This is a Phase 2 trial that will test the efficacy and safety of crizanlizumab for the treatment of retinal vasculopathy with cerebral leukoencephalopathy (RVCL), a very rare and uniformly fatal genetic condition that affects the microvasculature, especially of the brain and eye. There currently is no treatment for RVCL. A maximum of 20 patients will be enrolled.

Retinal vasculopathy with cerebral leukoencephalopathy (RVCL) is a very rare and uniformly fatal genetic condition that affects the microvasculature, especially of the brain and eye. Symptoms begin in adulthood (usually in the mid-30s to early 40s) and include loss of vision, mini-strokes, and dementia. Other patients have suffered from microvascular disease involving the kidneys, osteonecrosis, and gut ischemia. Some of these features of microvascular occlusive disease resemble ischemic events that occur during sickle cell disease. Currently, there is no effective treatment for RVCL.

The goal of this study is to test the efficacy of RVCL patients treated with crizanlizumab, a humanized monoclonal anti-P-selectin antibody that prevents leukocyte adhesion to the vascular endothelium, thereby limiting risk of microvascular occlusion. P-selectin is mobilized to the surface of activated vascular endothelial cells and promotes leukocyte adhesion to the blood vessel wall. The Miner laboratory has preliminarily observed a correlation with levels of soluble P-selectin and the number of brain lesions in patients with RVCL. Since leukocyte adhesion to the vascular endothelium promotes microvascular occlusion, we will determine if crizanlizumab will help to limit ischemia and brain lesions in patients with RVCL. This may lead to the development of fewer ischemic brain and eye lesions.

Up to 20 RVCL patients will receive intravenous infusions of crizanlizumab 5 mg/kg at weeks 1 and 3. Thereafter, patients will receive crizanlizumab 5 mg/kg every 28 days for a total of 24 total months. Monitoring will include standard-of-care serial MRI as well as standard-of-care eye disease monitoring at pre-defined intervals. High-risk medication monitoring will include blood work monitoring (CBC/CMP) 1 month after initiation of treatment and every 3 months thereafter. Standard-of-care assessments will be performed including radiological and physical examinations as well as eye imaging and examinations. Patients will be followed for at least 2 years after completion of crizanlizumab administration.

Inclusion Criteria:

1. A diagnosis of RVCL with confirmation by genetic test

2. At least 25 years of age with imaging evidence of brain or eye disease at the time of study registration

3. Normal hematologic function defined as: White blood cell count (WBC) > 4x109/L, Absolute neutrophil count (ANC) >1.5x109/L and Platelets > 100x109/L

4. Females of childbearing potential (FCBP) must agree to refrain from becoming pregnant while on study drug and for 3 months after discontinuation from study drug, and must agree to use adequate contraception including hormonal contraception, (i.e. birth control pills, etc), barrier method contraception (i.e. condoms), or abstinence during that time-frame

5. Able to understand and willing to sign an Internal Review Board (IRB)-approved written informed consent document (or that of legally authorized representative, if applicable)

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Exclusion Criteria:

1. Acute bacterial, fungal, or viral infection

2. Known HIV, untreated latent tuberculosis (TB), or active hepatitis B or C infection or zoster

3. Pregnant and/or breastfeeding. Negative serum pregnancy test required prior to starting study treatment. For females of child-bearing potential (FCBP), a negative urine pregnancy test is required before each infusion.

4. Known hypersensitivity to one or more of the study agents

5. Currently receiving or has received any investigational drugs within the 14 days prior to the first dose of study drug

6. Liver function tests (LFTs) higher than 3x the upper limit of normal within the last 30 days

7. Treatment with other monoclonal antibody medications within the last 30 days

8. Treatment with various forms of anticoagulation within last 30 days, including but not limited to clopidogrel or coumadin or direct thrombin inhibitors

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Data will be shared among the principle investigator and the other investigators

immediate

Individual Patient Data (IPD) will be available on REDCap or as provided by principal investigator

From enrollment for up to 4 years.