Our Mission:
Our mission is to ultimately find a cure for ATP6AP2-related rare diseases. We are dedicated to advancing research, raising awareness, and providing support to individuals and families affected by these conditions. Our vision extends beyond a single rare disease, aiming to contribute to the understanding and treatment of all rare diseases associated with the vacuolar H+-ATPase (V-ATPase) complex, which plays a fundamental role in maintaining the pH balance within cellular compartments.
Our AIM:
Luka’s mutation causes a single amino acid change resulting in a degraded function in the ATP6AP2 protein.
This protein is an assembly factor that mediates the formation of the V-ATPase complex, commonly known as the Proton Pump, found on organelle membranes.
This ATP6AP2 mutation belongs to a subset of V-ATPase defects linked to lysosomal storage disorders, congenital disorders of glycoslation, as well as neurological disorders.
We believe Lysosomal Storage Disorders or Congenital Disorders of Glycosylation are caused by a defect in enzymes and/or acidification.
Our aim is to harness acidification and protein synthesis to not only treat ATP6AP mutations, but mutations in lysosomal and glycosylation enzyme genes as well.
Who can we help:
Luka inherited an x-linked, missense mutation causing degraded-function in an assembly factor of the organellular proton pump, which enables a wide range of biological pathways, resulting in defective protein synthesis, degradation and elimination. Although this mutation has been classified as a subset of Congenital Disorders of Glycosulation, it belongs to a subset of V-ATPase defects linked to lysosomal storage disorders as well as neurological disorders.
When we were diagnosed in December 2021, we couldn’t believe there were only 4 patients in the world with this disease.
A few months later, we spoke to our genetic sequencing database GeneDx, who found 15 additional potential APT6AP2 patients, and 19 ATP6AP1 patients with the sister mutation.
OK - now we have some 30 patients, but there are other V-ATPase defects on other assembly factors or subunits of the V-ATPase that would benefit by being included. This includes ATP6AP1, ATP6V1A, ATP6V1G1, ATP6V0A2, and ATP6V0D1. So now we’re maybe at 150 patients. We can set up acquisition channels for unidentified patients to enter our study using phenotypic parameters, search engine/social media data, and communication to commonly used specialists that can refer potential patients to our study.
But there are also 16 subsets of CDGs impaired by this acidification defect, including Golgi Homeostasis, by which we could reach a far greater amount of people - we estimate maybe 70,000.
Establishing common phenotypes for adjacent mutations could result in a much broader targer disease and therapeutic population.
But defective proton pump function is not only linked to CDGs but also Lysosomal Disorders - they both are caused by a defect in enzymes and/or acidification. NOW we’re talking about 150,000 patients.
If we redefine the subsets of LSD & CDG with overlapping deficiencies, we can encapsulate “enzyme deficiencies” caused by acidification defects - and really target our therapeutic to those.
OUR GOALS for 2023:
Next steps will happen simultaneously:
to designate this disease pathogenic, meaning if someone has this mutation, it implies that it will cause or or is capable of causing disease with major implications. The pathogenic designation will allow us to contact the physicians of these potential patients who can recommend their patients enroll in our natural history study.
Because little is known about rare disease, it is important to enroll in a natural history study. This allows the progression of the disease to be studied over time to give better insight on proper clinical intervention and possible treatments and cures.
Create IPSC cell line and HEK Cells with the New York Stem Cell Foundation. (Update! as of October 2023, the cells are being created!) in order to start valuable research.
Create Mouse Models (Update! as of October 2023, our mice are about 3 months old!) that have our specific disease model.
Finalize all committed research agreements with institutions around the world, including at Penn, CHOP, Galway, Muenster, and Kyoto.
Let’s Aim Higher:
What would be the fun of stopping there? Beyond Glycosylation, there are other ramifications of loss-of-funtion V-ATPase disorders, like:
Development & Aging - embryonic brain development, adult neurogenesis and Alzheimers
pH Regulation - kidneys, brain, liver, heart function
Metabolism - Theapeutic potential in obesity
Immunity - Autophagy and NLRP3 inflammasome pathways
Autophagy - active in WNT and mTOR pathways and cell signaling
Cardiovascular - regulatory expression of tissue
SO what are the broader implications of a Proton Pump Therapeutic?
Congenital Disorders of Glycosylation
Lysosomal Storage Disorders
Chronic Kidney Disease
Bacterial infections
Parkinsonism with Spasticity
Multiple Myopathies
Inflammasome Deficiency