Targeting cellular pathways controlled by norrin can be used as a therapeutic strategy to prevent vision loss in patients with diabetes
Rats with diabetes, left, have a breakdown in the blood-retinal barrier, which results in a green haze. After treatment with norrin, right, the haze disappears. The bright green dots are blood vessels. Credit: Antonetti lab
In a new study published in the journal Diabetes, University of Michigan researchers showed that treatment with the molecule norrin can prevent vision loss from diabetic retinopathy in diabetic rat models.
Current therapies for diabetic retinopathy target vascular endothelial growth factor, or VEGF, a protein that causes new blood vessels to form. VEGF also increases blood vessel permeability or the capacity to allow water and nutrients to move in and out of the bloodstream into tissues.
In patients with diabetic retinopathy, excess VEGF causes the growth of abnormal, leaky blood vessels, both leading to vision loss. Although anti-VEGF agents are commonly used to treat diabetic retinopathy, it requires several injections and fails to fully manage half the treated patients.
“There is an urgent need for new therapies that can help preserve vision in patients with diabetic retinopathy,” said David Antonetti, PhD, Research Professor of Ophthalmology and Visual Sciences at Kellogg Eye Center.
“We have been working on the effects of norrin for several years and these results will help develop new therapies that can prevent vision loss.”
Preventing vision loss
In previous studies, the team showed that norrin can reverse the effects of VEGF on the blood vessel barrier in cells. In the current study, they found that after rats developed diabetes, their levels of norrin decreased and this was accompanied by decreased vision. When they injected these rats with norrin, the researchers could prevent vision loss.
“We are excited that norrin treatment can also reduce the loss of nerve cells involved in vision in diabetic rats,” said Laura González-González, Postdoctoral Fellow in the Antonetti lab.
Treatment with norrin also prevented retinal cell death and inflammation, both in early and late stages of diabetes. Starting norrin treatment even after vision loss prevented further loss in the diabetic rats. These results suggest that norrin can potentially help prevent vision loss in patients with diabetes.
The team identified several genes that were affected by norrin treatment, and they are working on understanding how they contribute to barrier restoration.
Clinical trials and retinal blood vessels
The work done by the Antonetti lab has helped target identification for a new diabetic retinopathy treatment method.
To this end, their work helped EyeBio and Merck develop clinical trials for drugs that can increase the activity of cell receptors that respond to norrin.
Menopause, defined as a year with no periods, marks the end of a woman’s reproductive years. Photo by Ayo Ogunseinde on Unsplash
Across the country’s townships and rural clinics, women are breaking inherited silences to redefine reproductive ageing on their own terms.
In South Africa, women are challenging the silence around menopause, and the expectation to endure it without support.
This is significant because research suggests that some women in South Africa never discuss menopause with a healthcare worker. In a 2017 study of 450 black women in communities near Pretoria, more than three-quarters had never sought medical help for their symptoms, possibly, researchers argue, because of a cultural view of menopause as a positive natural process.
Menopause, defined by the World Health Organisation (WHO) as a year with no periods, marks the end of a woman’s reproductive years. It’s a natural transition brought on as the ovaries stop releasing eggs and oestrogen levels fall, usually between the ages of 45 and 55. Joint and muscle pain, exhaustion, poor memory and hot flushes are among the most common symptoms, but a new review suggests there are up to 72 possible symptoms.
Hormone replacement therapy is the most effective treatment to ease hot flushes, according to South African Menopause Society (SAMS) guidance, but whether it’s the right choice will depend on each person’s medical history and preferences.
After researching women’s perceptions of menopause in Gauteng and North West, researcher Sostina Matina now believes that the limited use of menopause treatments in South Africa’s public healthcare sector should not be mistaken for a rejection of clinical care. Many women, she says, had simply never had their options explained to them.
Xoli Madlala, who experienced menopause early, has made it her personal mission to bring menopause out into the open. She travels across the country, speaking in settings ranging from corporate boardrooms to rural Bible study groups.
Wherever she goes, she says, women of different ages are open to talking about a subject that previous generations were often expected to endure without discussion.
How clinic staff can fuel midlife myths
Midlife women seeking menopause symptom relief are often turned away by health workers, Matina says, especially if they’re experiencing symptoms earlier than usual or as a result of surgery.
“They’ll say ‘it’s just menopause, there’s nothing we can do’,” she says.
The country’s treatment guidelines for clinics and hospitals include menopausal hormone therapy pills that can ease hot flushes and other symptoms. Women who have had a hysterectomy can usually be prescribed pills with only oestrogen. Those with a womb also need to take progestogen because oestrogen on its own can cause the uterine lining to become too thick, which can increase the risk of cancer.
