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Brooks et al. Rare Dis Orphan Drugs J 2024;3:15 https://dx.doi.org/10.20517/rdodj.2023.27 Page 11 of 14

Therefore, one promising strategy to increase the number of rare disease patients in clinical trials is to focus
on drugs targeting etiologies that are shared across multiple rare diseases. Such shared molecular etiologies
may include biochemical pathways that can be targeted by small molecule drugs. Using this approach, we
can create new disease entities based not on traditional clinical phenotypes, but on shared molecular
etiologies that are therapeutically actionable. As highlighted in an early publication , the rare disease field
[14]
could adapt the tissue agnostic basket trial approach that has been used successfully in the field of oncology,
and led to regulatory approvals in that area .
[15]

DRDRI has developed funding opportunities that specifically support basket trials in multiple rare diseases
for drugs targeting shared molecular etiologies across multiple different diseases, including RFA-TR-20-031
and RFA-TR-21-010. Under TR-20-031, we funded two projects. One project focuses on a clinical trial to
treat two rare mitochondrial diseases using an epigenetic modifier. The other project utilizes a Janus kinase
(JAK) inhibitor to treat multiple diseases with activating mutations in the JAK-STAT signaling pathway.
Importantly, as of the end of 2023, both projects met their key milestones of obtaining INDs (Investigational
New Drug) applications for the basket trials from the US FDA.

To raise awareness of the basket trial approach in rare diseases internationally, DRDRI initiated the Shared
Molecular Etiologies task force within IRDiRC Shared Molecular Etiologies Underlying Multiple Rare
[16]
Diseases - IRDiRC. The activity of this task force culminated in a recent publication .
Gene-targeted therapies and platforms
An estimated 80% of all rare diseases are monogenic, i.e., they result from mutations in a single gene.
Monogenic disease is, therefore, perhaps the most common shared molecular etiology of all rare diseases.
As such, these diseases are, in principle, amenable to gene-targeted therapies such as gene therapy, gene
editing, and oligonucleotides. Each of these approaches is, in fact, a therapeutic platform that can be readily
adapted to different diseases based on knowledge of the sequence of the disease-causing mutation(s). The
current approach is to use these therapeutic platforms to develop therapeutics for one disease at a time.
Unfortunately, this approach consumes much time and effort in commercially developing treatments for
the most common rare diseases, thereby leaving the largest fraction of less common rare diseases behind,
even though these less common rare diseases may be good, if not better, candidates for drug development.

To address this problem, DRDRI is involved in the leadership of several programs that seek to develop
gene-targeted therapies as therapeutic platforms that can be readily adopted for multiple patients and
diseases. Two projects focus on gene therapy using adeno-associated virus (AAV) vectors. The Platform
Vector Gene Therapies (PaVe-GT) program is testing the hypothesis that using the same AAV serotype,
manufacturing, and production facilities for multiple AAV gene therapies can increase the efficiency of the
start-up of AAV gene therapy trials. PaVe-GT is a collaborative effort between DRDRI, the Therapeutics
Development Branch of NCATS, and NIH clinical investigators from NHGRI and NINDS. One goal of
PaVe-GT is to disseminate information about the AAV gene therapy regulatory process to stakeholders,
specifically to those patient advocates trying to develop AAV gene therapies for rare diseases of no
commercial interest. In addition to an academic publication , we released our Orphan Drug Designation
[17]
for our first drug, AAV9-hPCCA, as well as our approved Rare Pediatric Disease Designation Request.
Additionally, we have provided fillable templates for each of these documents that can be used to prepare
and submit their own based on our approved documents.

The Bespoke Gene Therapy Consortium is a public-private partnership managed by the Foundation for the
NIH. The main goal of the BGTC is streamlining the navigation of the regulatory path for AAV gene