Cerebral cavernous malformations are lesions in brain or spinal vasculature caused by structurally abnormal collections of capillaries. Cavernous malformations—whether in the brain, spinal cord, or elsewhere in the body—are pockets or “caverns” that form in the presence of clusters of thin, weak capillary walls. Blood flows through and stretches the walls into caverns that fill will blood and slow the rate of flow through the capillaries. The NIH reports CCM affects approximately 0.5% of the worldwide population.
CCM is typically categorized into two forms: familial, otherwise known as genetic or hereditary, and sporadic, where there is no identifiable cause. Familial cases are associated with at least three genes: KRIT1, CCM2, and PDCD10. Despite progress in identifying these genes, the proteins they code for are still not fully understood, leaving questions over their precise roles and mechanisms. The CCM-CARE Act attempts to answer these questions by analyzing proteomic (protein), pharmacological (drug effects), and cellular mechanisms of CCM molecules.
Some geneticists hypothesize that these proteins might play a role in the structure of capillary walls. Gene mutations can result in abnormalities in the proteins that loosen the connections between cells. As the cells pull apart, the capillary walls are prone to leakage (bleeding), which can greatly increase pressure in the brain and lead to chronic neurological damage.
The familial form of CCM accounts for approximately 20% of all CCM cases worldwide and is most highly concentrated in New Mexico due to a specific mutation dubbed the “common Hispanic mutation” (Q455X mutation). The genetic mutation has been passed down from early Spanish settlers of what is now the American Southwest. Accordingly, many research groups and hospitals in the area have specific programs dedicated to CCM.
According to the NIH, the severity of CCM depends on the number and location of the abnormal clusters. While most cases only involve one cluster, familial forms often have multiple, resulting in often overlapping neurological problems. A cluster’s given location in the brain creates problems related to the specific brain or spinal cord function of the affected region.
While diagnostic methods such as imaging and genetic testing exist, most cases are not diagnosed until patients appear symptomatic. While the symptoms associated with CCM vary case to case, they can include, but are not limited to, migraines, paralysis, hemorrhages, seizures, and auditory or visual deficits. Approximately 25% of those afflicted with CCM experience no symptoms. Treatment options are primarily surgical but often include symptom management, such as the use of anticonvulsants to manage seizures. The CCM-CARE Act attempts to increase treatment and diagnostic methods available for CCM.
The bill specifically seeks to identify and develop biomarkers for FDA qualification, which can simplify and accelerate clinical trials. Biomarkers are measurable biological characteristics used to indicate normal or pathogenic processes and responses to exposure or intervention. Biomarker identification and development is potentially useful for diagnostic purposes as well as for clinical trials.
The bill also seeks to provide avenues for precision medicine for CCM targeted therapies. Targeted therapies identify and fix specific genes, molecules, proteins, and other underlying biological pathologies. Targeted gene therapy for CCM would target the genetic mutations associated with the familial form of CCM.