Lead Program: HERV-K vaccine

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive motor neuron loss, leading to muscle weakness, paralysis, and ultimately death. Despite intensive research efforts, the etiology of ALS remains poorly understood, and effective treatments are limited. Recent evidence suggests that human endogenous retroviruses (HERVs), particularly HERV-K, may play a significant role in ALS pathogenesis1-3. HERV-K is the most recently acquired HERV in the human genome and retains the ability to encode functional proteins. While normally silenced in adult tissues, aberrant HERV-K gene expression has been observed in several cancers4-6 and neurological disorders7,8, including ALS1,2,9,10.

Summary of Key Supporting Data in ALS and FTD:

  • Elevated HERV-K nucleic acid and protein expression in the motor cortex and spinal cord samples of ALS patients compared to control2, 4, 5, 11.

  • Direct neurotoxicity of recombinant HERV-K Envelope protein in cultured neurons and in vivo following brain inoculation and protective activity of a HERV-K monoclonal against HERV-K env10.

  • Development of a progressive ALS-like neuromuscular degeneration syndrome in transgenic mice with HERV-K Env expression driven under a neuronal promoter2.

  • Increased levels of antibodies against HERV-K Env protein epitopes in ALS patients versus healthy controls or other neurological patients9, 12.

  • Positive correlation between high antibody levels against certain HERV-K Env epitopes and increased survival in ALS patients9.

  • Co-localization of HERV-K proteins and mislocalized TDP-43 in neurons 11. TDP-43 has been shown to regulate HERV-K expression, while HERV-K RNA can interact with TDP-43 protein. This reciprocal regulation suggests a feed-forward loop that may contribute to disease progression12.

Summary of Key Supporting Data in Cancer:

  • Elevated levels of HERV-K nucleic acids and proteins in prostate cancer13, melanoma14, glioma15, teratocarcinoma16, leukemia17, lung cancer18 and breast cancer, specially in triple-negative19.

  • Levels of HERV-K correlate with disease progression and metastasis20.

  • HERV-K Env expression triggers cell proliferation in breast cancer, pancreatic cancer, leukemia, and teratocarcinoma21.

  • HERV-K contributes to the development of an immunosuppressive tumor microenvironment, since treatment with HML-2 Env peptides inhibited immune cell proliferation and altered cytokine secretion22.

  • Monoclonal antibodies against HERV-K Env and HERV-K env-specific CAR-T cells reduced tumor growth, cell invasion and migration in breast cancer23.

Bibliography

1. Li, W., et al. Human endogenous retrovirus-K contributes to motor neuron disease. Sci Transl Med 7(2015).

2. Steiner, J.P., et al. Human Endogenous Retrovirus K Envelope in Spinal Fluid of Amyotrophic Lateral Sclerosis Is Toxic. Ann Neurol 92, 545-561 (2022).

3. Garcia-Montojo, M., et al. Antibody Response to HML-2 May Be Protective in Amyotrophic Lateral Sclerosis. Ann Neurol 92, 782-792 (2022).

4. Doucet-O'Hare, T.T., et al. SMARCB1 deletion in atypical teratoid rhabdoid tumors results in human endogenous retrovirus K (HML-2) expression. Sci Rep 11, 12893 (2021).

5. Garcia-Montojo, M., Doucet-O'Hare, T., Henderson, L. & Nath, A. Human endogenous retrovirus-K (HML-2): a comprehensive review. Crit Rev Microbiol 44, 715-738 (2018).

6. Shah, A.H., et al. Human endogenous retrovirus K contributes to a stem cell niche in glioblastoma. J Clin Invest 133(2023).

7. Phan, K., et al. Pathological manifestation of human endogenous retrovirus K in frontotemporal dementia. Commun Med (Lond) 1(2021).

8. Dembny, P., et al. Human endogenous retrovirus HERV-K(HML-2) RNA causes neurodegeneration through Toll-like receptors. JCI Insight 5(2020).

9. Garcia-Montojo, M., et al. TDP-43 proteinopathy in ALS is triggered by loss of ASRGL1 and associated with HML-2 expression. Nat Commun 15, 4163 (2024).

