Pipeline & Disease Focus

Pipeline & Disease Focus

HAM/TSP: An orphan neurological disease and a model for other autoimmune diseases

HAM/TSP (HTLV-I Associated Myelopathy/tropical Spastic Paraparesis) is an orphan chronic progressive neurological disease that resembles Multiple Sclerosis (MS) in clinical manifestation[1]. Early symptoms of this debilitating disorder usually appear in patients 30-40 years of age and include bowel/bladder dysfunction, lower limb sensory changes and difficulty in walking. Disease progression significantly degrades patient’s quality of life and in late stage patients are wheelchair bound. The etiological agent of this disease is the first human retrovirus discovered (HTLV-I). Pathological analysis of HAM/TSP autopsy materials indicates that the disease affects the spinal cord, predominantly at the thoracic level with loss of myelin. Although the etiological agent of this disease is known to be a virus, HAM/TSP has been considered an immune-mediated disease[2]. There have been numerous studies indicating the presence of an activated state of immune response in these patients. They include elevated concentrations of inflammatory cytokines, presence of autoreactive T cells, as well as antibodies specific for the virus antigen[3-5].

HAM/TSP is a significant unmet medical need as currently, there is no FDA approved therapeutic for this disease. However, since the continuous activated immune response has been recognized as a culprit in the pathogenesis of this disease, immuno-modulation is considered a rationale therapeutic strategy for this disease. Many publications support the pathogenic role of inflammatory cytokines in HAM/TSP[6-8]. Monoclonal antibodies against any of the inflammatory cytokines or their receptors will theoretically be of value in treating this disease. However, an effective treatment requires simultaneous blockade of more than one inflammatory cytokine. The limitation of multiple monoclonal antibody therapy is the cost of the treatment and its burden on patients. As an alternative strategy, Bioniz technology can simultaneously block the cytokines that are critical in this disease, replacing the need for multiple monoclonal antibody therapies. Bioniz lead peptide, BNZ-γ, selectively inhibits IL-2, IL-9, and IL-15; three cytokines which are culprits of HAM/TSP pathogenesis.

An effective therapeutic agent for HAM/TSP will provide proof of concept in modulating the immune response, a characteristic that be of value in treating other immune-mediated diseases. Etiology of HAM/TSP is dependent on an ongoing immune response to viral proteins that are continuously presented to the immune system. Therefore, this disease shares similarities with other autoimmune disorders where autoantigens continuously activate the immune system. A therapy effective for HAM/TSP is highly likely to be effective in treating other autoimmune conditions such as MS[9].

References:

1. Poiesz BJ, Ruscetti FW, Gazdar AF, Bunn PA, Minna JD, Gallo RC. Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc Natl Acad Sci U S A. 1980 Dec;77(12):7415-7419.

2. Gallo RC. The discovery of the first human retrovirus: HTLV-1 and HTLV-2. 2005 Retrovirol 2: 17-25.

3. Tendler CL, Greenberg SJ, Blattner WA, et al. (1990) Transactivation of interleukin 2 and its receptor induces immune activation in human T-cell lymphotropic virus type I-associated myelopathy: pathogenic implications and a rationale for immunotherapy. 1990 Proc Natl Acad Sci U S A. 87:5218-5222.

4. Chen J, Petrus M, Bryant BR, et al. Induction of the IL-9 gene by HTLV-I Tax stimulates the spontaneous proliferation of primary adult T-cell leukemia cells by a paracrine mechanism. 2008 Blood.111:5163-5172.

5. Azimi, N., Nagai, M., Jacobson, S., Waldmann, T.A., IL-15 plays a major role in the persistence of Tax-specific CD8 cells in HAM/TSP patients. 2001 Proc. Natl. Acad. Sci. 98:14559-64.

6. Azimi, N., Mariner J., Jacobson S., Waldmann T.A., How does interleukin 15 contribute to the pathogenesis of HTLV type-1 associated myelopathy/tropical spastic paraparesis? 2000 AIDS Res. Hum. Retroviruses 16:1717-22.

7. Azimi, N., Jacobson, S., Leist, T., Waldmann, T.A., Involvement of IL-15 in the pathogenesis of human T lymphotropic virus type-I-associated myelopathy/tropical spastic paraparesis: implications for therapy with a monoclonal antibody directed to the IL-2/15R beta receptor. 1999 J. Immunol. 163:4064-72.

8. Azimi, N., Brown, K., Bamford, R.N., Tagaya, Y., Siebenlist, U., Waldmann, T.A., Human T cell lymphotropic virus type I Tax protein trans-activates interleukin 15 gene transcription through an NF-kappaB site. 1998 Proc. Natl. Acad. Sci. USA 95:2452-7.

9. OH, U., Jacobson S., Treatment of HTLV-I-Associated Myelopathy / Tropical Spastic Paraparesis: Towards Rational Targeted Therapy 2008 Neurol Clin. 2008 26: 781–785.