Progress in gene and cell therapies for the neuronal ceroid lipofuscinoses

ABSTRACT

Introduction: The neuronal ceroid lipofuscinoses (NCLs) are a subset of lysosomal storage diseases (LSDs) that cause myoclonic epilepsy, loss of cognitive and motor function, degeneration of the retina leading to blindness, and early death. Most are caused by loss-of-function mutations in either lysosomal proteins or transmembrane proteins. Current therapies are supportive in nature. NCLs involving lysosomal enzymes are amenable to therapies that provide an exogenous source of protein, as has been used for other LSDs. Those that involve transmembrane proteins, however, require new approaches.

Areas covered: This review will discuss potential gene and cell therapy approaches that have been, are, or may be in development for these disorders and those that have entered clinical trials.

Expert opinion: In animal models, gene therapy approaches have produced remarkable improvements in neurological function and lifespan. However, a complete cure has not been reached for any NCL, and a better understanding of the limits of the current crop of vectors is needed to more fully address these diseases. The prospects for gene therapy, particularly those that can be delivered systemically and treat both the brain and peripheral tissue, are high. The future is beginning to look bright for NCL patients and their families.

KEYWORDS:

• Batten disease
• cell therapy
• clinical trials
• gene therapy
• lysosomal storage disease
• neuronal ceroid lipofuscinosis

Article highlights

• The genes associated with NCLs represent a unique combination of secreted, transmembrane, and cytosolic proteins, complicating the development of therapies for these disorders.

• Bone marrow transplantation, somewhat effective for other lysosomal storage diseases, has proven ineffective for NCLs.

• Other cell therapies may be useful for enzymatic deficiencies. However, higher protein expression and better spread of the cells will be required.

• Initial forays into gene therapy provided only marginal improvements, either due to low transduction or poor spread.

• Newer gene therapy vectors, in contrast, show much promise, not only for soluble proteins but for transmembrane proteins as well.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This paper was not funded.