Hormone patches, which deliver hormones through the skin, are not on South Africa’s essential drug list, but they are listed as alternatives if the pills don’t work well for a particular patient or as an alternative when pill stocks are low, which a report by the National Essential Medicines List Committee suggests happens often.
Professor Lineo Matsela, an obstetrician, gynaecologist and president of SAMS, says it’s become common for public sector doctors to write prescriptions for menopausal hormone treatments so that patients can buy them at a private pharmacy.
Over the past three years, however, there have also been sporadic private sector shortages of menopausal hormone therapy treatments.
But access to medicines is only part of the problem, Matina says. Dismissing menopause can also mean the health system could be missing other health risks that can impact women in midlife, a phase that can span about 40% of their lives.
The transition is also associated with bone loss, and the stakes might be slightly higher for women living with HIV. Over five years, a Soweto study found a greater loss of bone-density among women living with HIV compared to those without HIV, though there wasn’t a difference in fractures between the two groups. Researchers didn’t have information on which HIV treatments participants were taking so they couldn’t untangle the effects of HIV itself from the possible impact of tenofovir, which is part of first-line HIV treatment and can contribute to bone loss.
US research suggests there could also be links between HIV, menopause and heart disease and an African study found higher rates of the “bad” kind of cholesterol after menopause regardless of HIV status.
Loss and liberation
People’s experiences of menopause vary widely across countries, cultures and generations.
Women in four rural villages in Limpopo, for instance, described menopause to researchers as a series of losses, of beauty, respect and quality of life even though older people were generally regarded as important veterans who deserve respect regardless of gender.
In some instances, researchers found that elders enforce a culture of silence about menopause. One premenopausal woman explained: “At the girls’ initiation when we were still young, old women told us blood will cease and since then no one ever talked to me about it. That is why I say it is my secret.”
In interviews at two Mamelodi clinics, researchers heard accounts linking pain and weight gain to blood that was no longer flowing out. “I do not know where this blood goes,” one participant said.
In a 2013 discussion of menopause and marriage, theologian Elijah Baloyi described a belief among Tsonga-speaking people that sex after menopause could cause semen to accumulate and a woman’s abdomen to swell.
In Johannesburg’s Soweto township, Matina found many postmenopausal women held beliefs about dirty blood, some saying they withdrew from sexual intimacy entirely or accepted the end of their intimate relationships.
For others, menopause brought liberation from the monthly financial burden of sanitary pads, or elevation to the level of an elder who could commune with ancestors.
Research conducted in South Africa and Zimbabwe suggests that inter-generational support can make all the difference to help women approach the milestone with acceptance.
One woman, who initially worried the changes she was experiencing were signs she could be dying, was calmed by her mother’s reassurance and positive outlook. Another told researchers: “[Menopause] is something I am looking forward to, why, because I am getting old. Yes, if time permits and if God allows it, with life, it’s okay.”
Language mirrors a society’s worldview, and where Western medicine isolated a clinical hormonal deficit, African linguistic traditions instead describe social shifts.
When clinical concepts are translated literally into local languages, they often produce phrases steeped in shame, stigma, or perceived uselessness such as kuguma ura (no longer bearing) in Shona or phelelo maikutlo (the end of one’s feelings) in Setswana.
In response, women may express their bodily changes through idioms and euphemisms, describing hot flushes as fufulelwa or framing the transition socially as ugugile (she has aged), sekhulile (growing older), or into zabogogo (grannies’ stuff).
Because nursing and medical school curricula spend little time on multicultural health communication or the endocrinology of ageing, Matina argues clinic staff frequently misinterpret these cultural expressions or fail to engage with them altogether.
“You know, I don’t know menopause properly… because sometimes people speak in such big English, so you don’t understand it, unless someone explains it to you”, an older woman in Soweto told researchers.
From stigma to selfhood
When researchers set out to learn about midlife health across South Africa and Zimbabwe, they discovered that women want something different from what their public health systems currently offer.
The women described leaving clinics without accessible information and with lingering physical distress or anxiety over health risks.
When asked what would help, participants explicitly requested clear, contextually relevant information so they could understand their bodies and take charge of their own health regardless of their access to more expensive hormone therapies.
The result is a series of question-and-answer booklets co-created with communities, doctors, translators and designers, which reflect the women’s firm rejection of the “old granny” stereotypes.
The participants banned old-fashioned dresses, which they felt aged menopausal women, and insisted on vibrant, modern images of smiling, active women. Also banished were medical jargon and deficit-based translations of “menopause”.
