ABSTRACT
The immune system contributes to amyotrophic lateral sclerosis (ALS) progression and survival, and therapies
to target the immune system are of burgeoning interest. However, the changes in the immune system during
the course of ALS and the sex-specific alterations in immune function warrant a more in depth analysis in order
to develop personalized ALS therapies and biomarkers. The long-term goals are to harness the immune sys-
tem’s potential to slow and stop the progression of ALS. The overall objective is to determine how peripheral
immune profiles, sex, age, and sex hormones, link to neuronal damage, neuroinflammation, and ALS progres-
sion and survival. The central hypothesis is that peripheral immune profiles are an important pathophysiologic
agent of ALS progression and survival; that sex, age and sex hormone levels impact these profiles; and that
insight into ALS patient-specific immune profiles will yield new drug targets and therapeutic windows. Our ra-
tionale is that linking patient-specific immune cell profiles to ALS progression and survival will facilitate person-
alized immunomodulatory therapeutic development for ALS and identify potential treatment windows. The cen-
tral hypothesis will be pursued with three aims: 1) Identify specific immune profiles that associate with ALS pro-
gression and survival rates.; 2) Evaluate the effects of sex hormones on ALS immune profiles, progression,
and survival; and 3) Identify immune profiles and corresponding cellular pathways that are most toxic to neu-
rons and that associate with central inflammation. In Aim 1 longitudinal immunophenotyping of peripheral blood
samples from ALS subjects will generate composite immune profiles that will then be linked to ALS subject
characteristics, progression, and survival. Aim 2 will determine if observed sex-dependent associations be-
tween immune profiles and ALS progression and survival are mediated by sex hormones, as sex hormones
can alter immune profiles. Aim 3 will enrich a cohort of ALS subjects by immune profile clusters; their periph-
eral immune populations will be analyzed using 1) RNA-seq and 2) cell toxicity studies via co-cultures with
iPSC-derived neurons; subjects will also have positron emission tomography (PET) imaging to quantify central
neuroinflammation. Datasets will be synthesized to build prediction models and create deep neural networks
capable of associating immune profiles with sex, age, disease severity, progression, and survival The research
proposed is innovative, in the applicants’ opinion, because it rigorously examines the effects of sex, age, and
sex hormone levels on immune cells and ALS progression and survival in a longitudinal study. It also accounts
for the interactions between immune cells by forming immune profiles for individual subjects and assesses how
specific profiles associate with dysregulated pathways, cytotoxicity, and neuroinflammation. The proposed re-
search is significant because it will provide critical data on the distinct immune profiles and pathways associ-
ated with ALS progression and survival in a sex-, age- and sex hormone- specific fashion.
