Nanotherapy offers new hope for the treatment of Typediabetes

Date:
January 17, 2022
Source:
Northwestern University
Summary:
Individuals living with Type 1 diabetes must carefully follow
prescribed insulin regimens every day, receiving injections of the
hormone via syringe, insulin pump or some other device. And without
viable long-term treatments, this course of treatment is a lifelong
sentence. Now a team of researchers has discovered a better way.



FULL STORY ========================================================================== Individuals living with Type 1 diabetes must carefully follow prescribed insulin regimens every day, receiving injections of the hormone via
syringe, insulin pump or some other device. And without viable long-term treatments, this course of treatment is a lifelong sentence.


========================================================================== Pancreatic islets control insulin production when blood sugar levels
change, and in Type 1 diabetes, the body's immune system attacks and
destroys such insulin-producing cells. Islet transplantation has emerged
over the past few decades as a potential cure for Type 1 diabetes. With
healthy transplanted islets, Type 1 diabetes patients may no longer need insulin injections, but transplantation efforts have faced setbacks as
the immune system continues to eventually reject new islets. Current immunosuppressive drugs offer inadequate protection for transplanted
cells and tissues and are plagued by undesirable side effects.

Now a team of researchers at Northwestern University has discovered
a technique to help make immunomodulation more effective. The method
uses nanocarriers to re-engineer the commonly used immunosuppressant
rapamycin. Using these rapamycin-loaded nanocarriers, the researchers
generated a new form of immunosuppression capable of targeting specific
cells related to the transplant without suppressing wider immune
responses.

The paper was published today (Jan. 17), in the journal Nature
Nanotechnology.

The Northwestern team is led by Evan Scott, the Kay Davis Professor and an associate professor of biomedical engineering at Northwestern's McCormick School of Engineering and microbiology-immunology at Northwestern
University Feinberg School of Medicine, and Guillermo Ameer, the Daniel
Hale Williams Professor of Biomedical Engineering at McCormick and
Surgery at Feinberg. Ameer also serves as the director of the Center
for Advanced Regenerative Engineering (CARE).

Specifying the body's attack Ameer has been working on improving
the outcomes of islet transplantation by providing islets with an
engineered environment, using biomaterials to optimize their survival
and function. However, problems associated with traditional systemic immunosuppression remain a barrier to the clinical management of patients
and must also be addressed to truly have an impact on their care,
said Ameer.



========================================================================== "This was an opportunity to partner with Evan Scott, a leader in immunoengineering, and engage in a convergence research collaboration that
was well executed with tremendous attention to detail by Jacqueline Burke,
a National Science Foundation Graduate Research Fellow," Ameer said.

Rapamycin is well-studied and commonly used to suppress immune responses
during other types of treatment and transplants, notable for its wide
range of effects on many cell types throughout the body. Typically
delivered orally, rapamycin's dosage must be carefully monitored to
prevent toxic effects. Yet, at lower doses it has poor effectiveness in
cases such as islet transplantation.

Scott, also a member of CARE, said he wanted to see how the drug could
be enhanced by putting it in a nanoparticle and "controlling where it
goes within the body." "To avoid the broad effects of rapamycin during treatment, the drug is typically given at low dosages and via specific
routes of administration, mainly orally," Scott said. "But in the case of
a transplant, you have to give enough rapamycin to systemically suppress
T cells, which can have significant side effects like hair loss, mouth
sores and an overall weakened immune system." Following a transplant,
immune cells, called T cells, will reject newly introduced foreign cells
and tissues. Immunosuppressants are used to inhibit this effect but can
also impact the body's ability to fight other infections by shutting
down T cells across the body. But the team formulated the nanocarrier
and drug mixture to have a more specific effect. Instead of directly
modulating T cells -- the most common therapeutic target of rapamycin --
the nanoparticle would be designed to target and modify antigen presenting cells (APCs) that allow for more targeted, controlled immunosuppression.



========================================================================== Using nanoparticles also enabled the team to deliver rapamycin through a subcutaneous injection, which they discovered uses a different metabolic pathway to avoid extensive drug loss that occurs in the liver following
oral administration. This route of administration requires significantly
less rapamycin to be effective -- about half the standard dose.

"We wondered, can rapamycin be re-engineered to avoid non-specific
suppression of T cells and instead stimulate a tolerogenic pathway by delivering the drug to different types of immune cells?" Scott said. "By changing the cell types that are targeted, we actually changed the
way that immunosuppression was achieved." A 'pipe dream' come true in
diabetes research The team tested the hypothesis on mice, introducing
diabetes to the population before treating them with a combination
of islet transplantation and rapamycin, delivered via the standard
Rapamune(R) oral regimen and their nanocarrier formulation. Beginning
the day before transplantation, mice were given injections of the altered
drug and continued injections every three days for two weeks.

The team observed minimal side effects in the mice and found the diabetes
was eradicated for the length of their 100-day trial; but the treatment
should last the transplant's lifespan. The team also demonstrated the population of mice treated with the nano-delivered drug had a "robust
immune response" compared to mice given standard treatments of the drug.

The concept of enhancing and controlling side effects of drugs via
nanodelivery is not a new one, Scott said. "But here we're not enhancing
an effect, we are changing it -- by repurposing the biochemical pathway
of a drug, in this case mTOR inhibition by rapamycin, we are generating
a totally different cellular response." The team's discovery could
have far-reaching implications. "This approach can be applied to other transplanted tissues and organs, opening up new research areas and
options for patients," Ameer said. "We are now working on taking these
very exciting results one step closer to clinical use." Jacqueline Burke,
the first author on the study and a National Science Foundation Graduate Research Fellow and researcher working with Scott and Ameer at CARE,
said she could hardly believe her readings when she saw the mice's
blood sugar plummet from highly diabetic levels to an even number. She
kept double-checking to make sure it wasn't a fluke, but saw the number sustained over the course of months.

Research hits close to home For Burke, a doctoral candidate studying
biomedical engineering, the research hits closer to home. Burke is
one such individual for whom daily shots are a well-known part of her
life. She was diagnosed with Type 1 diabetes when she was nine, and for
a long time knew she wanted to somehow contribute to the field.

"At my past program, I worked on wound healing for diabetic foot ulcers,
which are a complication of Type 1 diabetes," Burke said. "As someone
who's 26, I never really want to get there, so I felt like a better
strategy would be to focus on how we can treat diabetes now in a more
succinct way that mimics the natural occurrences of the pancreas in
a non-diabetic person." The all-Northwestern research team has been
working on experiments and publishing studies on islet transplantation for three years, and both Burke and Scott say the work they just published
could have been broken into two or three papers. What they've published
now, though, they consider a breakthrough and say it could have major implications on the future of diabetes research.

Scott has begun the process of patenting the method and collaborating with industrial partners to ultimately move it into the clinical trials stage.

Commercializing his work would address the remaining issues that have
arisen for new technologies like Vertex's stem-cell derived pancreatic
islets for diabetes treatment.

========================================================================== Story Source: Materials provided by Northwestern_University. Original
written by Lila Reynolds. Note: Content may be edited for style and
length.


========================================================================== Journal Reference:
1. Burke, J.A., Zhang, X., Bobbala, S. et al. Subcutaneous nanotherapy
repurposes the immunosuppressive mechanism of rapamycin to enhance
allogeneic islet graft viability.. Nat. Nanotechnol., 2022 DOI:
10.1038/ s41565-021-01048-2 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220117115111.htm

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