Abstract
Multiple sclerosis (MS) is a demyelinating autoimmune disease that attacks the brain, with year-on-year loss of brain volume, starting late teens and becoming manifest late twenties. There is no cure, and current therapies are immunosuppressive only. LIF is a vital stem cell growth factor active throughout life—and essential for health of the central nervous system (CNS), being tolerogenic, myelinogenic, and neuroprotective. Nano-formulation of LIF (LIFNano) using FDA-approved PLGA captures LIF's compound therapeutic properties, increasing potency 1,000-fold when targeted to CD4 (LIFNano-CD4). Moreover, circulating CD4+ lymphocytes are themselves regulated by LIF to express the Treg phenotype, known to release T cell-derived LIF upon engagement with cognate antigen, perpetuating antigen-specific self-tolerance. With the longer-term aim of treating inflammatory lesions of MS, we asked, does LIFNano-CD4 cross the blood–brain barrier (BBB)? We measure pK and pD using novel methodologies, demonstrate crossing of the BBB, show LIF-cargo-specific anti-inflammatory efficacy in the frontal cortex of the brain, and show safety of intravenous delivery of LIFNano-CD4 at doses known to provide efficacious concentrations of LIF cargo behind the BBB.
Highlights
There are no effective treatments of central nervous system (CNS) neurodegenerative diseases, where one block to progress is effective systemic delivery of a therapeutic that crosses the blood– brain barrier (BBB)
We show for the first time that LIFNano-CD4 (i) cross the blood–brain barrier (BBB); (ii) reduce pathogenic levels of IL-6 that accumulate behind the BBB during demyelinating autoimmunity; and (iii) are non-toxic at efficacious i.v. doses in a formal preclinical single ascending dose (SAD) trial
In addition to Multiple sclerosis (MS) with lesions linked to TH17 activity against myelin, the age-related dementias are causally linked to increasing levels of circulating IL-6 [13, 14]
Summary
There are no effective treatments of central nervous system (CNS) neurodegenerative diseases, where one block to progress is effective systemic delivery of a therapeutic that crosses the blood– brain barrier (BBB). Having identified LIF as a natural regulator of neuroimmune health, we developed LIFNano and demonstrated that (i) LIFNano-CD4 promotes antigen-specific Treg and suppresses TH17 immunity in vivo [1]; (ii) LIFNano-CD4 promotes recovery from EAE in a stringent Biozzi mouse model of neuroprotection [2]; (iii) LIFNano-NG2 is a highly potent inducer of myelin repair in vivo [3]—far superior to other myelinogenic agents; and (iv) LIFNanoCD4 partially reverses paralysis in the Hooke EAE model of progressive MS (manuscript in preparation) These properties are likely to extend to man, since both human and nonhuman primate studies [1] confirm efficacy of LIFNano-CD4 ex vivo. We asked, does LIFNano-CD4 cross the BBB following intravenous delivery? Novel methods to measure LIF cargo behind the BBB were developed, and delivery into the brain parenchyma was confirmed, as was efficacy in two models of EAE (RRMS and PMS), and safety in a formal preclinical trial
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