Program 1

Drugs that act on the receptor the deletion halves

The deletion removes one copy of CHRNA7, the gene for the alpha-7 nicotinic acetylcholine receptor. Drugs that boost this receptor already exist and have already been given to people. A positive allosteric modulator, AVL-3288 completed phase 1 trials with acceptable safety and was then set aside when its original indications did not pan out. It has not been tried in 15q13.3.

Reed's Reach will prepare and submit orphan drug designation request for 15q13.3 microdeletion syndrome. Designation gives the companies that own these drugs a reason to bring them to a rare condition: seven years of market exclusivity, tax credits on trial costs, and waived FDA fees. Our part is the scientific rationale and the patient population; the trials themselves need a sponsor, and designation is how we make sponsoring one worth doing.

Galantamine, approved for Alzheimer's disease, acts on the same receptor and is available now. Reed's Reach is working with clinicians toward a controlled clinical trial of galantamine in 15q13.3, so that families and physicians have evidence rather than anecdote when they decide whether to use it.

Program 2

A natural history study that can serve as a control arm

No phase 2 or 3 trial in a rare condition gets far without a well-described untreated population to compare against. 15q13.3 does not have one yet. Reed's Reach is building it from two sources: Simons Searchlight, the registry that holds the largest set of caregiver-reported data on 15q13.3, and OpenReach, the registry Reed's Reach is building, which imports a participant's electronic health records with their consent and adds structured surveys over time.

Together these give a longitudinal record of seizures, medications, development, behavior and daily function across the community. That record is what a trial sponsor needs to design endpoints, size a study and, where a placebo arm is not feasible, serve as the external control. The pre-conference survey our families are answering now is the first instrument in this study.

Program 3

Preclinical work on OTUD7A and Ankyrin-G

The deletion also removes one copy of OTUD7A. Published work from Dr. Karun Singh's lab shows that OTUD7A maintains a protein called Ankyrin-G, which is reduced in 15q13.3 neurons and mice, and that the reduction shortens the axon initial segment and thins dendritic branching. Separately, in other models, lithium and inhibitors of an enzyme called GSK-3β restore Ankyrin-G dependent structure. Whether that holds in 15q13.3 has not been tested.

Reed's Reach is funding that test. Candidate compounds are lithium, GSK-3β inhibitors and cAMP enhancers, and the work moves in order:

• computational models
• iNeurons grown from patient cells
• the 15q13.3 mouse
• a clinical trial

Each stage decides whether the next one runs. Nothing goes into a person on the strength of a model or a mouse alone. A positive result would put a drug class with existing human exposure in front of the syndrome and would confirm the OTUD7A and Ankyrin-G axis as a target for the genetic medicines in Program 4.

Program 4

Gene therapy for OTUD7A and CHRNA7

A deletion cannot be edited back, but the genes it removes can be delivered. The coding sequences of OTUD7A and CHRNA7 together fit inside a single AAV vector, the delivery vehicle behind approved gene therapies for other neurological conditions, and single-gene replacement for a deletion syndrome has already reached clinical trials in Phelan-McDermid syndrome. Reed's Reach is pursuing gene therapy for both genes, starting with the preclinical questions that decide dose, delivery route and which cells need the gene. Program 3 supplies the target validation this program depends on.