Third session of the Longevity Therapeutics summit. For our coverage of the opening session, see here; for part 1 of “Developing Innovative Therapeutic Approaches Targeting Age-Related Diseases,” see here.
Therapeutics from Plasma: Targeting Chronokines for Disorders of Aging (Steven Braithwaite, CSO, Alkahest Inc.)
Alkahest is based on somewhat creepy foundational science: parabiosis experiments in which the circulatory systems of old and young mice were connected. The young mice experienced a worsening of memory, including defects in neurogenesis and synaptic activity—but the old mice experienced an opposite effect. So, what is the active principle in young plasma that can reverse age-related processes—and could the same effects be observed in humans?
The plasma proteome changes dramatically over the course of aging, with as much as 30% of proteins present at significantly different levels in old and young people. Braithwaite refers to the biological function drivers that change with aging as “chronokines”. Alkahest is seeking ways to reduce or antagonize damaging chronokines with target-directed therapeutics, while increasing or supplementing the declining chronokines with plasma-derived products.
Boldly, they have set their sights on Alzheimer’s disease (AD). In preliminary experiments, they showed that aged mice treated with plasma from 18-year-old humans exhibited dramatically infused performance in a memory task. In a very small trial of patients with moderate AD, the results were encouraging: in addition to being safe and well tolerated, patients who received plasma enjoyed functional improvements in executive function and activites of daily living.
However, plasma has multiple disadvantages: it is immunogenic, requires crossmatching of blood types, poses logistical challenges (e.g., the cold chain) and risks transmission of viruses or other kinds of contamination. To overcome these issues, Alkahest examined plasma fractions (PFs), which are safer and more well-defined than total plasma (and often more stable). To date, Alkahest has identified a PF that returns aged mice to the performance range of of young mice in the same memory task. Indeed, under certain dosing paradigms, the PF was more effective than total plasma.
The effects of PF treatment can be both rapid and dramatic, including increased c-Fos activity (a marker of neuronal activity) within just a couple of hours after administration. The therapy also increases neurogenesis and reduces inflammation in a model of Parkinson’s disease. Overall, the PF has multiphasic functions at different timescales neural activation, inhibition of neuroinflammation, stimulation of network activity, and stimulation of neurogenesis and neural health.
In addition to assessing their efficacy, Alkahest also wants to understand how the chronokines are working at a cell and molecular level. This is especially important for the increasing chronokines (those whose levels rise with age, consistent with a role in driving aging), which cannot be straightforwardly depleted form the plasma of elderly patients, and must instead be targeted with small-molecule drugs.
Mitochondrial Dysfunction & Aging: Elamipretide as a Potential Intervention (Mark Bamberger, CSO, Stealth BioTherapeutics)
Stealth, based in Newton, MA, focuses primarily on rare diseases caused by mitochondrial dysfunction. They have several drugs in clinical trials, including treatments for mitochondrial myopahty, Barth syndrome, Leber’s optic neuropathy, and macular degeneration.
The company’s primary lead compound, elamipretide, is a small mitochondrially-targeted tetrapeptide that decreases generation of reactive oxygen species and stabilizes cardiolipin, which constitutes around 20% of the mitochondrial inner membrane and is critical for that membrane’s curved structure.
Elamipretide normalized mitochondrial peroxide production, which increases with aging, in skeletal muscle fibers. One hour after a single injection in old mice, ATP production rises to normal young levels, and daily injections for one week dramatically improve muscle function. In elderly humans with demonstrated mitochondrial function, the drug increased ATO production and improved performance in a muscle fatigue test. Strikingly, the improvement in skeletal muscle 2 hours post-infusion was comparable to what can be achieved by 6 months of training.
Stealth is also pursuing a therapy for dry age-related macular degeneration (AMD), a leading cause of blindnss in older adults in the developed world.