DFT383 is an investigational
gene therapy
Gene therapy is Health technology, medical technology that aims to produce a therapeutic effect through the manipulation of gene expression or through altering the biological properties of living cells.
The first attempt at modifying human DNA ...
under development by
Novartis
Novartis AG is a Swiss multinational corporation, multinational pharmaceutical company, pharmaceutical corporation based in Basel, Switzerland. Novartis is one of the largest pharmaceutical companies in the world and was the eighth largest by re ...
for the treatment of
cystinosis
Cystinosis is a lysosomal storage disease characterized by the abnormal accumulation of cystine, the oxidized dimer of the amino acid cysteine. It is a genetic disorder that follows an autosomal recessive inheritance pattern. It is a rare autosom ...
, a rare autosomal recessive lysosomal storage disorder caused by mutations in the
CTNS gene, leading to cystine accumulation in cells.
The therapy delivers a functional copy of the CTNS gene via autologous
hematopoietic stem cell
Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within the ...
(HSC) transplantation to address the disease’s root cause, targeting patients both pre- and post-kidney transplant.
Mechanism of action
DFT383 involves extracting a patient’s hematopoietic stem cells, genetically modifying them ex vivo with a
lentiviral vector
A viral vector is a modified virus designed to gene delivery, deliver genetic material into cell (biology), cells. This process can be performed inside an organism or in cell culture. Viral vectors have widespread applications in basic research, ...
to insert a functional CTNS gene, and reinfusing them after myeloablation.
The modified cells are intended to produce functional
cystinosin, a lysosomal cystine-proton
symporter
A symporter is an integral membrane protein that is involved in the transport of two (or more) different molecules across the cell membrane in the same direction. The symporter works in the plasma membrane and molecules are transported across th ...
, reducing
cystine
Cystine is the oxidized derivative of the amino acid cysteine and has the formula (SCH2CH(NH2)CO2H)2. It is a white solid that is poorly soluble in water. As a residue in proteins, cystine serves two functions: a site of redox reactions and a mec ...
accumulation throughout the body, including in the kidneys, eyes, and other organs.
In preclinical studies using ''Ctns''
−/− mice, treatment with lentiviral-based ''CTNS'' gene therapy resulted in significant reductions in tissue cystine levels and preservation of kidney, eye, and thyroid function.
Development history
DFT383 was initially developed by AVROBIO as AVR-RD-04, with early clinical trials sponsored by the University of California, San Diego.
A Phase I/II trial, approved by the FDA in November 2018, enrolled six adult patients and showed sustained engraftment, reduced leukocyte cystine levels, and improvements in visual and motor functions up to 36 months post-treatment, with patients discontinuing oral cysteamine.
No serious adverse events related to the therapy were reported.
In May 2023, Novartis acquired DFT383 from AVROBIO for $87.5 million, including intellectual property and transition services, to bolster its gene therapy pipeline.
Novartis committed to collaborating with the cystinosis community to advance the program, though timelines from AVROBIO’s initial projections were adjusted during the transition.
Clinical trials
As of August 2024, DFT383 is in
Phase I and
Phase II clinical trials to assess safety and efficacy.
The trial builds on AVROBIO’s Phase I/II data, which demonstrated durable reductions in cystine levels and potential systemic benefits.
Novartis is expected to release further results in 2025, though specific trial details remain limited.
DFT383 aims to address limitations of the current standard treatment,
cysteamine, which reduces cystine levels but has side effects and does not restore kidney function.
Challenges include optimizing trial timelines post-acquisition and ensuring long-term efficacy across diverse patient populations, including children.
Future phases may expand eligibility to pediatric patients, pending regulatory approval.
References
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External links
Novartis Official WebsiteCystinosis Research FoundationCystinosis Foundation UK
Gene therapy