10. Douville, R., Liu, J., Rothstein, J. & Nath, A. Identification of active loci of a human endogenous retrovirus in neurons of patients with amyotrophic lateral sclerosis. Ann Neurol 69, 141-151 (2011).

11. Liao, Y.Z., Ma, J. & Dou, J.Z. The Role of TDP-43 in Neurodegenerative Disease. Mol Neurobiol 59, 4223-4241 (2022).

12.Chang, Y.H. & Dubnau, J. Endogenous retroviruses and TDP-43 proteinopathy form a sustaining feedback driving intercellular spread of Drosophila neurodegeneration. Nat Commun 14, 966 (2023).

13.Goering W., Schmitt K., Dostert M., Schaal H., Deenen R., Mayer J., Schulz W.A. Human Endogenous Retrovirus HERV-K(HML-2) Activity in Prostate Cancer Is Dominated by a Few Loci. Prostate. 2015;75:1958–1971.

14.Büscher K., Trefzer U., Hofmann M., Sterry W., Kurth R., Denner J. Expression of Human Endogenous Retrovirus K in Melanomas and Melanoma Cell Lines. Cancer Res. 2005;65:4172–4180

15.Shah AH, Rivas SR, Doucet-O'Hare TT, Govindarajan V, DeMarino C, Wang T, Ampie L, Zhang Y, Banasavadi-Siddegowda YK, Walbridge S, Maric D, Garcia-Montojo M, Suter RK, Lee MH, Zaghloul KA, Steiner J, Elkahloun AG, Chandar J, Seetharam D, Desgraves J, Li W, Johnson K, Ivan ME, Komotar RJ, Gilbert MR, Heiss JD, Nath A. Human endogenous retrovirus K contributes to a stem cell niche in glioblastoma. J Clin Invest. 2023 Jul 3;133(13):e167929.

16.Doucet-O'Hare TT, DiSanza BL, DeMarino C, Atkinson AL, Rosenblum JS, Henderson LJ, Johnson KR, Kowalak J, Garcia-Montojo M, Allen SJ, Orr BA, Santi M, Wang T, Fathi S, Lee MH, Sampson K, Li W, Zhuang Z, Nath A. SMARCB1 deletion in atypical teratoid rhabdoid tumors results in human endogenous retrovirus K (HML-2) expression. Sci Rep. 2021 Jun 18;11(1):12893. 

17.Alcazer V., Bonaventura P., Tonon L., Michel E., Mutez V., Fabres C., Chuvin N., Boulos R., Estornes Y., Maguer-Satta V., et al. HERVs Characterize Normal and Leukemia Stem Cells and Represent a Source of Shared Epitopes for Cancer Immunotherapy. Am. J. Hematol. 2022;97:1200–1214.

18.Yang C., Guo X., Li J., Han J., Jia L., Wen H.-L., Sun C., Wang X., Zhang B., Li J., et al. Significant Upregulation of HERV-K (HML-2) Transcription Levels in Human Lung Cancer and Cancer Cells. Front. Microbiol. 2022;13:850444.

19.Johanning G.L., Malouf G.G., Zheng X., Esteva F.J., Weinstein J.N., Wang-Johanning F., Su X. Expression of Human Endogenous Retrovirus-K Is Strongly Associated with the Basal-like Breast Cancer Phenotype. Sci. Rep. 2017;7:41960

20.Costa B, Vale N. Exploring HERV-K (HML-2) Influence in Cancer and Prospects for Therapeutic Interventions. Int J Mol Sci. 2023 Sep 27;24(19):14631. 

21.Grandi N., Tramontano E. HERV Envelope Proteins: Physiological Role and Pathogenic Potential in Cancer and Autoimmunity. Front. Microbiol. 2018;9:462.

22.Morozov V.A., Dao Thi V.L., Denner J. The Transmembrane Protein of the Human Endogenous Retrovirus—K (HERV-K) Modulates Cytokine Release and Gene Expression. PLoS ONE. 2013;8:e70399.

23.Zhou F., Krishnamurthy J., Wei Y., Li M., Hunt K., Johanning G.L., Cooper L.J., Wang-Johanning F. Chimeric Antigen Receptor T Cells Targeting HERV-K Inhibit Breast Cancer and Its Metastasis through Downregulation of Ras. Oncoimmunology. 2015;4:e1047582

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