Propranolol, a drug that is efficacious against infantile haemangiomas (“strawberry naevi,” resembling birthmarks), can also be used to treat cerebral cavernous malformations, a condition characterized by misshapen blood vessels in the brain and elsewhere.
This has been shown by researchers at Uppsala University in a new study published in the scientific journal Stroke.
“Up to now, there’s been no drug treatment for these patients, so our results may become hugely important for them,” says Peetra Magnusson of the University’s Department of Immunology, Genetics and Pathology, who headed the study.
Cerebral cavernous malformations (CCMs, also called cavernous angiomas or cavernomas) are vascular lesions on blood vessels in the brain and elsewhere caused by genetic changes that may be hereditary or arise spontaneously.
Today, an operation to remove these lesions is the only possible treatment. However, surgical interventions in the brain are highly risky. Since the vascular malformations, moreover, recur in the hereditary form of the condition, a drug treatment for CCMs is urgently required instead.
The uses of propranolol, a beta blocker, include treating cardiovascular diseases and conditions such as high blood pressure. But it can also be used to treat a haemangioma (“strawberry naevus”), a common blood-vessel malformation in children. There are some indications that the preparation might work against CCMs as well.
The new study is a collaboration involving researchers at Uppsala University, the Swedish University of Agricultural Sciences and, in Italy, IFOM—The FIRC Institute of Molecular Oncology and the Mario Negri Institute of Pharmacological Research.
The researchers have been investigating how propranolol affects the emergence of vascular lesions in the form of CCMs.
“We examined mice with vascular malformations in the brain – cavernomas or CCMs, as they’re called – that corresponded to the hereditary form of the condition in humans. The mice were given propranolol in their drinking water, and we were able to see that the cavernomas were becoming fewer and smaller.
The blood vessels functioned better, too, with less leaking and improved contacts between their cells,” Magnusson says.
The propranolol dose administered to the animals was equivalent to the dose used to treat diseases in humans. Using an electron microscope, the researchers were able to study in detail how the drug affected the cavernomas.
“What makes the study especially interesting is that right now, in Italy, a clinical study is under way in which CCM patients are to get two years’ treatment with propranolol. During this period, they’re being monitored by means of magnetic resonance imaging of the blood vessels, to see how the malformations are developing,” says Professor Elisabetta Dejana of Uppsala University’s Department of Immunology, Genetics and Pathology and IFOM in Italy.
Cerebral cavernous malformations (CCMs) are vascular anomalies caused by mosaic inactivation of KRIT1 (also known as CCM1), CCM2, or PDCD10 (also known as CCM3) (1). We recently used CRISPR/Cas9 mutagenesis to mosaically inactivate zebrafish ccm2, resulting in multicavernous CCM-like lesions in the embryonic caudal venous plexus (CVP) caused by abortive intussusceptive angiogenesis (ref. 2 and Supplemental Figure 1; supplemental material available online with this article; https://doi.org/10.1172/JCI144893DS1).
In addition to its gross resemblance to CCM, the multicavernous CVP lesion shares a common pathogenesis with mammalian CCM through its initiation by mosaicism for CCM2 and its dependence on KLF2 transcription factors. Thus, the zebrafish CVP cavernoma serves as a facile in vivo model for rapid analysis of mechanisms of CCM formation.
Several case reports (3–7) and an ongoing randomized, controlled pilot trial, Treat_CCM (ClinicalTrials.gov NCT03589014) (8), have proposed treating CCMs with propranolol, a pleiotropic, nonselective β adrenergic receptor blocker. It is unclear whether the anecdotally reported effects impact lesion growth or bleeding.
Propranolol has been the frontline therapy for infantile hemangioma since 2015, when results from a randomized, controlled trial showed it to be effective (9), and it has been proposed for the treatment of other vascular abnormalities (10).
The mechanism of action of propranolol in vascular malformations is unclear; however, recent studies proposed that the effect of propranolol on infantile hemangiomas is ascribable to its capacity to inhibit SOX18 rather than to induce β adrenergic antagonism (11).
A potential effect of propranolol on CCM has not been investigated in animal models, and a mechanism of action has not been defined.
Zebrafish β-adrenergic receptor orthologs including adrb1 and adrb2a have been identified (12), and β antagonists, such as propranolol and metoprolol, alter heart function in zebrafish, analogous to their effects in mammals (13, 14).
Here, we investigated the effect of propranolol on embryonic zebrafish multicavernous malformation and on lesion burden and hemorrhage in 2 murine chronic CCM models. Using the zebrafish CVP model, we show that the beneficial effect could be ascribed to β-adrenergic receptor antagonism and that silencing of the β1-adrenergic receptor had a similar beneficial effect on lesion formation.
We conducted studies in murine models involving the loss of Ccm3/Pdcd10 because of this model’s exceptional disease aggressiveness (15). The sensitized heterozygous (Pdcd10+/– Trp53–/–) chronic disease model has already been used in several studies investigating the effect of other treatments on CCM disease, including Rock inhibition and B cell depletion (16, 17).
More recently, the induced homozygous (Pdcd10ECKO) chronic disease model was used to determine the effect of Rock inhibition, tempol, and vitamin D on CCM lesions (18).
We demonstrated that propranolol reduced lesion burden in all 3 animal models involving 2 species and different CCM genes. Effects were observed in both sexes. Thus, these preclinical studies provide support for clinical trials of propranolol or more β1-selective antagonists in CCM.
reference link: https://www.jci.org/articles/view/144893
More information: Oldenburg. J. et al. (2021), Propranolol Reduces the Development of Lesions and Rescues Barrier Function in Cerebral Cavernous Malformations, Stroke. DOI: 10.1161/STROKEAHA.120.029676