Instead, they opted for culturally relevant terms of dignity and strength such as Ubufazi in isiZulu and Sesadi in Setswana, both of which simply mean “womanhood”.
Researchers have developed a new iron-based contrast agent for magnetic resonance imaging that can be used for both diagnosis and treatment. In a study conducted on lab-grown human heart tissue, it was demonstrated that the contrast agent accumulates in the fibrotic tissue, that its signal intensity on the MRI image increases with disease severity, and that it slows disease progression.
The Biomolecular Nanotechnology research group led by Ikerbasque research professor Aitziber L. Cortajarena developed the iron-based contrast agent. The study, led by Cortajarena and conducted in collaboration with Ana Villar’s group at the Institute of Biomedicine and Biotechnology of Cantabria (IBBTEC, UC-CSIC), has been published in Advanced Functional Materials. It paves the way for a possible alternative to gadolinium, the metal currently used in almost all contrast-enhanced MRI scans.
Cardiac fibrosis
Cardiac fibrosis is one of the main factors leading to heart failure, a disease that affects millions of people worldwide. There is currently no approved treatment specifically designed to slow down this condition. When the heart is damaged or under sustained strain (for example, after a heart attack or due to hypertension), a repair process begins, and the collagen production process is activated to repair and strengthen the tissue. However, this process often does not stop: the collagen continues to accumulate, the heart becomes stiff and finds it increasingly difficult to fill and pump the blood properly.
One of the techniques currently used for diagnosing fibrosis of the heart is MRI. In many cases, an intravenous contrast agent is administered to the patient, and is almost always based on gadolinium, which is retained in the damaged areas and lights them up. Although gadolinium works very well, it has various disadvantages. It is a metal that is foreign to the body. Its use is restricted in people with kidney failure, and it is known that small amounts of may be retained in different tissues for many years. This is especially concerning in patients who require repeated MRIs to monitor the progression of their disease, which is the case with cardiac fibrosis.
Iron atoms encapsulated in a custom-designed protein
For this reason, for many years researchers have sought to develop contrast agents based on iron, a metal that the body is familiar with and knows how to store and eliminate. However, there is a problem with existing iron-based contrast agents since, instead of illuminating the damaged area, they darken it, making it difficult to distinguish it in the images. Many of them have even been withdrawn from the market. The group led by Cortajarena, Scientific Director at CIC biomaGUNE, has been able to “overcome these problems by using designer proteins”, explains CIC biomaGUNE researcher Lydia Martínez Parra, lead author of the study. Martínez adds, “the contrast agent consists of a specially designed protein that encapsulates and isolates minute clusters of iron atoms measuring approximately 1.4 nanometres (around 50 000 times thinner than a hair). It is also worth noting that this compound is safer for the body, is stable, releases very little iron and is of low toxicity to cells. Furthermore, it is easy and sustainable to manufacture, since it is produced in water, without toxic reagents or extreme conditions.”
A lab-grown fibrotic heart
The CIC biomaGUNE group has tested the efficacy of the contrast agent in cardiac tissue created with 3D tissue engineering using patients’ heart cells, developed by Ana Villar’s group (IBBTEC, UC-CSIC). These tissues replicate certain characteristics of cardiac fibrosis, such as the accumulation of collagen and increase in tissue stiffness, and enable new therapeutic strategies to be evaluated in more representative conditions than conventional cell cultures.
Thus, the research team has verified that the contrast agent moves towards and accumulates predominantly in the fibrotic tissue, that the signal on the MRI increases with the severity of the fibrosis, and that it slows its progression since it reduces the production and storage of collagen and prevents the tissue from becoming stiff. “That is, as well as indicating where the damage is, this material shows antifibrotic activity in the models studied”, says research professor Cortajarena. This is a ‘theranostic’ agent that offers diagnosis and treatment in the same material.”
Martínez points out that “this new compound enables the achievement of a contrast in magnetic resonance imaging comparable to that of gadolinium-based agents. It also retains this capacity in both magnetic fields commonly used in clinical practice and stronger magnetic fields used in preclinical research.” The compound formed by the iron atoms encapsulated by the protein make the tissue appear bright on the MRI.
The team behind the study affirms that “there’s still a way to go to reach the patient. For now, this new contrast agent has been tested in cells and human tissue in the laboratory. The next step will be to study it so that it can be used in clinical practice, to see how it is distributed and eliminated from the body and how it behaves on a real cardiac scanner. Our goal is that, in the future, patients with cardiac fibrosis, including those who cannot receive gadolinium, can have a safer imaging test that also forms part of their treatment.
