“When I first read about this in Europe, I thought, ‘this is incredible, we need to be doing this here.’ It’s so nice to have options since a lot of people don’t do traditional allergy shots because it’s so inconvenient,” Dr Patterson told Medscape Medical News.

“The Europeans followed people 3 years out and saw sustained efficacy, so we’re banking on that,” she added.

Results from the study by Dr Patterson’s team were presented as a late-breaking poster here at the American Academy of Allergy, Asthma & Immunology 2015.

First Evidence

The double-blind trial involved 15 teenagers with grass-pollen-induced rhinoconjunctivitis, three of whom also reported mild intermittent asthma.

The patients were randomly assigned to receive three intralymphatic injections of either extract from North American grass pollen or placebo, administered at least 4 weeks apart and timed to be completed before the start of the grass-pollen season.

Escalating doses — 0.1 mL, 0.2 mL, and 0.5 mL — were administered with a 1.5-inch 25-gauge needle inserted into the subcapsular node space, Dr Patterson explained.

“The main aim was to show that we could take American extracts, which are standardized differently than European extracts, and that we could do this safely,” she said.

You hardly ever see this kind of compliance.

Patients were assessed for adverse safety events — such as erythema, pruritus, and edema — 2 and 5 hours after the injection and then 1 week later. There were no differences in safety scores between the treatment and placebo groups.

Of note, all the teenagers completed 100% of their injections, Dr Patterson reported. “When I told other allergists this, they were so surprised; you hardly ever see this kind of compliance.”

When she was asked about allergists’ access to ultrasound guidance for the injections, Dr Patterson explained that “we need to figure out the science first. Once that’s more established, we can figure out how to give the shots because it’s a pretty simple procedure.”

“It’s interesting,” said Hugh Sampson, MD, from Kravis Children’s Hospital at Mount Sinai in New York City, who was not involved in the study.

“It does seem safe and, if you can do it in three doses, you’re definitely going to get better compliance,” he told Medscape Medical News.