CMA Activators Expand Hematopoietic Stem Cells

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Solution Overview

Problem

Hematopoietic stem cells (HSCs) efficiency declines with age due to deterioration of chaperone-mediated autophagy (CMA), leading to stem cell exhaustion and bone marrow failure, as CMA's role in protein quality control and metabolic regulation is compromised, especially during activation and quiescence transitions.

Innovation Solution

Culturing HSCs in the presence of a CMA activator to expand the HSC population while maintaining them in an undifferentiated state, and administering CMA activators to subjects to treat or prevent diseases related to HSC dysfunction, including cancers, by enhancing proteostasis and promoting effective blood cell production.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If HSCs are repeatedly activated and exposed to cellular insults, then blood cell production capacity is improved, but HSC function deteriorates due to accumulated DNA damage and compromised proteostasis

Engineering Contradiction:

Improveblood cell production capacityVSAvoidHSC function

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent applies preliminary action by activating CMA before HSC exhaustion occurs through repeated activations. The compound of Formula I is administered to pre-emptively enhance protein quality control and proteostasis, preventing the accumulation of damaged proteins and DNA damage that would otherwise compromise HSC function during subsequent activations and cell cycle transitions.

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent converts the harmful effect of repeated HSC activation (which causes proteostasis deterioration and DNA damage) into a beneficial outcome by using CMA activators. The compound of Formula I transforms the stress of repeated activations into an opportunity to enhance proteolytic capacity and protein quality control, thereby maintaining HSC function despite multiple cell cycle transitions and blood cell production demands.

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

2Productivity

If HSCs undergo multiple cell cycle transitions, then blood cell regeneration is improved, but proteostasis deteriorates leading to stem cell exhaustion

Engineering Contradiction:

Improveblood cell regenerationVSAvoidproteostasis

Core Design Contradiction:

ProductivityVSStability of the object's composition

Solution Approach 1:

The patent applies preliminary action by enhancing CMA activity before proteostasis deterioration occurs during multiple cell cycle transitions. The compound of Formula I is administered to pre-emptively strengthen protein quality control mechanisms, ensuring that proteostasis is maintained throughout repeated HSC activations and blood cell regeneration processes before damage accumulates.

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent ensures continuity of useful action by maintaining active CMA throughout multiple cell cycle transitions. The compound of Formula I sustains enhanced proteolytic capacity and protein quality control continuously during repeated HSC activations, preventing interruptions in proteostasis that would otherwise lead to stem cell exhaustion and compromised blood cell regeneration.

Inventive Principle:

Principle #20Continuity of useful action

3Reliability

If CMA activity is enhanced, then protein quality control is improved, but additional therapeutic intervention is required

Engineering Contradiction:

Improveprotein quality controlVSAvoidtherapeutic intervention

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent applies parameter changes by modifying the activity level of CMA through the compound of Formula I. Rather than introducing a completely new biological system, the invention changes the kinetic parameter of CMA activity, enhancing its proteolytic capacity and protein quality control function through pharmacological activation, which simplifies the therapeutic approach compared to gene therapy or cell transplantation.

Inventive Principle:

Principle #35Parameter changes

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The method effectively expands HSC populations, maintains their undifferentiated state, and treats various hematological and extra-hematological diseases by improving proteostasis and blood cell production, thereby addressing age-related declines in HSC function and preventing conditions like bone marrow failure and cancers.

Implementation Method 1

deterioration of chaperone-mediated autophagy (CMA), the housekeeping process that removes damaged proteins and other waste materials

Methodology Applied

Scientific EffectChaperone-mediated autophagy:

Implementation Method 2

enhancing proteostasis and promoting effective blood cell production

Methodology Applied

Scientific EffectProteostasis enhancement:

Implementation Method 3

Hematopoietic (blood-forming) stem cells (HSCs) produce all mammalian blood cells, including key immune cells

Methodology Applied

Scientific EffectHematopoiesis:

Data Source

PatentUS20240156872A1Use of Chaperone-Mediated Autophagy Activators For Treating Or Preventing Blood Cancers And Myelodysplastic Syndromes And Enriching Hematopoietic Stem Cell Populations

Publication Date: 2024.05.16 ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV

AI summary

The present disclosure provides methods of treating disease and disorders of the hematological system. The disclosure provides a method of expanding a population of hematopoietic stem cells (HSCs) while maintaining the population in an undifferentiated state comprising contacting the population of HSCs in the presence of a CMA activator for a period of time until a sufficient number of HSCs is obtained thereby producing an expanded HSC population.