Precision Medicine Immunotherapy for the Treatment of Neurodegeneration in HERV-K-Positive Patients with Amyotrophic Lateral Sclerosis
Abstract
Since 1980, more than 80 randomized controlled trials (RCTs) on amyotrophic lateral sclerosis (ALS) have been published, and just two drugs, riluzole and edaravone, have emerged as U.S. Food and Drug Administration-approved therapies for the disease. Reasons for the negative results of RCTs may include an incomplete understanding of ALS disease mechanisms, clinical diversity of ALS progression, shortcomings of study design, and how certain genetic profiles influence drug effectivity. About 8% of the human genome has been found to consist of endogenous retroviruses such as human endogenous retrovirus-K (HERV-K), which are believed to be remnants of ancient viral infections that invaded our genetic code during evolution. These retroviruses initially infected a human egg or sperm cell and entrenched themselves in the human genetic code, allowing them to spread from one generation to the next. Over many millenia, the HERV genomic sequences have largely become mutated or otherwise rendered unable to produce gene products by protective mechanisms guarding against their expression. HERV-K are the most recent retrovirus to invade our genome and one of their subclasses, called HML2, can still activate gene expression, particularly when the protective defenses become weakened. Aberrant expression of HERV-K messenger RNA and proteins has been shown to be particularly toxic to certain cells like the large motor neurons that degenerate in ALS. In particular, the envelope (Env) protein expressed by HERV-K HML2 causes cell death when exposed to laboratory cultured human brain cells or when experimentally expressed in the nervous system of mice. In recent years, mechanisms that guard against inappropriate gene expression have been shown to become weakened in the motor neurons of patients with ALS. A master regulator of gene expression called TDP-43 is commonly mutated or becomes dysfunctional in ALS. The discovery that TDP-43 normally governs the expression of genomic HERV-K sequences along with the discovery of HERK-V Env protein expression in degenerating ALS motor neurons has pointed to a novel disease mechanism and therapeutic opportunity for some forms of ALS. If one could readily identify patients with ALS, in which brain cell HERV-K activation is prominent, then a vaccine could be developed against the toxic Env protein to protect neurons in ALS. Just as vaccination against other viral maladies such Shingles can provide disease protection, this approach brings a well-proven therapeutic concept to the treatment of ALS. To test this exciting and innovative hypothesis, we have assembled a collaboration between the world s foremost knowledgeable lab on HERV-K biology in ALS with two biotech companies that are developing cutting edge diagnostic and therapeutic technologies. This collaboration will allow the development of biomarkers to conveniently track nervous system activation of HERV-K and vaccines to target the most promising portions of the HERV-K Env protein as a novel precision medicine approach for ALS. The project will test whether active vaccination against the Env protein of HERV-K will safely generate immunity and provide clinical benefit in a mouse model that simulates HERV-K induced ALS. Results from this study will bring us a step further in the development of precision medicine for this subset of ALS patients. Given the prior investment in the required technologies by the collaborating partners, we envision this project to identify a lead therapeutic candidate with animal model proof-of-concept and the requisite biomarkers for clinical development with approximately 2 years.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310564
Entities
People
- Ajay Verma
Organizations
- United States Army