Feigin A, Evans EE, Fisher TL, Leonard JE, Smith ES, Reader A, Mishra V, Manber R, Walters KA, Kowarski L, Oakes D, Siemers E, Kieburtz KD, Zauderer M, Huntington Study Group SIGNAL investigators. Pepinemab antibody blockade of SEMA4D in early Huntington's disease: a randomized, placebo-controlled, phase 2 trial. Nat Med. 2022 Oct;28(10):2183-2193. Epub 2022 Aug 8 PubMed. Correction.
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Vaccinex, Inc.
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Thank you for citing our recent publication about the role of astrocytes in Huntington disease (HD). We are particularly pleased to share this with the AD community as we believe astrocyte reactivity is a pathogenic mechanism that can contribute to disease progression in both HD and AD.
We were able to demonstrate in postmortem sections of both HD and AD brains that semaphorin 4D (SEMA4D) is highly upregulated on neurons and that this serves as a ligand to trigger reactivity through plexin-B1/B2 receptors commonly expressed on astrocytes (Evans et al. 2022). It was of particular interest that an early phase of disease in HD is marked by decline in FDG-PET SUVR in striatum that appears to be associated with degeneration of medium spiny neurons and is not dependent on SEMA4D-induced astrocyte reactivity.
In contrast, decline in FDG-PET SUVR in multiple other brain regions during disease progression is prevented by SEMA4D-blockade. Treatment also appeared to be associated with improvement in several exploratory and post hoc measures of cognition in HD patients with early manifest disease.
References:
Evans EE, Mishra V, Mallow C, Gersz EM, Balch L, Howell A, Reilly C, Smith ES, Fisher TL, Zauderer M. Semaphorin 4D is upregulated in neurons of diseased brains and triggers astrocyte reactivity. J Neuroinflammation. 2022 Aug 6;19(1):200. PubMed.
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