# Hematopoietic stem cell gene therapy for infantile neuronal ceroid lipofuscinosis

> **NIH NIH R01** · DANA-FARBER CANCER INST · 2021 · $358,913

## Abstract

PROJECT SUMMARY/ABSTRACT
Infantile neuronal ceroid lipofuscinosis (INCL), caused by defects in the CLN1 gene coding for palmitoyl
protein-thioesterase-1 (PPT1), is the most rapidly progressing and one of the most severe neuronal ceroid
lipofuscinoses, which are a group of autosomal recessively inherited monogenic lysosomal storage disorders
(LSDs) with an incidence of 1-8 in about 100,000 live births worldwide. Despite great efforts, available
treatments remain mainly symptomatic and experimental approaches are unable to relieve the burden of
toxicity caused by loss of PPT1 in patients. Insufficient widespread delivery of PPT1 activity to the entire CNS
and inability to successfully address the complex disease pathogenesis by the tested strategies are likely
reasons for this poor outcome. Thus, the long–term goal of our proposal is to develop an innovative therapeutic
approach for INCL leading to widespread biodistribution of wild type PPT1 to the entire CNS and control of
secondary disease mechanisms, with potential for an overall profound benefit for affected patients. This
approach is based on the use of i) hematopoietic and progenitor cells (HSCs) as source of a tissue infiltrating
myeloid progeny cells able to delivery PPT1 and other therapeutic molecules to the CNS upon transplantation
in myeloablated recipients, ii) lentiviral vectors (LVs) allowing for an efficacious transfer of the cDNA encoding
for PPT1 (and possibly other therapeutic molecules) into HSCs for sustained expression, iii) innovative
protocols for the delivery of the engineered HSCs into myeloablated recipients allowing to achieve a robust and
timely engraftment of the transplanted cells and their progeny in the CNS and iv) the delivery, in addition to
PPT1, of a metallothionein (MT) peptide known to favorably impact INCL secondary disease mechanisms. Our
central hypothesis is that a HSC gene therapy approach exploiting these components could generate a rapid
but long-lasting, widespread and sustained source of the functional PPT1 for metabolic rescue and shape a
neuro-protective environment in the brain and spinal cord of NCLI patients. This is expected to have relevant
impact on the disease. In the proposed project we will thus challenge the efficacy, feasibility and safety of this
approach in the disease animal model, as well as on in vitro and in vivo models of human hematopoiesis, and
identify key determinants of efficacy and clinical benefit. By completion of this project, we expect to generate a
solid basis for future clinical testing of HSC gene therapy in INCL children.

## Key facts

- **NIH application ID:** 10197176
- **Project number:** 5R01HD095935-04
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Christian Brendel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $358,913
- **Award type:** 5
- **Project period:** 2018-08-21 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10197176

## Citation

> US National Institutes of Health, RePORTER application 10197176, Hematopoietic stem cell gene therapy for infantile neuronal ceroid lipofuscinosis (5R01HD095935-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10197176. Licensed CC0.

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