ABSTRACT
Retrotransposons are viral-like DNA sequences that constitute approximately 41% of the human genome. Studies in Drosophila, mice, cultured cells, and human brain indicate that retrotransposons are activated in settings of tauopathy, including Alzheimer's disease, and causally drive neurodegeneration. The anti-retroviral medication 3TC (lamivudine), a nucleoside analog reverse transcriptase inhibitor, limits retrotransposon activation and suppresses neurodegeneration in tau transgenic Drosophila, two mouse models of tauopathy, and in brain assembloids derived from patients with sporadic Alzheimer's disease. We performed a 24-week phase 2a open-label clinical trial of 300 mg daily oral 3TC (NCT04552795) in 12 participants aged 52-83 years with a diagnosis of mild cognitive impairment due to suspected Alzheimer's disease. Primary outcomes included feasibility, blood brain barrier penetration, effects of 3TC on reverse transcriptase activity in the periphery, and safety. Secondary outcomes included changes in cognition and fluid-based biomarkers of neurodegeneration and neuroinflammation. All participants completed the six-month trial; one event of gastrointestinal bleeding due to a peptic ulcer was reported. 3TC was detected in blood and cerebrospinal fluid (CSF) of all participants, suggestive of adherence to study drug and effective brain penetration. Cognitive measures remained stable throughout the study. Glial fibrillary acidic protein (GFAP) (P=0.03) and Flt1 (P=0.05) were significantly reduced in CSF over the treatment period; Aß42/40 (P=0.009) and IL-15 (P=0.006) were significantly elevated in plasma. While this is an open label study of small sample size, the significant decrease of some neurodegeneration- and neuroinflammation-related biomarkers in CSF, significantly elevated levels of plasma Aß42/40, and a trending decrease of CSF NfL after six months of 3TC exposure suggest a beneficial effect on subjects with mild cognitive impairment due to suspected Alzheimer's disease. Feasibility, safety, tolerability, and central nervous system (CNS) penetration assessments further support clinical evaluation of 3TC in a larger placebo-controlled, multi-dose clinical trial.
ABSTRACT
Published guidelines for treating injured workers include the need for personalized treatment to manage chronic pain symptoms and increase functional status. However, they often fail to clarify how to objectively personalize these treatments. Further, certain patients need analgesic relief beyond the short term. In these cases, it is not sufficient or reasonable to utilize the typical broad protocol-based justifications for reduction of opioids and other medications in a haphazard manner based purely on poor response, without attempting to elucidate possible pharmacogenetic reasons for this. These guidelines acknowledge the problem of substance abuse and set forth methods for treatment and prevention. Although it has been established in the scientific community that an individual's experience of pain and likelihood for addiction both have genetic components, genetic testing is not routinely included as part of the overall treatment plan for injured workers with chronic pain. Because decisions in cases of workplace injury should be based on scientific evidence, genetic testing results can add some objective information to the existing subjective and objective clinical data; help ascertain the efficacy and potential for toxicity of treatment; and therefore provide more information for accurate clinical decisions. We propose the addition of genetic testing to consensus guidelines for treating injured workers in order to improve patients' functional status, increase productivity, improve safety of prescribing, decrease the likelihood of substance abuse, and save on overall healthcare costs.
